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Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

In this study involving nearly 3400 patients with venous thromboembolism, both prophylactic and therapeutic doses of rivaroxaban were superior to aspirin in reducing the risk of recurrent thromboembolism with a similar risk of bleeding. Venous thromboembolism, which includes deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular death after myocardial infarction and stroke. 1 – 3 The mainstay of treatment is anticoagulation, 4 and in patients without active cancer, guidelines suggest the use of direct oral anticoagulant agents such as rivaroxaban over vitamin K antagonists such as warfarin. 4 Anticoagulation therapy is administered for 3 months or longer, depending on the balance between the risk of recurrent venous thromboembolism and the risk of bleeding. 4 In patients without reversible risk factors, the risk of recurrent venous thromboembolism is as much as 10% in the first . . .

Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

An amendment to this paper has been published and can be accessed via the original article.

In patients undergoing total knee replacement, a single injection of abelacimab (an antibody to factor XI) administered postoperatively was superior to standard care with enoxaparin for the prevention of venous thromboembolism. Bleeding events were rare.

In a randomized trial, 1050 patients with cancer who had acute venous thromboembolism were assigned to receive either dalteparin or edoxaban for 6 to 12 months. Edoxaban was noninferior to dalteparin with respect to the outcome of recurrent venous thromboembolism or major bleeding.

No longitudinal study addressed whether systolic blood pressure level (SBPL) or within-visit variability (SBPV) predict arterial properties or vice versa . In families randomly recruited from a Flemish population, we determined SBPL and SBPV from five consecutive blood pressure readings. The indexes of SBPV were variability independent of the mean, the difference between maximum and minimum SBPL, and average real variability. We measured carotid intima-media thickness and distensibility by ultrasound and carotid–femoral pulse wave velocity by tonometry (SphygmoCor, version 8.2). Effect sizes were computed for 1-s.d. increments in the predictors, while accounting for covariables and family clusters. Among 1087 participants (50.4% women; mean age, 41.8 years), followed up for 2.55 years (median), higher SBPL predicted ( P ⩽0.019) higher carotid intima-media thickness (+15 μm), lower carotid distensibility (−1.53 10 −3  kPa −1 ) and faster carotid–femoral pulse wave velocity (+0.285 m s −1 ) at follow-up, whereas none of the SBPV indexes predicted the arterial traits at follow-up ( P ⩾0.11). In a subset of 713 participants, followed up for another 3.14 years, lower carotid distensibility predicted ( P <0.01) higher SBPL (+2.57 mm Hg), variability independent of the mean (+0.531 units), difference between maximum and minimum SBPL (+1.75 mm Hg) and average real variability (+0.654 mm Hg). Higher carotid–femoral pulse wave velocity predicted a 1.11 mm Hg increase SBPL ( P =0.031). In conclusion, temporality and effect size suggest that SBPL but not within-visit SBPV cause arterial stiffness and carotid intima-media thickness. Carotid stiffness, independent of SBPL, predicts within-visit SBPV, possibly because baroreflexes originating from a stiff carotid artery wall are impaired. Finally, stiffness of the aorta contributes to the age-related SBPL possibly, because faster returning reflected waves augments SBPL.

In a single-group trial, 352 patients with acute major bleeding while taking a factor Xa inhibitor were treated with andexanet. Andexanet markedly reduced anti–factor Xa activity, and 82% of the patients had excellent or good hemostatic efficacy at 12 hours.

Enoxaparin is used to prevent deep-vein thrombosis in patients undergoing total knee arthroplasty. In this study, an antisense oligonucleotide against factor XI was more effective than enoxaparin in preventing deep-vein thrombosis and caused less bleeding. Patients undergoing total knee arthroplasty are at risk for postoperative venous thromboembolism. Conventional therapies for the prevention of this complication involve inhibitors of factor Xa or thrombin, such as enoxaparin. These drugs are effective but are associated with a risk of bleeding. 1 The pathogenesis of venous thromboembolism after surgery is incompletely understood, but tissue factor exposed at the surgical site is thought to be the major driver through the extrinsic pathway of coagulation (Figure 1). 2 The role of the intrinsic pathway in this process is uncertain. Experimental data suggest that targeting factor XI, a key component of the intrinsic pathway, . . .

Intravenous idarucizumab, an antibody fragment of a human antibody specific for dabigatran, produced rapid reversal of the anticoagulant effect in patients with bleeding or an urgent surgical indication with no apparent toxic effects or rebound hypercoagulable state. A non–vitamin K antagonist oral anticoagulant, dabigatran etexilate (dabigatran) is an oral thrombin inhibitor that is licensed for the prevention of stroke in patients with nonvalvular atrial fibrillation and for the prevention and treatment of venous thromboembolism. Although dabigatran is associated with less serious bleeding than warfarin, 1 – 3 life-threatening bleeding can occur; in addition, dabigatran-treated patients may require urgent surgery or intervention, and dabigatran can increase the risk of perioperative bleeding. To improve the treatment of such patients, a specific dabigatran-reversal agent would be beneficial. Idarucizumab, a monoclonal antibody fragment, binds dabigatran with an affinity that is 350 times as . . .