bivalirudin and efegatran

To obtain more reliable and precise estimates of the effect of direct thrombin inhibitors in the management of acute coronary syndromes, including patients undergoing percutaneous coronary intervention, we undertook a meta-analysis based on individual patients' data from randomised trials comparing a direct thrombin inhibitor (hirudin, bivalirudin, argatroban, efegatran, or inogatran) with heparin.. We included trials that involved at least 200 patients. The primary efficacy outcome was death or myocardial infarction, and the primary safety outcome was major bleeding. Data from individual trials were combined by use of a modified Mantel-Haenszel method.. In 11 randomised trials, 35,970 patients were assigned up to 7 days' treatment with a direct thrombin inhibitor or heparin and followed up for at least 30 days. Compared with heparin, direct thrombin inhibitors were associated with a lower risk of death or myocardial infarction at the end of treatment (4.3% vs 5.1%; odds ratio 0.85 [95% CI 0.77-0.94]; p=0.001) and at 30 days (7.4% vs 8.2%; 0.91 [0.84-0.99]; p=0.02). This was due primarily to a reduction in myocardial infarctions (2.8% vs 3.5%; 0.80 [0.71-0.90]; p<0.001) with no apparent effect on deaths (1.9% vs 2.0%; 0.97 [0.83-1.13]; p=0.69). Subgroup analyses suggested a benefit of direct thrombin inhibitors on death or myocardial infarction in trials of both acute coronary syndromes and percutaneous coronary interventions. A reduction in death or myocardial infarction was seen with hirudin and bivalirudin but not with univalent agents. Compared with heparin, there was an increased risk of major bleeding with hirudin, but a reduction with bivalirudin. There was no excess in intracranial haemorrhage with direct thrombin inhibitors.. Direct thrombin inhibitors are superior to heparin for the prevention of death or myocardial infarction in patients with acute coronary syndromes. This information should prompt further clinical development of direct thrombin inhibitors for the management of arterial thrombosis.

Topics: Angina, Unstable; Antithrombins; Arginine; Glycine; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Oligopeptides; Peptide Fragments; Pipecolic Acids; Piperidines; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Survival Rate; Thrombin

Topics: Anticoagulants; Antithrombins; Arginine; Blood Platelets; Clinical Trials as Topic; Epoprostenol; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Oligopeptides; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Thrombin; Thrombolytic Therapy

In addition to its pivotal role in blood coagulation, thrombin is one of the most important agonists for platelet recruitment and aggregation. Thrombin inhibitors impede thrombin-induced platelet aggregation but have no effect on aggregation induced by other agonists. A review is presented of selective thrombin inhibitors now in clinical investigation, some of which are also orally active.

Topics: Administration, Oral; Adult; Animals; Antithrombins; Arginine; Blood Platelets; Boron Compounds; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Glycine; Hirudin Therapy; Hirudins; Humans; Naphthalenes; Oligopeptides; Peptide Fragments; Pipecolic Acids; Piperidines; Recombinant Proteins; Sulfonamides; Thrombin

Thrombotic disorders can lead to uncontrolled thrombin generation and clot formation within the circulatory system leading to vascular thrombosis. Direct inhibitors of thrombin have been developed and tested in clinical trials for the treatment of a variety of these thrombotic disorders. The bleeding complications observed during these trials have raised questions about their clinical use. The development of a computer-based model of coagulation using the kinetic rates of individual reactions and concentrations of the constituents involved in each reaction within blood has made it possible to study coagulation pathologies in silico. We present an extension of our initial model of coagulation to include several specific thrombin inhibitors. Using this model we have studied the effect of a variety of inhibitors on thrombin generation and compared these results with the clinically observed data. The data suggest that numerical models will be useful in predicting the effectiveness of inhibitors of coagulation.

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Blood Coagulation; Computer Simulation; Dose-Response Relationship, Drug; Glycine; Hirudins; Humans; Kinetics; Models, Cardiovascular; Oligopeptides; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin

The relation between the antithrombotic effect in vivo, and the inhibition constant (Ki) and the association rate constant (k(on)) in vitro was investigated for eight different thrombin inhibitors. The carotid arteries of anaesthetized rats were exposed to FeCl3 for 1 h, and the thrombus size was determined from the amount of incorporated 125I-fibrinogen. The thrombin inhibitors were given intravenously, and complete concentration- and/or dose-response curves were constructed. Despite a 50,000-fold difference between the Ki-values comparable plasma concentrations of hirudin and melagatran were needed (0.14 and 0.12 micromol l(-1), respectively) to obtain a 50% antithrombotic effect (IC50) in vivo. In contrast, there was a comparable in vitro (Ki-value) and in vivo (IC50) potency ratio for melagatran and inogatran, respectively. These results can be explained by the concentration of thrombin in the thrombus and improved inhibition by the low-molecular-weight compounds. For all eight thrombin inhibitors tested, there was an inverse relationship between k(on)-values in vitro and the slope of the dose response curves in vivo. Inhibitors with k(on)-values of < 1 x 10(7) M(-1) s(-1) gave steep dose response curves with a Hill coefficient > 1. The association time for inhibition of thrombin for slow-binding inhibitors will be too long to give effective antithrombotic effects at low plasma concentrations, but at increasing concentrations the association time will decrease, resulting in a steeper dose-response curve and thereby a more narrow therapeutic interval.

Topics: Amino Acid Chloromethyl Ketones; Animals; Anticoagulants; Arginine; Azetidines; Benzylamines; Carotid Artery Thrombosis; Dose-Response Relationship, Drug; Fibrinolytic Agents; Glycine; Hemodynamics; Heparin; Hirudin Therapy; Hirudins; Kinetics; Male; Oligopeptides; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Piperidines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sulfonamides; Thrombin; Thrombin Time

Topics: Antifibrinolytic Agents; Antithrombin III; Antithrombins; Aprotinin; Arginine; Binding Sites; Boron Compounds; Enzyme Activation; Fibrinolysis; Heparin; Hirudins; Humans; Oligopeptides; Peptide Fragments; Pipecolic Acids; Protein C; Recombinant Proteins; Sulfonamides; Thrombin

Site-directed thrombin inhibitors are being currently assessed clinically for their antithrombotic efficacy. Although these agents are claimed to be specific and direct thrombin inhibitors, their mechanism of inhibition varies. The objective of these studies was to compare four such agents in in vitro systems and to assess their relative anticoagulant efficacy. The four agents utilized in these studies were argatroban, Efegatran, hirulog, and hirudin. While hirulog and hirudin are specific irreversible inhibitors of thrombin, argatroban and Efegatran are reversible. All four agents were found to have a concentration-dependent anticoagulant effect when supplemented into normal human plasma, as assessed in the global clotting tests (PT, APTT, and Heptest). The most potent anticoagulant on a molar basis was hirudin in all three tests. The other three agents had similar anticoagulant actions. All four agents were also capable of inhibiting the generation of thrombin and factor Xa as determined by an amidolytic method after intrinsic or extrinsic activation of fibrinogen-deficient human plasma. Except for hirulog, all agents inhibited the extrinsic generation of thrombin, with hirudin being the most potent agent. The intrinsic generation of thrombin was blocked by the reversible thrombin inhibitors (argatroban and Efegatran) but not by the irreversible inhibitors (hirulog and hirudin). While all agents were capable of inhibiting the intrinsic generation of factor Xa at very low concentrations, only Efegatran was capable of blocking the extrinsic generation of the same factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Anticoagulants; Antithrombins; Arginine; Endopeptidases; Feedback; Hirudins; Humans; Molecular Sequence Data; Oligopeptides; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides