hirudin and Syndrome

Accomplishing a successful percutaneous coronary intervention in a patient with a suspected or diagnosed heparin-induced thrombocytopenia (HIT) requires the selection of an appropriate alternative anticoagulant and a thorough assessment of bleeding and thrombotic risks. In this review, we suggest an evidence-based management algorithm that takes into account the clinical phase of HIT (acute, recent, and remote HIT) and the associated risk when patients present with acute coronary syndrome. The algorithm also integrates preventive measures directed at decreasing the bleeding risk associated with the antithrombotic and invasive therapies used for HIT and percutaneous coronary intervention.

Topics: Algorithms; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Fondaparinux; Heparin; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombocytopenia; Vitamin K

The anticoagulant properties of heparin were discovered in 1916, and by the 1930s researchers were evaluating its therapeutic use in clinical trials. Treatment of unstable angina with unfractionated heparin (UFH), in addition to aspirin, was introduced into clinical practice in the early 1980s. UFH was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with acute coronary syndromes (ACS) or patients undergoing percutaneous coronary intervention (PCI). However, UFH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation. Clinical trials have demonstrated that newer agents, such as the low-molecular-weight heparins (LMWHs), are superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction. Increasingly, the LMWHs have been used as the anticoagulant of choice for patients presenting with ACS. For patients undergoing PCI, LMWH provides no sub-stantial benefit over UFH for anticoagulation; however, direct thrombin inhibitors (DTIs) have demonstrated safety and efficacy in this setting. UFH is likely to be replaced by more effective and safer antithrombin agents, such as DTIs. DTIs have antiplatelet effects, anticoagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UFH. The FDA has approved 4 parenteral DTIs for various indications: lepirudin, argatroban, bivalirudin, and desirudin. The antiplatelet, anticoagulant, and pharmacokinetic properties of bivalirudin support its use as the anticoagulant of choice for both lower- and higher-risk patients, including those undergoing PCI.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Molecular; Molecular Structure; Myocardial Ischemia; Peptide Fragments; Pipecolic Acids; Platelet Activation; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombosis

Topics: Administration, Oral; Anticoagulants; Arginine; Critical Care; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; International Normalized Ratio; Nurse's Role; Nursing Assessment; Partial Thromboplastin Time; Patient Selection; Pipecolic Acids; Platelet Count; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Sulfonamides; Syndrome; Thrombocytopenia; Time Factors

Bivalirudin is a member of the direct thrombin inhibitor group of anticoagulants. It has been evaluated as an alternative to unfractionated and low-molecular-weight heparins in the settings of percutaneous coronary intervention (PCI) and acute coronary syndrome (ACS). Results of clinical trials to date suggest bivalirudin is a viable alternative to the use of a heparin combined with a glycoprotein (GP) IIb/IIIa inhibitor in these settings. Thrombin has a central role in coagulation and platelet activation in ACS and during PCI. Its direct inhibition is an attractive target for therapy in these settings. Bivalirudin is a 20 amino acid polypeptide hirudin analog. It displays bivalent and reversible binding to the thrombin molecule, inhibiting its action. Direct inhibition of thrombin with bivalirudin has theoretical pharmacokinetic and pharmacodynamic advantages over the indirect anticoagulants. A reduction in rates of bleeding without loss of anti-thrombotic efficacy has been a consistent finding across multiple clinical trials. There may be economic benefits to the use ofbivalirudin if it permits a lower rate of use of the GP IIb/IIIa inhibitors. This article reviews the pharmacology of bivalirudin and clinical trial evidence to date. There are now data from multiple clinical trials and meta-analyses in the setting of ACS and PCI. Early results from the acute catheterization and urgent intervention strategy (ACUITY) trial are discussed.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Hemorrhage; Heparin; Hirudins; Humans; Myocardial Ischemia; Peptide Fragments; Platelet Aggregation Inhibitors; Recombinant Proteins; Secondary Prevention; Syndrome; Thrombin; Thrombosis

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Disease; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thromboembolism; Thrombosis; Venous Thrombosis

Coronary artery thrombosis is usually triggered by platelet-rich thrombus superimposed on a spontaneously or mechanically disrupted atherosclerotic plaque. Thrombin and platelets both play a role in this process. Unfractionated heparin and aspirin have served as cornerstones in the prevention and treatment of intracoronary thrombus, but unfractionated heparin has several limitations that necessitate the use of adjunctive therapies, such as glycoprotein IIb/IIIa receptor inhibitors and clopidogrel, in order to reduce the risk of ischemic events. These combination therapies, however, typically increase the risk for bleeding complications, as well as the cost and complexity of treatment. Bivalirudin (Angiomax, The Medicines Company), a thrombin-specific anticoagulant, does not share heparin's limitations. Bivalirudin appears to provide clinical advantages over unfractionated heparin therapy in acute coronary syndrome patients and those undergoing percutaneous coronary intervention, without increasing cost or complexity of treatment for most patients.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials as Topic; Coronary Disease; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins; Syndrome; Thrombosis

Ximelagatran and bivalirudin are direct thrombin inhibitors that have been studied for the prevention and treatment of thrombosis and have potential advantages over the traditional indirect thrombin inhibitors (i.e., warfarin, unfractionated heparin and low molecular-weight heparin). They are both reversible inhibitors of thrombin and block both circulating and fibrin-bound thrombin. Ximelagatran and bivalirudin possess favourable pharmacokinetic and pharmacodynamic profiles including wider therapeutic indices, faster onsets of action and less interpatient variability compared to indirect thrombin inhibitors. Ximelagatran has shown favourable clinical trial results in venous thromboembolism prophylaxis and atrial fibrillation. Similarly, bivalirudin has shown positive results in patients with acute coronary syndromes, however, further investigation is needed. Ximelagatran and bivalirudin have shown promising results in the management of thrombosis and the results of future studies confirming their use for the aforementioned indications are anticipated.

Topics: Acute Disease; Administration, Oral; Antithrombins; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Coronary Disease; Double-Blind Method; Hirudins; Humans; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Syndrome; Thrombosis

Heparin was first discovered in 1916 and at present is used in more than 12 million patients a year. In the 1950s, several physicians noticed an uncommon paradoxical phenomenon in which heparin appeared to function as a procoagulant instead of an anticoagulant. This phenomenon is now known as the immune-mediated heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS). Our understanding of this syndrome has evolved over the last 2 to 3 decades, and therapeutic options are arising. This article will focus on the most extensively studied therapy for HIT, which is the class of drugs known as the direct thrombin inhibitors. Specifically, we will focus on the mechanisms by which direct thrombin inhibitors may be useful in this syndrome, the evidence for their use, and the unique characteristics of the two FDA-approved agents in this class, lepirudin and argatroban.

Topics: Anticoagulants; Arginine; Binding Sites; Heparin; Hirudins; Humans; Models, Biological; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombocytopenia; Treatment Outcome

Unfractionated heparin has been the cornerstone of antithrombin therapy in the treatment of non-ST-segment elevation acute coronary syndromes for more than a decade. Several new anticoagulants have emerged in recent years and have been studied extensively in patients with unstable coronary syndromes and in the percutaneous coronary intervention setting.. Direct thrombin inhibitors comprise a family of agents with promising properties that offer several potential advantages over unfractionated heparin. Hirudin has been studied in patients with ST-elevation myocardial infarction, non-ST-elevation coronary syndromes, and coronary angioplasty. Bivalirudin has been studied in patients undergoing percutaneous coronary revascularization, with very promising efficacy and safety profile compared with unfractionated heparin.. The clinical trials of direct thrombin inhibitors in non-ST-elevation acute coronary syndromes and coronary angioplasty are reviewed.

Topics: Angioplasty, Balloon, Coronary; Arginine; Clinical Trials as Topic; Coronary Disease; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombolytic Therapy

Inhibiting thrombin as a key enzyme of the coagulation cascade is therapeutically useful in thromboembolic diseases. In coronary thrombosis, direct thrombin inhibitors promise to be useful for an efficacious therapy. Hirudin and recombinant or synthetic mimetics like hirulog, argatroban and melagatran have proven their efficacy in clinical studies.. Therapy with direct thrombin inhibitors such as hirudin and analogous substances reduces coronary events. Moreover, the agents are useful for therapy of thromboembolic diseases, especially in the case of heparin induced thrombocytopenia type II.

Topics: Acute Disease; Angina, Unstable; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Antithrombins; Arginine; Azetidines; Benzylamines; Fibrinolytic Agents; Glycine; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Rabbits; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thromboembolism; Thrombosis; Time Factors

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or without thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).

Topics: Antibodies; Anticoagulants; Antithrombin III; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Gangrene; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Leg; Platelet Activation; Platelet Factor 4; Protein C Deficiency; Receptors, IgG; Recombinant Proteins; Retrospective Studies; Syndrome; Thrombin; Thrombocytopenia; Venous Thrombosis; Warfarin

Unfractionated heparin is commonly used as standard therapy along with aspirin for the management of acute ischaemic syndromes. However, heparin has many limitations including a poor dose effect response and an inability to inactivate clot bound thrombin. Direct thrombin inhibitors inactivate clot bound thrombin and also prevent thrombin induced platelet aggregation. The prototypical direct thrombin inhibitor, hirudin, has been tested in the TIMI 9 and GUSTO II trials. These trials showed a 14% reduction in reinfarction at 30 days, but there was no effect on mortality or on the combined end point of death and nonfatal myocardial infarction (10.8% heparin versus 10.0% hirudin). More moderate bleeding occurred with hirudin than with intravenous heparin. Hirulog has been shown to increase the rate of TIMI grade 3 patency (from 35% to 48%, p = 0.03) at 90 minutes after streptokinase administration, and this is now being tested in a large mortality trial. Further trials are necessary to further test whether patient care can be improved by appropriate doses of these agents administered for an appropriate duration.

Topics: Antithrombins; Clinical Trials as Topic; Dose-Response Relationship, Drug; Hirudins; Humans; Myocardial Ischemia; Syndrome; Thrombolytic Therapy

Thrombin plays a key role in the pathophysiology of acute coronary artery syndromes. The "thrombin hypothesis" states that more complete and consistent thrombin inhibition may improve clinical outcomes in acute ischemic syndromes. The direct thrombin inhibitors hirudin and bivalirudin are potentially superior agents to heparin and have been tested in several clinical trials. More predictable and less variable levels of anticoagulation have been demonstrated. Adverse clinical events have been reduced during active treatment with hirudin or bivalirudin, but increased bleeding, including intracerebral hemorrhage, can occur with excessive anticoagulation. Unfortunately, the short-term benefit has not been sustained during follow-up. The multiplicity of pathways for platelet activation, inadequate treatment duration, or the inability to block thrombin generation may explain the limited efficacy. In contrast, inhibitors of the glycoprotein IIb/IIIa platelet receptor are associated with a more dramatic and durable reduction in clinical events.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Clinical Trials as Topic; Coronary Disease; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Syndrome

Hirulog therapy has been studied extensively in numerous settings including prevention of DVT, treatment of unstable angina, treatment of acute myocardial infarction during thrombolysis, and prevention of acute complications of PTCA. Being one of the first direct thrombin inhibitors in clinical development, it has had to 'test the waters', so to speak, of the relationship between pathophysiology and clinical trial design: what are the correct indications, patient entry criteria, endopoints, frequency and duration of dosing, and so on? Our findings validate a role for thrombin in treating arterial thromboembolism and demonstrate clinical activity and tolerability of Hirulog.

Topics: Acute Disease; Antithrombins; Coronary Disease; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Syndrome; Thrombophlebitis

The coronary artery bypass grafting (CABG) heparin-induced thrombocytopenia thrombosis syndrome (HITTS) on- and off-pump safety and efficacy (CHOOSE-ON) trial was designed as a safety and efficacy trial of bivalirudin for use in anticoagulation during cardiopulmonary bypass (CPB) in patients with confirmed or suspected HIT and (or) antiplatelet factor 4/heparin (anti-PF4/H) antibodies.. In an open-label, multicenter trial, 50 patients were enrolled prospectively. The primary study endpoint was in-hospital acute procedural success, defined as the absence of death, Q-wave myocardial infarction (MI), repeat operation for coronary revascularization, and stroke at day seven after surgery or hospital discharge, whichever occurred first. The secondary study endpoints were procedural success, defined as the absence of death, Q-wave MI, repeat operation for coronary revascularization, and stroke, at 30 days and 12 weeks after surgery. Perioperative blood loss, transfusions, and the incidence of major bleeding events were also captured.. There were 49 patients treated with bivalirudin of which 43 had acute HIT and thrombosis syndrome (HITTS) with antibodies at time of surgery. Procedural success in-hospital or at 7 days was achieved in 46 (94%) patients. At day 30 procedural success was achieved in 42 (86%) patients, and after 12 weeks in 40 (82%) patients. Mean intraoperative blood loss was 575 +/- 524 mL, and mean 24-hour postoperative blood loss was 998 +/- 595 mL. Forty-one (84%) patients received transfusions before day 7 or discharge with a mean of 5.6 +/- 3.8 units of red blood cells, 8.6 +/- 7.2 units of platelets, and 6.0 +/- 4.7 units of fresh frozen plasma. No differences in outcome among bivalirudin-treated patients were observed between those in the overall group and those with moderately impaired renal function (n = 10).. The current investigation expands the experience of safe and effective anticoagulation with bivalirudin during CPB to patients with confirmed or suspected HIT and anti-PF4/H antibodies, including in the setting of impaired renal function.

Topics: Acute Disease; Aged; Aged, 80 and over; Antibodies; Anticoagulants; Blood Loss, Surgical; Cardiopulmonary Bypass; Erythrocyte Transfusion; Female; Heparin; Hirudins; Humans; Intraoperative Care; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Syndrome; Thrombocytopenia; Thrombosis; Time Factors; Treatment Outcome

The goal of this study was to evaluate glycoprotein IIb/IIIa inhibition with eptifibatide when administered with indirect thrombin inhibition as compared with monotherapy with direct thrombin inhibition with bivalirudin among patients with non-ST-segment elevation acute coronary syndromes (ACS).. The optimal combination of antiplatelet and antithrombin regimens that maximizes efficacy and minimizes bleeding among patients with non-ST-segment elevation ACS undergoing percutaneous coronary intervention (PCI) is unclear.. A total of 857 patients with non-ST-segment elevation ACS were assigned randomly to eptifibatide + reduced dose unfractionated heparin (n = 298), eptifibatide + reduced-dose enoxaparin (n = 275), or bivalirudin monotherapy (n = 284).. Among angiographically evaluable patients (n = 754), the primary end point of post-PCI coronary flow reserve was significantly greater with bivalirudin (1.43 vs. 1.33 for pooled eptifibatide arms, p = 0.036). Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade more often was normal with eptifibatide treatment compared with bivalirudin (57.9% vs. 50.9%, p = 0.048). The duration of ischemia on continuous Holter monitoring after PCI was significantly longer among patients treated with bivalirudin (169 vs. 36 min, p = 0.013). There was no excess of TIMI major bleeding among patients treated with eptifibatide compared with bivalirudin (0.7%, n = 4 vs. 0%, p = NS), but TIMI minor bleeding was increased (2.5% vs. 0.4%, p = 0.027) as was transfusion (4.4% to 0.4%, p < 0.001).. Among moderate- to high-risk patients with ACS undergoing PCI, coronary flow reserve was greater with bivalirudin than eptifibatide. Eptifibatide improved myocardial perfusion and reduced the duration of post-PCI ischemia but was associated with higher minor bleeding and transfusion rates. Ischemic events and biomarkers for myonecrosis, inflammation, and thrombin generation did not differ between agents.

Topics: Acute Disease; Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Drug Therapy, Combination; Enoxaparin; Eptifibatide; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Peptide Fragments; Peptides; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins; Syndrome

Enoxaparin is an established therapy for the treatment of patients with acute coronary syndrome (ACS), and bivalirudin is commonly used as the antithrombotic agent during percutaneous coronary intervention (PCI). This study was designed to examine the safety of switching from enoxaparin to bivalirudin in these patients.. The Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes without ST-segment Elevation Undergoing Percutaneous Coronary Intervention (SWITCH) trial was a prospective, open-label, multicenter study including 91 patients who presented with an ACS without ST-segment elevation, and who had received greater than or equal to 1 dose of enoxaparin (1 mg/kg SC) within the 12 hours prior to PCI. Patients were enrolled into 3 time categories: Group 1: 0-4; Group 2: 4-8; and Group 3: 8-12 hours from last enoxaparin dose to PCI. The primary endpoint of the study was major bleeding complications.. Baseline characteristics and average number of enoxaparin injections prior to PCI were similar in all 91 patients and among the groups. There was no occurrence of death, Q-wave myocardial infarction (MI), or acute revascularization in any group and no incidence of intracranial or retroperitoneal bleeding. The overall rate of major bleeding (7.7%) was comparable among groups (p = 0.39), as was the incidence of periprocedural non-Q-wave MI (overall 12%; p = 0.58), irrespective of the time interval between enoxaparin and bivalirudin administration.. Switching from enoxaparin to bivalirudin for patients with ACS undergoing PCI appears to be clinically safe without increased risk of major bleeding complications, regardless of the time of enoxaparin administration, and is safe enough to warrant testing it in larger numbers.

Topics: Acute Disease; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Disease; Enoxaparin; Female; Hemorrhage; Hirudins; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Retreatment; Risk Assessment; Syndrome

A safe and effective alternative is needed for patients in whom unfractionated heparin (UFH) or protamine is contraindicated (e.g., those with heparin-induced thrombocytopenia or allergy to protamine). Furthermore, choice of anticoagulant may influence graft patency in coronary surgery and may therefore be important even when there is no contraindication to UFH. Direct thrombin inhibitors have several potential advantages over UFH, demonstrated in acute coronary syndromes. However, there are also potential difficulties with their use related to lack of reversal agents and paucity of clinical experience in monitoring their anticoagulant activity at the levels required for cardiac surgery with cardiopulmonary bypass (CPB). In the first prospective randomized trial of an alternative to heparin in cardiac surgery, we compared bivalirudin (a short-acting direct thrombin inhibitor) with UFH in 100 patients undergoing off-pump coronary artery bypass (OPCAB) surgery. Blood loss for the 12 hours following study drug initiation in the bivalirudin group was not significantly greater than in the heparin group. Median graft flow was significantly higher in the bivalirudin group. We concluded that anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. A larger study is needed to investigate the impact of improved graft patency on other clinical outcomes after cardiac surgery.

Topics: Ancrod; Angiography; Anticoagulants; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Prospective Studies; Protamines; Recombinant Proteins; Regional Blood Flow; Syndrome; Thrombin; Time Factors; Treatment Outcome

We compared the effects of hirudin and heparin on thrombin generation and activity among 350 patients with acute coronary syndromes enrolled in the GUSTO-IIb trial.. We obtained blood at baseline; at 4, 8, and 24h into infusion; at drug termination; and 6 and 24h after termination. We assayed for thrombin activity (fibrinopeptide A, activated protein C, thrombin-antithrombin complex), thrombin generation (prothrombin fragment 1.2), and platelet activation (platelet factor 4). Median baseline fibrinopeptide A and platelet factor 4 levels were elevated. Thrombin formation tended to increase with hirudin and decrease with heparin; by 8h into infusion, thrombin formation was significantly less for heparin (P<0.01). Most patients showed reduced thrombin activity and platelet activation during infusion of either agent. Hirudin-assigned patients had significantly lower fibrinopeptide A levels during infusion. Six h post-termination, both groups had increased thrombin activity. Thrombin formation was increased in heparin patients (P<0.0001), significantly more than with hirudin (P=0.005). Higher values of haemostasis markers tended to be associated with poorer 30-day outcomes.. Although hirudin did not prevent generation of new thrombin, it appeared to inhibit thrombin activity more than did heparin and produced slower increases in thrombin formation after discontinuation. The reelevation of thrombotic markers after stopping intravenous antithrombin therapy and the tendency toward increased thrombotic events with post-treatment increases in marker levels suggest an ongoing, clinically significant prothrombotic state. These results raise the possibility of improving on current antithrombotics by preventing thrombin generation and thrombin activity and by sustained suppression of the prothrombotic state.

