Milvexian is an oral factor XIa inhibitor in development for prevention of major thromboembolic conditions. This randomized, double-blind, placebo- and positive-controlled, multiple-dose, four-period crossover study assessed the cardic safety of milvexian (including effects on the QT interval of the electrocardiogram), with a supporting in vitro component. Sixty-six participants were enrolled. In each treatment period, participants received milvexian (100 or 200 mg) or placebo every 12 h for 4 days. A single-dose moxifloxacin (400 mg) served as a positive control. Electrocardiographs and time-matched pharmacokinetic samples were collected during each period. In mixed-effects models, the upper limit of the two-sided 90% confidence interval for the least squares means for change from baseline QTc (Fridericia [QTcF], as the primary correction method) for milvexian versus placebo (ΔΔQTc) was ˂10 ms at all time points after each milvexian regimen. In addition, there was no apparent relationship between ΔΔQTcF and plasma milvexian concentrations. Moxifloxacin response confirmed assay sensitivity. Milvexian inhibited human ether-a-go-go-related gene potassium, sodium, and L-type calcium ion channel currents with weak-to-moderate potency at concentrations exceeding the highest mean unbound maximum plasma concentrations of TQT study participants. Milvexian regimens were safe and well tolerated. These data indicate that milvexian does not prolong the QTc interval at clinically relevant concentrations.

Abstract: Milvexian is a selective, oral factor XIa inhibitor. Individuals receiving anticoagulation may require prompt reversal of anticoagulative effects. This study assessed reversal of milvexian's anticoagulant effects by recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants. This was a 2-part, randomized, crossover study. In part A, milvexian (100 or 500 mg single doses) was followed by rFVIIa (30 μg/kg) or placebo 4 hours later. In part B, milvexian 200 mg was administered q12h for 3 consecutive days, with 4F-PCC (50IU/kg) or placebo given 4 hours after last dose in the morning of day 4. Anticoagulation was assessed through activated partial thromboplastin time (aPTT) and thrombin generation [endogenous thrombin potential (ETP), peak thrombin] using 2 activators: kaolin [intrinsic pathway (IP) effects] and tissue factor [extrinsic pathway (EP) effects]. rFVIIa partially reversed milvexian's effects on aPTT (milvexian 100 mg: ∼18%; 500 mg: ∼15%), IP-induced ETP (milvexian-induced ETP reversal; 100 mg: ∼50%; 500 mg: ∼80%) and peak thrombin, and EP-induced peak thrombin but not ETP. Milvexian 200 mg prolonged aPTT, strongly inhibited IP-induced ETP/peak thrombin, and mildly inhibited EP-induced ETP. 4F-PCC partially reversed milvexian's effect on aPTT (∼17%) and IP-induced ETP/peak thrombin; it reversed milvexian's effect on EP-initiated ETP (∼68% increase). Reversal was rapid (15 minutes) and long-lasting (≥8 hours). Milvexian pharmacokinetics were unchanged by reversal agents. Regimens were generally safe and well tolerated. In conclusion, milvexian's anticoagulant effect was partially reversed by rFVIIa and 4F-PCC. These results may offer clinicians options in situations where reversal of milvexian might be considered.

Milvexian, an activated factor XI inhibitor, is being evaluated in the LIBREXIA phase III program for the prevention of thrombotic events, including in patients with atrial fibrillation (LIBREXIA AF). To guide the selection of a phase III dose regimen for LIBREXIA AF, two main approaches were used: (1) population pharmacokinetics and exposure-response modeling of milvexian phase I and phase II (AXIOMATIC-TKR) study data was performed to characterize the relationship between milvexian population pharmacokinetics and clinical efficacy, safety, and coagulation biomarkers; and (2) a model-based meta-analysis was developed using published clinical trial data from comparator anticoagulants in total hip or knee replacement patients. When used to simulate exposures for an atrial fibrillation population, the milvexian 100 mg twice-daily dose regimen had a concentration maximum peak-to-trough ratio of 1.35. At this regimen, the simulated median venous thromboembolism rate was 9.4% (lower than enoxaparin at ~21%). No relationship between bleeding and milvexian exposure was observed. Simulations using the model-based meta-analysis estimated that milvexian 100 mg twice-daily would lead to a systemic embolism odds ratio of 0.84 (95% CI: 0.65, 1.12) compared with apixaban 5 mg twice-daily for patients with atrial fibrillation. This integrated model-informed dose-selection approach supported 100 mg twice-daily as a regimen of milvexian to be evaluated in the phase III milvexian LIBREXIA AF study.

