Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P\u3c0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.)

Elastase-mediated fibrinogenolysis by chemoattractant-stimulated neutrophils occurs in the presence of physiologic concentrations of antiproteinases.

Plasma levels of the HNE-derived fibrinopeptide A alpha 1-21 reflect in vivo enzyme activity. To provide a possible explanation for the presence of circulating A alpha 1-21 in individuals with normal plasma antiproteinase concentrations we investigated whether PMN-associated HNE is more resistant to inhibition than the free enzyme. PMN were stimulated to migrate across 125I-fibrinogen-coated nitrocellulose filters in response to 10(-7) M FMLP, and the extent of fibrinogenolysis was determined by measuring release of A alpha 1-21 and 125I-labeled fibrinogen degradation products. The fibrinogenolytic activity of migrating PMN was then compared with that of free HNE present in PMN lysates or secreted by PMN stimulated with FMLP. Whereas the fibrinogenolytic activity of soluble HNE was completely inhibited by low concentrations (1%) of plasma or serum and macromolecular antiproteinase (alpha 1 proteinase-inhibitor and soybean trypsin-inhibitor), even in the presence of undiluted plasma or serum the activity of the migrating PMN was incompletely blocked (81-85%). Further, concentrations of alpha 1 proteinase-inhibitor and soybean trypsin-inhibitor that totally inhibited free HNE activity also incompletely blocked (88-89%) the fibrinogenolytic activity of migrating PMN, indicating that FMLP-stimulated PMN demonstrate significant fibrinogenolytic activity in the presence of antiproteinases as small as 20,000 mol wt. A specific low molecular weight HNE inhibitor (MeO-Suc-Ala2-Pro-ValCH2Cl), however, totally blocked PMN-mediated fibrinogenolysis without affecting intracellular HNE activity, HNE secretion from PMN, or PMN migration in response to FMLP. These findings support the hypothesis that PMN migrating on a fibrinogen-coated surface form zones of close contact with fibrinogen, thus preventing access of plasma antiproteinases to HNE released at the cell-substrate interface. The occurrence of this phenomenon in vivo would explain the presence of circulating A alpha 1-21 in individuals with normal antiproteinase concentrations

Trends in Prescribing Oral Anticoagulants in Canada, 2008–2014

AbstractPurposeThe non–vitamin K antagonist oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, provide several advantages over vitamin K antagonists, such as warfarin. Little is known about the trends of prescribing OACs in Canada. In this study we analyzed changes in prescription volumes for OAC drugs since the introduction of the NOACs in Canada overall, by province and by physician specialty.MethodsCanadian prescription volumes for warfarin, dabigatran, rivaroxaban, and apixaban from January 2008 to June 2014 were obtained from the Canadian Compuscript Audit of IMS Health Canada Inc and were analyzed by physician specialty at the national and provincial levels. Total prescriptions by indication were calculated based on data from the Canadian Disease and Therapeutic Index for all OAC indications and for each commonly prescribed dose of dabigatran (75, 110, and 150 mg), rivaroxaban (10, 15, and 20 mg), and apixaban (2.5 and 5 mg).FindingsThe overall number of OAC prescriptions in Canada has increased annually since 2008. With the availability of the NOACs, the proportion of total OAC prescriptions attributable to warfarin has steadily decreased, from 99% in 2010 to 67% by June 2014, and the absolute number of warfarin prescriptions has been decreasing since February 2011. The greatest decline in proportionate warfarin prescriptions was in Ontario. In general, the increase of NOAC prescriptions coincided with the introduction of provinces’ reimbursement of NOAC prescription costs. The proportion of total OAC prescriptions represented by the NOACs varied by specialty, with the greatest proportionate prescribing found among orthopedic surgeons, cardiologists, and neurologists.ImplicationsSince their approval, the NOACs have represented a growing share of total OAC prescriptions in Canada. This trend is expected to continue because the NOACs are given preference over warfarin in guidelines on stroke prevention in patients with atrial fibrillation, because of growing physician experience, and due to the emergence of potential new indications. An understanding of the current prescribing patterns will help to encourage knowledge translation and possibly influence policy/reimbursement strategies

Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients

The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin. METHODS: In this double-blind, double-dummy, placebo-controlled trial, we randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated. RESULTS: A total of 6528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome - 2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P = 0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P = 0.04). CONCLUSIONS: In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparinSupported by Bristol-Myers Squibb and Pfize

Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin

Type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA), circulates as a complex with the abundant plasma glycoprotein, vitronectin. This interaction stabilizes the inhibitor in its active conformation. In this report, the effects of vitronectin on the interactions of PAI-1 with fibrin clots were studied. Confocal microscopic imaging of platelet-poor plasma clots reveals that essentially all fibrin-associated PAI-1 colocalizes with fibrin-bound vitronectin. Moreover, formation of platelet-poor plasma clots in the presence of polyclonal antibodies specific for vitronectin attenuated the inhibitory effects of PAI-1 on t-PA-mediated fibrinolysis. Addition of vitronectin during clot formation markedly potentiates PAI-1-mediated inhibition of lysis of 125I-labeled fibrin clots by t-PA. This effect is dependent on direct binding interactions of vitronectin with fibrin. There is no significant effect of fibrin-associated vitronectin on fibrinolysis in the absence of PAI-1. The binding of PAI-1 to fibrin clots formed in the absence of vitronectin was characterized by a low affinity (Kd ~ 3.5 μM) and rapid loss of PAI-1 inhibitory activity over time. In contrast, a high affinity and stabilization of PAI-1 activity characterized the cooperative binding of PAI- 1 to fibrin formed in the presence of vitronectin. These findings indicate that plasma PAI-1-vitronectin complexes can be localized to the surface of fibrin clots; by this localization, they may modulate fibrinolysis and clot reorganization

Development of robotic technology platform for intellectual repair of road load

The work is devoted to the creation of a robotic complex capable of automated repair of the roadway, in particular pits. The robot should be autonomous, but you need to take into account the possibility of instant interception of control

Apixaban for extended treatment of venous thromboembolism

Background: Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. Methods: in this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. Results: a total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. Conclusions: extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893)

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .)

The Lectin-like Domain of Thrombomodulin Confers Protection from Neutrophil-mediated Tissue Damage by Suppressing Adhesion Molecule Expression via Nuclear Factor κB and Mitogen-activated Protein Kinase Pathways

Thrombomodulin (TM) is a vascular endothelial cell (EC) receptor that is a cofactor for thrombin-mediated activation of the anticoagulant protein C. The extracellular NH2-terminal domain of TM has homology to C-type lectins that are involved in immune regulation. Using transgenic mice that lack this structure (TMLeD/LeD), we show that the lectin-like domain of TM interferes with polymorphonuclear leukocyte (PMN) adhesion to ECs by intercellular adhesion molecule 1–dependent and –independent pathways through the suppression of extracellular signal–regulated kinase (ERK)1/2 activation. TMLeD/LeD mice have reduced survival after endotoxin exposure, accumulate more PMNs in their lungs, and develop larger infarcts after myocardial ischemia/reperfusion. The recombinant lectin-like domain of TM suppresses PMN adhesion to ECs, diminishes cytokine-induced increase in nuclear factor κB and activation of ERK1/2, and rescues ECs from serum starvation, findings that may explain why plasma levels of soluble TM are inversely correlated with cardiovascular disease. These data suggest that TM has antiinflammatory properties in addition to its role in coagulation and fibrinolysis