Topics: Acute Disease; Aged; Blood Coagulation; Double-Blind Method; Female; Fibrinolytic Agents; Heart Diseases; Hemostasis; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Syndrome; Thrombin; Treatment Outcome

Although intravenous heparin is routinely used in the treatment of patients with acute coronary syndromes, this anticoagulant requires antithrombin III as a cofactor, has no affinity to clot-bound thrombin, and is bound or inactivated by several plasma proteins and platelet factor 4. Recombinant hirudin, the prototypic direct thrombin inhibitor, has been demonstrated in pilot studies to yield improved angiographic and clinical outcomes compared with heparin. We compared these two antithrombins in a large-scale randomized trial.. At 275 participating hospitals in 12 countries, patients within 12 hours from the onset of ischemic chest discomfort with an abnormal ECG were randomly assigned to receive a 72- to 120-hour infusion of heparin (5000-U bolus and 1000- to 1300-U/h infusion, adjusted to activated partial thromboplastin time (APTT) of 60 to 90 seconds or hirudin (0.6-mg/kg bolus and 0.2-mg/kg per hour infusion without aPTT adjustment) on a double-blind basis. Although recruitment of 12,000 patients was planned, the trial was stopped earlier because of an excess of intracerebral hemorrhagic events after 2564 patients were enrolled. The overall incidence of hemorrhagic stroke tended to be higher for patients receiving hirudin (1.3%) compared with heparin (0.7%), P = .11, but the incidence was significantly higher in patients receiving thrombolytic therapy (1264 patients, 1.8%) compared with those who did not (1168 patients, 0.3%), P < .001. The hemorrhagic stroke rate varied by the thrombolytic and antithrombin combination: tissue-type plasminogen activator and heparin, 0.9%; with hirudin, 1.7%; streptokinase with heparin, 2.7%; with hirudin, 3.2%. All these rates are higher than the overall incidence of hemorrhagic stroke in the patients receiving thrombolytic therapy and intravenous heparin in the GUSTO I trial (30,892 patients with rate of 0.7%, 95% CI of 0.6 to 0.8%). Among the 26 patients who had intracerebral hemorrhages, the aPTT was significantly elevated compared with the event-free patients (110 +/- 46 versus 87 +/- 36 seconds at 12 hours of therapy, respectively), P = .03.. At the dose of hirudin tested, there was a trend of an excess of hemorrhagic stroke compared with heparin. Heparin, at a slightly higher dose than previously used in a large-scale trial (approximately 20% increase) was accompanied by a twofold risk of hemorrhagic stroke in patients receiving thrombolytic therapy. With both thrombin inhibitors, the aPTT appears to be a useful index for predicting risk of hemorrhagic stroke in patients receiving thrombolytic therapy.

Topics: Acute Disease; Aged; Cerebral Hemorrhage; Cerebrovascular Disorders; Coronary Disease; Double-Blind Method; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Syndrome; Thrombolytic Therapy

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Drug Hypersensitivity; Fibrinolytic Agents; Hemorrhage; Hirudins; Humans; Risk Assessment; Syndrome; Thrombosis

Topics: Anticoagulants; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Middle Aged; Recombinant Proteins; Renal Artery Obstruction; Renal Insufficiency; Syndrome; Thrombocytopenia; Thrombosis

Topics: Aged; Anticoagulants; Cardiopulmonary Bypass; Coronary Artery Bypass, Off-Pump; Enzyme-Linked Immunosorbent Assay; Heparin; Hirudins; Humans; Male; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Syndrome; Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a potentially serious syndrome. Since there are some alternatives to treatment with heparin in patients who develop HIT, the decision as to which to use should be based on renal and hepatic function, drug availability and the available monitoring resources. We report a patient who received heparin for mechanical aortic valve replacement. Her clinical course was complicated by HIT, which was treated initially by danaparoid. The syndrome progressed with new thrombotic complications, and eventually was treated successfully by bivalirudin (Angiomax; Medison Pharma Ltd, Petach Tikva, Israel) for 9 days. We propose that treatment with bivalirudin for several days is a safe and effective alternative to heparin therapy in patients who develop HIT.

Topics: Anticoagulants; Aortic Valve; Fatal Outcome; Female; Follow-Up Studies; Heart Valve Prosthesis; Heparin; Hirudins; Humans; Middle Aged; Peptide Fragments; Platelet Count; Recombinant Proteins; Syndrome; Thrombocytopenia

The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition is not inferior to heparin plus GPIIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. The extent to which this applies to patients with acute coronary syndromes (ACS) is unclear. Therefore, we sought to determine if bivalirudin has similar efficacy in ACS patients as compared with "stable" patients in the REPLACE-2 trial.. We analyzed the outcomes of ACS patients compared with stable patients and the outcomes of ACS patients according to whether or not they had received bivalirudin, including the economic costs. The trial enrolled 1351 ACS patients (myocardial infarction within 7 days or unstable angina within 48 hours, but not on ongoing GPIIb/IIIa or heparin therapy) and 4554 stable patients.. Patients with ACS had a similar rate of death or myocardial infarction at 30 days compared to stable patients (7.2% vs 6.7%, P = .51) and death at 1 year (1.6% vs 2.2%, P = .169), but a higher rate of urgent coronary artery bypass graft at 30 days (1.0% vs 0.3%, P = .002). Patients with ACS treated with bivalirudin had a similar rate of 30-day death, myocardial infarction, or urgent revascularization compared with ACS patients treated with heparin and GPIIb/IIIa inhibitors (8.7% vs 8.0%, P = .616) and death at 1 year (1.5% vs 1.8%, P = .701), but a higher rate of revascularization at 6 months (12% vs 8.4%, P = .04). Patients with ACS treated with bivalirudin had less major bleeding than ACS patients treated with heparin and GPIIb/IIIa inhibitors, although this was not statistically significant (2.7% vs 4.5%, P = .07). Mean 30-day costs for patients with ACS were dollar 12415 for those treated with bivalirudin and dollar 12806 for those treated with heparin plus GPIIb/IIIa inhibitors (P = .022).. Bivalirudin with provisional GPIIb/IIIa inhibitor use in low-risk ACS patients (not receiving preprocedural GPIIb/IIIa blockade) appears to provide similar protection against death and myocardial infarction as the combination of heparin and GPIIb/IIIa inhibitors, although we observed a higher rate of revascularization at 6 months.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Combined Modality Therapy; Drug Therapy, Combination; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins; Syndrome; Treatment Outcome; United States

Heparin with adjunctive glycoprotein IIb/IIIa platelet receptor (GP IIb/IIIa) inhibitors has demonstrated its effectiveness in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, has recently been shown to be an effective alternative for patients undergoing elective PCI.. To assess the angiographic and clinical outcomes of adjunctive pharmacological strategies in a high-risk population presenting with ACS.. Of 891 consecutive PCI patients with ACS, 304 received bivalirudin (60.5% male, 68+/-11 years) and were compared with 283 who received heparin (58.7% male, 66+/-12 years). A 30-day major adverse cardiac event was defined as the occurrence of cardiac death, nonfatal myocardial infarction, urgent revascularization or major hemorrhage.. Adjunctive GP IIb/IIIa inhibitors were used in 14.1% of the bivalirudin group and in 72.4% of the heparin group (P<0.010). The occurrence of Thrombolysis In Myocardial Infarction (TIMI) flow less than grade 3 was lower and the achievement of angiographic success was higher in the bivalirudin group than in the heparin group (5.2% versus 8.2%, 94.7% versus 89.7%, P=0.039 and P<0.010, respectively). There was no difference between groups in the incidence of bleeding events (bivalirudin 2.0% versus heparin 3.5%, P not significant) and in 30-day major adverse cardiac events (bivalirudin 8.3% versus heparin 5.7%, P=0.223).. In the high-risk cohort undergoing PCI, bivalirudin with provisional GP IIb/IIIa inhibitors achieved better angiographic results. Although not powered to show a difference, and while acknowledging that a selection bias could have affected the data, the present study showed that bivalirudin may be as clinically effective and safe as heparin with adjunctive GP IIb/IIIa inhibitors.

Topics: Acute Disease; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Angiography; Coronary Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Risk Factors; Syndrome; Treatment Outcome

Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconium-induced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60-70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response.

Topics: Antibodies, Monoclonal; CD11b Antigen; Complement Activation; Complement C5a; Complement System Proteins; Dose-Response Relationship, Drug; Flow Cytometry; Hirudins; Humans; Infant, Newborn; Inflammation; L-Selectin; Meconium; Meconium Aspiration Syndrome; Neutrophil Activation; Neutrophils; Oxidative Stress; Protein Binding; Recombinant Proteins; Respiratory Burst; Syndrome

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Cardiac Catheterization; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Ischemia; Recombinant Proteins; Secondary Prevention; Syndrome