Background Despite current antiplatelet therapy, patients remain at risk of recurrent ischemic events after acute coronary syndromes (ACS), which may reflect persistently elevated thrombin generation. Factor XIa inhibition reduces thrombin generation and may improve clinical outcomes with minimal bleeding risk. Design Librexia ACS (ClinicalTrials.gov NCT05754957) is a Phase 3, randomized, double-blind, placebo-controlled, event-driven trial to test the efficacy and safety of milvexian, an oral, selective factor XIa inhibitor, in addition to conventional antiplatelet therapy after a recent ACS. Eligibility criteria include symptoms of spontaneous ischemia, a diagnosis of ACS and cardiac biomarker elevation indicative of myonecrosis within 7 days before randomization, along with at least 2 risk-enhancing factors. Participants are randomly assigned to oral milvexian (25 mg twice daily) or a matched placebo. Randomization is stratified according to the planned duration and type of antiplatelet therapy. The primary efficacy endpoint is the time to first occurrence of the composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke that will enroll approximately 16,000 patients with follow-up until 875 events are accrued. The first major secondary endpoint is time to the first occurrence of cardiovascular death, MI, ischemic stroke, major adverse limb events, and symptomatic venous thromboembolism. The principal safety endpoint is Bleeding Academic Research Consortium 3c or 5 bleeding. Summary The Librexia-ACS trial will determine the efficacy and safety of milvexian after ACS and will be the first trial to test whether factor XIa inhibition in addition to standard-of-care antiplatelet therapy reduces major adverse cardiovascular events without an increased risk of significant bleeding.

Background Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. Methods LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. Conclusion The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. Trial registration ClinicalTrials.gov NCT05757869

Background: Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking in clinical settings. Aims: Exploring safe and efficient methods to target hematopoietic cells carrying SRSF2 mutations might be a powerful tool not just for leukemia prevention and treatment, but also to understand the mechanisms behind SRSF2 mutations. Methods: We generated five SRSF2 Mut (P95H) isogenic cell lines with CRISPR/CAS9 system and performed high throughput drug screen with 3988 compounds in a single dose. After we narrowed down our targets, dose response assay was performed on four different ROCK inhibitors (ROCKi). The leading ROCKi compound was validated in vivo with SRSF2 Mut AML xenograft models. Next, we aimed at understanding why ROCKi target SRSF2 Mut cells and used proteomics, gene expression and imaging of the cytoskeletal system to study the effect of ROCKi on Mut and WT cells. Results: In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 Mut in MOLM14 and AML2 cells. To study the efficacy of RKI-1447 on human samples, we conducted six AML patient-derived xenograft (PDX) experiments, with SRSF2 Mut samples. In four out of the six primary AML samples, RKI-1447 significantly reduced engraftment compared to the untreated group and inhibited the engraftment of both leukemic blasts and pre leukemic-HSPCs (preL-HSPCS). RKI-1447 was not toxic to mice nor human cells. ROCKi induced mitotic catastrophe (G2M arrest and multipolar spindles) through their apparent effects on microtubules and nuclear organization, and leading to cell death. Confocal imaging and transmission electron microscopy (TEM) data revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, which is reminiscent of the nuclear shape of Pelger–Huët anomaly (PHA). The nuclear volume and area were significantly higher in SRSF2 Mut compared with WT MOLM14 cells regardless of ROCKi. To investigate why SRSF2 Mut cause the structural changes, we looked into the cytoplasmic intrusions that segment the nuclei, and the structures that connect the lobes of the nuclei by TEM. This examination revealed enrichment of microtubule bundles inside the nuclear indentations. More importantly, these microtubules were located at the tip of the cytoplasmic intrusions suggesting that they take an active role in the nuclear segmentation process. After exposure to RKI-1447, the cytoskeletal and nuclear morphological abnormalities of SRSF2 Mut are augmented to a level which are incompatible with cell survival. Image:Summary/Conclusion: We believe it is the first report describing in high resolution the changes in the nucleus after SRSF2 mutations are introduced. The mechanisms we identified are most probably relevant to other SMMs and to the dysplastic phenotype observed in MDS and AML. Accordingly, our findings have wide implications as ROCKi might be even more useful than describe here. Altogether, we provide data from many directions that ROCKi should be tested in clinical trials.

Spliceosome machinery mutations are common early mutations in myeloid malignancies, however effective targeted therapies against them are still lacking. In the current study, we used an in vitro high-throughput drug screen among four different isogenic cell lines and identified ROCK inhibitors (ROCKi) as selective inhibitors of SRSF2 mutants. ROCKi targeted SRSF2 Mut primary human samples in a xenografts model and were not toxic to mice nor human cells. ROCKi induced mitotic catastrophe through their apparent effects on microtubules and nuclear organization. Transmission electron microscopy revealed that SRSF2 mutations induce deep nuclear indentation and segmentation, driven by microtubule-rich cytoplasmic intrusions, which were exacerbated by ROCKi. The severe nuclear deformation driven by the combination of SRSF2 Mut and ROCKi prevent cells from completing mitosis. These findings shed light on new ways to target SRSF2 and on the role of the microtubule system in SRSF2 Mut cells.

