Thromb Haemostasis
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Randomized Controlled Trial
A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.
Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. ⋯ Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.
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Randomized Controlled Trial Multicenter Study
Darexaban (YM150) versus enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a randomised phase IIb dose confirmation study (ONYX-3).
This double-blind, double-dummy, randomised, phase IIb study (NCT00902928) evaluated different dosing regimens of darexaban compared with enoxaparin (randomised 1:1:1:1:1 to 15 mg twice daily [bid], 30 mg once daily [qd], 30 mg bid or 60 mg qd or enoxaparin 40 mg qd) in patients undergoing elective total hip arthroplasty. Patients, investigators, pharmacists and sponsor were all blinded to treatment allocation. Darexaban administration started 6-10 hours (h) post-surgery. ⋯ Darexaban was well tolerated, without signs of liver toxicity. In conclusion, darexaban, administered qd or bid, and at total daily doses of 30 mg or 60 mg, appears to be effective for VTE prevention and was well tolerated. Data suggest no significant differences between a once- or twice-daily dosing regimen.
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Randomized Controlled Trial Comparative Study Clinical Trial
Comparison of the CHADS2, CHA2DS2-VASc and HAS-BLED scores for the prediction of clinically relevant bleeding in anticoagulated patients with atrial fibrillation: the AMADEUS trial.
Many of the risk factors for stroke in atrial fibrillation (AF) are also important risk factors for bleeding. Wetested the hypothesis that the CHADS2 and CHA2DS2-VASc scores (used for stroke risk assessment) could be used to predict serious bleeding, and that these scores would compare well against the HAS-BLED score, which is a specific risk score designed for bleeding risk assessment. From the AMADEUS trial, we focused on the trial's primary safety outcome for serious bleeding, which was "any clinically relevant bleeding". ⋯ The HAS-BLED score also demonstrated significant NRI for the outcome of "any clinically relevant bleeding" when compared with CHADS2 (p=0.001) and CHA2DS2-VASc (p=0.04). In conclusion, the HAS-BLED score demonstrated significant discriminatory performance for "any clinically relevant bleeding" in anticoagulated patients with AF, whilst the CHADS2 and CHA2DS2-VASc scores did not. Bleeding risk assessment should be made using a specific bleeding risk score such as HAS-BLED, and the stroke risk scores such as CHADS2 or CHA2DS2-VASc scores should not be used.
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Randomized Controlled Trial Multicenter Study
Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: insights from the switching anti-platelet (SWAP) study.
The prevalence of high platelet reactivity (HPR) in patients who have switched from clopidogrel to prasugrel during maintenance phase after an acute coronary syndrome (ACS) event is unknown. Therefore, the effect of switching from clopidogrel to prasugrel on the prevalence of HPR was evaluated. This analysis from the previously reported SWAP (SWitching Anti Platelet) study assessed HPR at baseline, 2 and 24 hours, and seven days after switching from clopidogrel to prasugrel maintenance dose (MD), with or without a prasugrel loading dose (LD) using four definitions: maximum platelet aggregation (MPA) >65% (primary endpoint), MPA >50%, P2Y12 reaction units (PRU) >235, and platelet reactivity index (PRI) ≥ 50%. ⋯ A significantly higher HPR prevalence was observed during clopidogrel versus the combined prasugrel therapy groups at seven days as measured by MPA >65% (21.2% vs. 4.5%, p<0.05), PRU >235 (18.8% vs. 0%, p=0.001), and PRI ≥ 50 % (66.7% vs. 7.9%, p<0.0001). There was a significantly higher percentage of subjects carrying at least one reduced function allele with HPR measured by MPA >65% (p=0.02) or PRU >235 (p=0.05) than non-carriers with HPR. Switching ACS patients during maintenance clopidogrel therapy to prasugrel with or without an LD is associated with a reduced HPR prevalence and may provide an alternative strategy to treat patients with HPR, independent of CYP2C19 genotype.
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Randomized Controlled Trial
Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers.
The new anticoagulants dabigatran and rivaroxaban can be responsible for haemorrhagic complications. As for any anticoagulant, bleeding management is challenging. We aimed to test the effect of all putative haemostatic agents on the anticoagulant activity of these new drugs using thrombin generation tests. ⋯ For both anticoagulants, lower doses of FEIBA, corresponding to a quarter to half the dose usually used, have potential reversal profile of interest. In conclusion, some non-specific reversal agents appear to be able to reverse the anticoagulant activity of rivaroxaban or dabigatran. However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation regarding their use in this context is required.