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

Background A residual risk of ischemic events following an acute coronary syndrome ( ACS ) remains despite antiplatelet therapy. The addition of an antithrombin as part of a “dual pathway” approach may further improve outcomes as thrombin generation persists for several months post‐ ACS . The present study evaluates the safety and efficacy of “dual pathway” therapy (rivaroxaban plus aspirin) as compared with aspirin monotherapy among post‐ ACS patients. Methods and Results A total of 1477 patients were analyzed in a pooled analysis of subsets of the ATLAS ACS ‐ TIMI (Anti‐Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction) 46 and ATLAS ACS 2‐ TIMI 51 trials including post‐ ACS patients receiving aspirin monotherapy and randomized to either rivaroxaban 2.5 mg BID or rivaroxaban 5 mg BID or placebo. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction ( MI ), or stroke (ischemic, hemorrhagic, or of uncertain cause). The primary safety end point was TIMI ‐non‐coronary artery bypass ( CABG ) major bleeding. The combined rivaroxaban group (2.5 or 5 mg BID ) among stabilized post‐ ACS patients on a background of aspirin monotherapy was associated with a significant reduction in the primary end point as compared with placebo (hazard ratio=0.65, 95% CI =0.45–0.92, P =0.016). Although the combined rivaroxaban dose groups were associated with higher rates of non‐ CABG TIMI major bleeding, the 2.5 mg dose group was not, and the overall number of patients experiencing a non‐ CABG TIMI major bleeding event was low (1.5%). Conclusions Among patients in the immediate post‐ ACS period, a “dual pathway” approach using aspirin and low‐dose rivaroxaban may reduce the risk of secondary atherothrombotic events, but increase bleeding risk. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00402597; NCT 00809965.

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study. (C) 2018 The Authors. Published by Elsevier Inc.

Persistent elevation of thrombin following brain ischemia may account, at least in part, for the adverse sequelae among patients who sustain a stroke [(1)][1]. In the central nervous system, thrombin is associated with neural cell apoptosis, inflammatory responses, oxidative stress, vascular

Real World Evidence Showed Similar Efficacy and Safety for Ticagrelor Compared with Prasugrel in a Secondary Prevention Population Following Acute Coronary Syndrome Introduction: Direct comparative...

Introduction: Clinical trials demonstrated better efficacy in preventing cardiovascular events for the new generation of P2Y12 receptor antagonists (prasugrel and ticagrelor) as compared with clopi...

Introduction: Factor X-mediated thrombin overproduction following a stroke may contribute to central nervous system injury and neurological disability. Thrombin induces a dose-dependent apoptotic r...

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

Objectives The present analysis reports on the pre-specified subgroup of ST-elevation myocardial infarction (STEMI) patients, in whom anticoagulant therapy has been of particular interest.Background In ATLAS ACS-2-TIMI-51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51), rivaroxaban reduced cardiovascular events across the spectrum of acute coronary syndrome (ACS).Methods Seven thousand eight hundred seventeen patients in ATLAS ACS-2-TIMI 51 presented with a STEMI. After being stabilized (1 to 7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for intention-to-treat (ITT) and modified ITT (mITT) analyses.Results Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (ITT: 8.4% vs. 10.6%, hazards ratio [HR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.97, p = 0.019; mITT: 8.3% vs. 9.7%, HR: 0.85, 95% CI: 0.70 to 1.03, p = 0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, p = 0.042) and was evident in analyses that included events while patients received background dual antiplatelet therapies (ITT: 7.9% vs. 11.9%, p = 0.010; mITT: 7.7% vs. 10.1%, p = 0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, p = 0.006; mITT: 2.2% vs. 3.9%, p = 0.006), which was not seen with 5 mg of rivaroxaban. Rivaroxaban versus placebo increased non-coronary artery bypass grafting Thrombolysis In Myocardial Infarction major bleeding (2.2% vs. 0.6%, p < 0.001) and intracranial hemorrhage (0.6% vs. 0.1%, p = 0.015) without a significant increase in fatal bleeding (0.2% vs. 0.1%, p = 0.51).Conclusions In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965) 2013 by the American College of Cardiology Foundation

Abstract OBJECTIVES AND BACKGROUND: In ATLAS ACS 2-TIMI 51, rivaroxaban reduced cardiovascular events across the spectrum of ACS. The present analysis reports on the pre-specified subgroup of STEMI patients, in whom anticoagulant therapy has been of particular interest. METHODS: 7,817 patients in ATLAS ACS 2-TIMI 51 presented with a STEMI. After being stabilized (1-7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for ITT and modified ITT (mITT) analyses. RESULTS: Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, MI, or stroke, as compared with placebo (ITT: 8.4% vs. 10.6%, HR 0.81, 95% CI 0.67-0.97, P=0.019; mITT: 8.3% vs. 9.7%, HR 0.85, 95% CI 0.70-1.03, P=0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, P=0.042) and was evident in analyses that included events while on background antiplatelet therapies (ITT: 7.9% vs. 11.8%, P=0.010; mITT: 7.7% vs. 10.1%, P=0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, P=0.006; mITT: 2.2% vs. 3.9%, P=0.006), which was not seen with 5 mg. Rivaroxaban vs. placebo increased non-CABG TIMI major bleeding (2.2% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.1%, P=0.015), without a significant increase in fatal bleeding (0.2% vs. 0.1%, P=0.51). CONCLUSION: In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban as compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding.