hirudin and Angina--Unstable

Controversy regarding the optimal antiplatelet/antithrombotic regimen indicates a need to re-evaluate the place of these agents in treating patients with unstable angina/non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.. Although clinical trial data suggest that glycoprotein IIb-IIIa inhibition benefits moderate-risk to high-risk patients, recent studies question the use of intensive antiplatelet therapy in lower risk patients. The resultant shift towards less intensive alternative regimens raises questions about identifying patients in whom an alternative strategy is preferable. The concept of risk stratification for coronary intervention has evolved from lesion-based categorization to include clinical factors, for example, elevated levels of cardiac troponin.. Risk factors for periprocedural complications during percutaneous coronary intervention can be divided into anatomic (unprotected left main stenting, bifurcation lesions, and diffuse disease) and clinical (older age, diabetes, renal disease, left ventricular function, recent myocardial damage, and female sex) factors. These may interact additively or synergistically, increasing the likelihood of complications in patients who might otherwise have been considered at low risk. We need to reconsider, therefore, how we identify appropriate options and, hopefully, optimize clinical outcomes. This review evaluates risk factors for periprocedural complications in an effort to determine patients who may benefit most from intensive antiplatelet regimens.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Perioperative Care; Platelet Aggregation Inhibitors; Recombinant Proteins; Risk Factors

Previously, indirect thrombin inhibitors such as unfractionated heparin or low-molecular-weight heparin were used as a standard anticoagulation during percutaneous coronary intervention to prevent procedural thrombotic complications but at a risk of hemorrhagic complications. More recently, bivalirudin, a member of the direct thrombin inhibitor class, has been shown to have 1) predictable pharmacokinetics, 2) ability to inhibit free- and clot-bound thrombin, 3) no properties of platelet activation, 4) avoidance of heparin-induced thrombocytopenia, and 5) a significant reduction of bleeding without a reduction in thrombotic or ischemic endpoints compared to heparin and glycoprotein IIbIIIa inhibitors when used in patients presenting with acute coronary syndrome who are planned for an invasive treatment strategy.

Topics: Acute Coronary Syndrome; Anemia; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Blood Coagulation; Comorbidity; Coronary Thrombosis; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombocytopenia

Antithrombotic and powerful antiplatelet therapies, in addition to early percutaneous coronary intervention (PCI) are considered the treatment of choice for moderate- to high-risk patients with acute coronary syndromes (ACS; unstable angina and non-ST-segment elevation myocardial infarction). However, despite the integration of newer therapies including stents, glycoprotein IIb/IIIa inhibitors (GPI), and thienopyridines, the rate of adverse ischemic events still remains unacceptably high. Intensive pharmacologic regimens used to stabilize the disrupted atherosclerotic plaque and support angioplasty as well as surgical revascularization procedures, elicit a high rate of bleeding complications. Recent trials (ACUITY and HORIZONS studies) added evidence regarding safety and efficacy of bivalirudin use in acute coronary syndromes. In summary, is has been shown that bivalirudin alone is safe and effective in the vast majority of patients suffering from acute coronary syndromes and being treated invasively. The cost-effectiveness of such an approach will have to be determined. It remains to be a matter of discussion whether there are still patient subgroups being in need of more aggressive treatment strategies including GPI. In practice, it might be reasonable to perform a baseline assessment of hemorrhagic risk facilitating the choice of an antithrombotic regimen with a favourable safety and efficacy profile. With this tailored therapy it might be possible to further improve outcomes for individual patients with ACS.

Topics: Acute Coronary Syndrome; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins

Economic evaluation plays an important role during almost all stages of pharmaceutical design and use. This paper reviews the recent pharmacoeconomic literature on the use of anticoagulants for acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI). Both ACS and PCI are common reasons for hospitalization and contribute significantly to costs of care. ACS and PCI practice standards are still evolving. For ACS enoxaparin does appear to be more cost-effective around the globe than unfractionated heparin (UFH) when clopidrogel and glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors are not used. With the high prevalence of clopidrogel and GP IIb/IIIa use, the question may be moot. Since the cost of UFH therapy, including the cost of anticoagulant monitoring, is less expensive than enoxaparin therapy, UFH is probably the more cost-effective strategy. For PCI, as ischemic complications were reduced during the mid'90's, bleeding complications have become the most common problem and a major cost driver. Other complications that can drive costs include the occurrence of MI and revascularization procedures (repeat PCI or CABG). Results suggest that bivalirudin plus a provisional GP IIb/IIIa inhibitor is the most cost-effective strategy for patients undergoing elective PCI. There is no clear evidence regarding its use in urgent PCI. ACS and PCI practice standards are still evolving. It would be useful to embed economic studies within new clinical trials. Full economic analysis of groups at high risk for bleeding while undergoing PCI is needed.

Topics: Acute Coronary Syndrome; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Cost-Benefit Analysis; Drug Costs; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Stents

In addition to antiplatelet therapy with aspirin, anticoagulation therapy with unfractionated heparin decreases the risk of myocardial infarction and death in patients with acute coronary syndromes. However, unfractionated heparin has pharmacologic limitations that limit efficacy and safety. Enoxaparin, fondaparinux, and bivalirudin are new anticoagulant therapy options with either superior efficacy or better safety than unfractionated heparin. Compared with unfractionated heparin, enoxaparin and fondaparinux are easier to administer, do not require monitoring, and facilitate longer treatment duration. Bivalirudin offers advantages for patients undergoing early percutaneous revascularization. Careful attention to dosing and excellent vascular access site management after cardiac catheterization are required to decrease the risk of bleeding and blood transfusion, which have been associated with increased mortality risk.

Topics: Angina, Unstable; Anticoagulants; Electrocardiography; Enoxaparin; Fondaparinux; Heart Conduction System; Heparin, Low-Molecular-Weight; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Polysaccharides; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

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

Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, may be noninferior to heparins (unfractionated heparin/low molecular weight heparin) in providing protection against cardiovascular events, with significantly fewer bleeding complications. Whether this advantage is consistent has not been fully defined. We evaluated cardiac outcomes with bivalirudin vs the heparins in management of acute coronary syndromes (ACS), including patients undergoing percutaneous coronary interventions (PCI). Formal computer-aided searches of electronic databases (MEDLINE, PubMed, Cochrane Controlled Trials Registry) were performed by scrutiny of the reference lists of trials and review articles, abstracts, meeting proceedings, and the manufacturers of direct thrombin inhibitors. Five randomized controlled trials (BAT, 1995; CACHET, 2002; REPLACE-2, 2003; REPLACE-1, 2004; and ACUITY, 2006) comparing bivalirudin to the heparins in patients with ACS, including patients undergoing PCI, were identified. The meta-analysis consisted of 25 457 patients (bivalirudin, 15 077; heparins, 10 380). The primary safety end point was major bleeding, defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss leading to a hemoglobin drop exceeding 3 g/dL (or 10% of hematocrit) and transfusion of 2 or more units of whole blood or packed red blood cells. The combined relative risks (RR) across all of the studies and the 95% confidence intervals of death, myocardial infarction (MI), and revascularization (bivalirudin vs heparins) were computed using the Mantel-Haenszel fixed-effect model, whereas the random-effect model was used for major bleeding. A 2-sided alpha error < .05 was considered to be significant. There were no significant differences in patient characteristics between the 2 groups. Compared to the heparins, the risk of death, MI, revascularization, and composite ischemic end points were similar with bivalirudin monotherapy. However, the risk of major bleeding was significantly lower with bivalirudin use (RR = 0.553; 95% CI = 0.402-0.761; P = .001). The present meta-analysis suggests that bivalirudin may be noninferior to the heparins in reducing the composite of ischemic end points. Additionally, compared to the heparins, bivalirudin monotherapy may lower the rate of major bleeding.

Topics: Acute Coronary Syndrome; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins

For patients with heparin-induced thrombocytopenia (HIT), reexposure to heparin is generally not recommended. However, these patients are likely to require anticoagulation therapy at some point in the future. During acute HIT, when thrombocytopenia and anti-heparin-platelet factor 4 antibodies (or HIT antibodies) are present, therapy with heparin must be avoided. In patients with subacute HIT, when platelets have recovered but HIT antibodies are still present, therapy with heparin should be avoided. In patients with a remote history of HIT, when HIT antibodies have cleared, heparin reexposure may be safe, although recurrent HIT has been described in some patients. For all of these patients, the use of alternate anticoagulant agents, including direct thrombin inhibitors and anti-Xa agents, is preferable. There is an increasing amount of data supporting the use of these alternative agents in a wide variety of clinical circumstances, including thromboprophylaxis and treatment of acute thrombosis. Except for a few clinical situations, it is generally possible to avoid heparin reexposure in patients with a history of HIT.

Topics: Angina, Unstable; Antibodies; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Female; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Male; Multiple Organ Failure; Platelet Factor 4; Polysaccharides; Pregnancy; Preoperative Care; Recombinant Proteins; Thrombin; Thrombocytopenia; Venous Thrombosis

The central role of thrombin in the initiation and propagation of intravascular thrombus provides a strong rationale for direct thrombin inhibitors in acute coronary syndromes (ACS). Direct thrombin inhibitors are theoretically likely to be more effective than indirect thrombin inhibitors, such as unfractionated heparin or low-molecular-weight heparin, because the heparins block only circulating thrombin, whereas direct thrombin inhibitors block both circulating and clot-bound thrombin. Several initial phase 3 trials did not demonstrate a convincing benefit of direct thrombin inhibitors over unfractionated heparin. However, the Direct Thrombin Inhibitor Trialists' Collaboration meta-analysis confirms the superiority of direct thrombin inhibitors, particularly hirudin and bivalirudin, over unfractionated heparin for the prevention of death or myocardial infarction (MI) during treatment in patients with ACS, primarily due to a reduction in MI (odds ratio, 0.80; 95% confidence interval, 0.70 to 0.91) with little impact on death. The absolute risk reduction in the composite of death or MI at the end of treatment (0.8%) was similar at 30 days (0.7%), indicating no loss of benefit after cessation of therapy. Supportive evidence for the superiority of direct thrombin inhibitors over heparin derives from the recently reported Hirulog and Early Reperfusion or Occlusion (HERO)-2 randomized trial with ST-segment elevation ACS, which demonstrated a similar benefit of bivalirudin over heparin for the prevention of death or MI at 30 days (absolute risk reduction 1.0%), again primarily due to a reduction in MI during treatment (odds ratio, 0.70; 95% confidence interval, 0.56 to 0.87), with little impact on death. Further evaluation of hirudin and bivalirudin in the antithrombotic management of patients with ACS is warranted.

Topics: Acute Disease; Angina, Unstable; Antithrombins; Coronary Thrombosis; Fibrinolytic Agents; Forecasting; Heparin; Hirudins; Humans; Meta-Analysis as Topic; Myocardial Infarction; Outcome Assessment, Health Care; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Thrombin

Topics: Angina, Unstable; Aspirin; Drug Therapy, Combination; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Ticlopidine; Treatment Outcome

Topics: Angina, Unstable; Aspirin; Drug Therapy, Combination; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Ticlopidine

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

Studies of the anticoagulant effects of hirudin, which is derived from the saliva of the leech Hirudo medicinalis, led to the development of compounds that can directly inhibit thrombin activity without the need for additional cofactors. One of these is the direct thrombin inhibitor bivalirudin, which has recently been approved by the US Food and Drug Administration for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.. This is a review of the pharmacologic properties, efficacy, tolerability, and potential cost-effectiveness of bivalirudin in the treatment of ischemic coronary syndromes.. Articles were identified by searches of MEDLINE (1966-September 2001), International Pharmaceutical Abstracts (1970-September 2001), and the Iowa Drug Information Service (1966-September 2001) using the terms bivalirudin and Hirulog. The reference lists of retrieved articles were also reviewed for relevant articles.. Bivalirudin is a synthetic polypeptide that directly inhibits thrombin by binding simultaneously to its active catalytic site and its substrate recognition site. After intravenous administration, peak plasma concentrations occur in 2 minutes. In patients given a 1.0-mg/kg bolus followed by a 2.5-mg/kg per hour infusion, a median activated clotting time of 346 seconds is achieved with little interpatient or intrapatient variability. Clearance of bivalirudin occurs through a combination of renal elimination and proteolytic cleavage, and doses may need to be decreased in the presence of renal dysfunction. In patients undergoing percutaneous coronary interventions, bivalirudin has been associated with equivalent efficacy but lower bleeding rates (P < 0.001) than unfractionated heparin (UFH). Data from the Hirulog Early Reperfusion/Occlusion-2 study suggest no reduction in mortality with bivalirudin compared with heparin when either is added to aspirin and streptokinase in patients with acute myocardial infarction, despite a lower reinfarction rate (P < 0.001). Experience with bivalirudin in patients with unstable angina and heparin-induced thrombocytopenia (HIT), as well as in patients receiving glycoprotein IIb/IIIla inhibitors, is limited. The differences in bleeding rates between bivalirudin and heparin in published clinical trials probably reflect differences in levels of anticoagulation achieved in comparator groups.. Given its high cost, bivalirudin should be reserved for use as an alternative to UFH, primarily in patients with HIT, until clinical trials have more clearly demonstrated its benefits in terms of efficacy or safety.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clinical Trials as Topic; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombocytopenia; Thrombosis

Bivalirudin, a synthetic analogue of hirudin, is a specific and reversible inhibitor of thrombin which binds directly with both fluid-phase and clot-bound thrombin. In patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA), results from a large well designed study and its reanalysis (n = 4312) indicate that bivalirudin is more effective than heparin in the prevention of ischaemic complications for up to 90 days after the start of treatment. In addition, among patients undergoing PTCA for post myocardial infarction (MI) bivalirudin may be more effective than heparin in preventing ischaemic complications for up to 180 days after treatment was started. Data from dose-finding studies indicate bivalirudin has potential in the treatment of patients with unstable angina not undergoing percutaneous coronary intervention (PCI); however, well designed comparative studies are needed before firm conclusions can be made. Among patients with acute ST elevation MI, randomised trials have demonstrated bivalirudin to be significantly more effective than heparin in improving early patency in patients receiving thrombolytic therapy with streptokinase. Data from the Hirulog and Early Reperfusion/Occlusion (HERO)-1 trial (n = 412) indicate that bivalirudin recipients were significantly more likely to have Thrombin Inhibition in Myocardial Ischaemia (TIMI) grade 3 flow at 90 to 120 minutes than heparin recipients. In addition, data from the HERO-2 trial (n = 17 073) show bivalirudin was significantly more effective than heparin in reducing adjudicated 96-hour reinfarction and 30-day investigator-reported death/reinfarction than heparin. Bivalirudin was as effective as heparin in reducing 30-day mortality. Data from a meta-analysis of four randomised trials among patients undergoing PTCA or treatment for acute coronary syndromes indicate that, at after 30 to 50 days of follow-up, bivalirudin was significantly more effective than heparin in reducing the incidence of nonfatal MI and the combined endpoint of death or nonfatal MI. The most significant adverse events associated with bivalirudin are bleeding complications. In individual trials, bivalirudin was as well tolerated as heparin with, in general, a reduced incidence of bleeding complications. Additionally, bivalirudin provides a more consistent, predictable anticoagulant response. In 4312 patients with unstable angina undergoing PTCA the incidence of retroperitoneal bleeding, blood tr. Bivalirudin is an effective alternative to heparin in the prevention of ischaemic complications in patients with unstable angina undergoing PTCA. In addition, the drug has shown potential in the treatment of patients with unstable angina not undergoing PCI. For patients with MI, it is clear that bivalirudin can replace heparin in the management of MI where streptokinase is used as the thrombolytic agent. Further data are required on the efficacy of bivalirudin in patients undergoing thrombolysis with newer thrombolytics.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Dose-Response Relationship, Drug; Drug Evaluation; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins

To review the primary literature describing the pharmacology and clinical uses of bivalirudin.. A MEDLINE search (January 1966-May 2001) was conducted that used bivalirudin, hirulog, and direct thrombin inhibitor as key words. References from retrieved articles and unpublished information acquired from the manufacturer and the Internet were also used.. All acquired articles that discussed the pharmacology, pharmacokinetics, and clinical efficacy of bivalirudin were reviewed.. Articles were selected based on content regarding the pharmacology and clinical use of bivalirudin. Given the paucity of data pertaining to the clinical use of bivalirudin, most articles were used, including abstracts and communications with the manufacturer.. Bivalirudin is a direct thrombin inhibitor that inactivates both unbound and fibrin-bound thrombin. Bivalirudin rapidly induces anticoagulation and has a relatively short duration of action. Bivalirudin displays linear kinetics and is primarily eliminated renally. Bivalirudin was proven effective in preventing postprocedural ischemic complications in patients with unstable or postinfarction angina who received percutaneous transluminal coronary angioplasty (PTCA). Yet, further investigations that include less critically ill patients and use the current clinical practice of administering glycoprotein IIb/IIIa antagonists and/or inserting intracoronary stents are needed to fully evaluate its efficacy. Bivalirudin has also induced early patency in patients with myocardial infarction in combination with streptokinase, but its use with newer thrombolytics needs to be studied. Bivalirudin has been used in patients with immunologically mediated, heparin-induced thrombocytopenia (HIT) without complications. Bleeding is the major adverse effect and occurs more commonly in patients with renal dysfunction.. At present, bivalirudin is worthy of consideration in patients requiring PTCA who have HIT. Advocating the routine use of bivalirudin in patients experiencing an acute coronary syndrome or HIT is premature.

Topics: Amino Acid Sequence; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials as Topic; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins

Much progress has been made in understanding and treating acute coronary syndromes. For patients undergoing percutaneous transluminal coronary angioplasty, anticoagulant therapy during the procedure must strike a balance between providing sufficient anticoagulation to prevent thrombus formation and ischemic complications while averting hemorrhagic complications. Bivalirudin, a thrombin-specific anticoagulant, is the only anticoagulant that reduces both ischemic and bleeding complications associated with percutaneous coronary intervention (PCI). Bivalirudin is easy to use, provides predictable anticoagulation, inactivates both free and clot-bound thrombin, and blocks thrombin-mediated platelet activation and aggregation. Drug-drug interaction studies have found no clinically relevant interactions between bivalirudin and ticlopidine, abciximab, tirofiban, or eptifibatide. Bivalirudin is well tolerated by patients who previously received low-molecular-weight heparin (LMWH), when LMWH is discontinued 8-14 hours before bivalirudin is started. Similarly, switching from heparin to bivalirudin at the time of PCI reduces both ischemic and bleeding events.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clinical Trials as Topic; Coronary Thrombosis; Drug Interactions; Fibrinolytic Agents; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombocytopenia; Ticlopidine

In a large phase III study of patients with unstable angina treated with percutaneous transluminal coronary angioplasty (PTCA), the thrombin-specific anticoagulant bivalirudin produced relative risk reductions of 22% (p = 0.039) for ischemic complications and 62% (p < 0.001) for bleeding complications compared with heparin. Subsequent reports have shown that between-treatment differences favoring fewer complications with bivalirudin also extend to high-risk patients. Early heparinization promotes heparin resistance and decreases activated clotting time achieved during PTCA. These effects are relevant to patients with postinfarction angina, which is associated with a greater likelihood of early vessel closure and procedural failure. In 1006 patients with one or both of these risk factors, bivalirudin significantly reduced combined ischemic and bleeding complications compared with heparin (8.6% vs 18%, p < 0.001). Treatment separations favoring bivalirudin increased with risk, suggesting decreased heparin effectiveness in patients at heightened risk. Findings in three additional risk groups-women, the elderly, and patients not receiving glycoprotein IIb/IIIa inhibitors-also showed fewer complications with bivalirudin therapy. Preliminary data suggest that bivalirudin can be combined safely with glycoprotein IIb/Illa antagonists in percutaneous coronary intervention (PCI), including PTCA. An ongoing trial is aimed at determining the efficacy and safety of heparin with planned glycoprotein IIb/IIIa therapy versus bivalirudin with provisional glycoprotein IIb/IIIa therapy. The use of bivalirudin in patients with heparin-induced thrombocytopenia also is being evaluated after favorable findings in early compassionate-use studies. The fact that between-treatment differences favoring bivalirudin were especially outstanding among the high-risk patients considered in this review reinforces the impression that bivalirudin is a promising and unprecedented alternative to heparin in PCI.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clinical Trials as Topic; Drug Therapy, Combination; Female; Heparin; Hirudins; Humans; Male; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Renal Insufficiency; Sex Factors

Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin-lepirudin-has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.

Topics: Angina, Unstable; Clinical Trials as Topic; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Thrombocytopenia

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

This review focuses on the use of bivalirudin as a replacement anticoagulant for heparin in patients undergoing percutaneous coronary intervention, or who are being treated for unstable angina pectoris, ST-elevation, or non-ST-elevation myocardial infarction. Potential advantages of bivalirudin include a lack of dependence on antithrombin III for anticoagulant activity, the ability to inactivate both fibrin-bound and soluble thrombin, a lack of aggregatory effects on platelets, a predictable anticoagulant response without monitoring, and a wider therapeutic window. Clinical trial results to date suggest that bivlirudin is at least as effective as heparin with superior safety due to lower bleeding rates.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials as Topic; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins

The goals of therapy for unstable angina and non-Q-wave myocardial infarction (MI) are to maintain myocardial perfusion by inhibiting platelet aggregation and fibrin deposition at sites of plaque rupture, thereby preventing ongoing or new myocardial ischemia and cardiac death. Although aspirin and heparin sodium are cornerstones in the management of unstable angina and non-Q-wave MI, both have significant limitations that have prompted the development of new agents. The thienopyridines, ticlopidine hydrochloride and clopidogrel, appear to be at least as effective as aspirin in the management of unstable angina. Glycoprotein IIb/IIIa receptor antagonists are a new class of platelet inhibitors that are more potent than aspirin, because they target the final common pathway of platelet aggregation. Low-molecular-weight heparins provide a more stable pharmacodynamic response and are more convenient to use than unfractionated heparin. Direct thrombin inhibitors show promise for inhibiting thrombin-mediated platelet aggregation and fibrin deposition. We focus on the opportunities presented by these agents, detailing mechanisms of action, advantages over aspirin and heparin, and performance in recent clinical trials.

Topics: Angina, Unstable; Antithrombins; Clopidogrel; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Thromboxane; Recombinant Proteins; Thromboxane-A Synthase; Ticlopidine

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Controlled Clinical Trials as Topic; Coronary Thrombosis; Dose-Response Relationship, Drug; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombolytic Therapy

Revascularization procedures and particularly percutaneous transluminal coronary angioplasty are being performed more and more often in patients with unstable coronary artery disease, despite the fact that these procedures are known to carry a higher risk in such patients than in those with stable disease. This article reviews studies that have investigated the potential of modern antithrombotic therapy -- low-molecular-weight heparin, anti-Xa agents, direct antithrombin inhibitors and glycoprotein IIb/IIIa inhibitors -- to reduce the post-procedural event rate in such patients. The results are promising.

Topics: Abciximab; Angina, Unstable; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Aspirin; Clinical Trials as Topic; Combined Modality Therapy; Diabetes Complications; Drug Therapy, Combination; Eptifibatide; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Immunoglobulin Fab Fragments; Myocardial Revascularization; Oligosaccharides; Peptide Fragments; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Thrombocytopenia; Thrombosis; Time Factors; Tirofiban; Treatment Outcome; Tyrosine

Plaque rupture has been thought to cause acute coronary syndrome. To manage the patients with unstable angina, it is necessary to understand the patients' pathophysiology. Based on the classification of unstable angina, initial medical treatment including aspirin and oral isosorbide dinitrate should be started immediately after admission. Ca antagonist and beta-blocking agent should be added according to the symptoms. If ischemic symptoms continue after administration of those oral medical treatments, intravenous nitroglycerin and heparin should be started. K channel opener (nicorandil) may be effective to stabilize the symptom. However, high-risk patients should immediately receive coronary angiography to decide further medical or interventional therapy.

Topics: Angina, Unstable; Anticoagulants; Aspirin; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

The goal of anticoagulant therapy in unstable angina is to prevent progression of a subocclusive coronary thrombus to complete occlusion of the coronary artery, thereby preventing myocardial infarction and death. Although these have been many advances in therapy with anticoagulants, considerable morbidity and mortality remains. Also, although combination therapy with potent novel anticoagulants and antiplatelet agents may be an alternative strategy, this needs to be balanced against the risks of hemorrhagic complications. More precise and biologically relevant methods of monitoring anticoagulant effect, along with appropriately modified doses given in combination offers promise.

Topics: Angina, Unstable; Anticoagulants; Antithrombins; Arginine; Clinical Trials as Topic; Coronary Thrombosis; Disease Progression; Heparin; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Warfarin

Antithrombotic and antiplatelet agents, particularly unfractionated heparin and aspirin, are longstanding therapeutic mainstays for acute coronary syndromes such as unstable angina and non-Q-wave myocardial infarction (MI). Early studies demonstrated that aspirin reduces the risk of mortality or nonfatal MI by 50-70% in patients presenting with unstable angina or non-Q-wave MI. Added to aspirin, heparin regimens further diminish the incidence of these myocardial ischemic events in the acute setting. Three major clinical studies demonstrated that such enhanced risk reductions can be achieved without significant increases in bleeding complications. The low-molecular-weight (LMW) heparin, dalteparin, proved superior to placebo but not unfractionated heparin in diminishing the incidence of (1) death or MI; (2) death, MI, or recurrence of angina; or (3) frequency of revascularization procedures. On the other hand, another LMW heparin, enoxaparin, did reduce these events at 14 and 30 days, as well as 1 year after treatment. The principal biophysical limitation of heparins, however, is that they cannot inactivate clot-bound thrombin, which probably contributes to morbidity and mortality in acute coronary syndromes. The natural leech-derived polypeptide hirudin and its derivatives (e.g., lepirudin) inactivate both fibrin-bound and free thrombin. Lepirudin has been approved in certain countries for the treatment of heparin-induced thrombocytopenia and is now being evaluated in the clinical management of acute myocardial ischemic syndromes. The well-documented pathophysiologic foundation for acute coronary syndromes is partial or intermittent thrombotic occlusion of a coronary artery as the result of atherosclerosis. Although a stable atherosclerotic plaque may not be clinically problematic, plaque rupture, which occurs under a variety of stimuli, touches off a cascade of enzymatic and cellular responses that frequently culminate in thrombotic occlusion. In the coronary circulation, such an occlusion may cause transmural MI, unstable angina, or non-Q-wave MI. Because the pathogenetic mechanisms of atherosclerosis with thrombotic complications have been elucidated, this knowledge can be translated into a rational clinical approach using antithrombotic therapies.

Topics: Acute Disease; Angina, Unstable; Anticoagulants; Aspirin; Clinical Trials as Topic; Coronary Disease; Dalteparin; Enoxaparin; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Recombinant Proteins

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

Hirudin and its derivatives represent the first parenteral anticoagulants introduced since the discovery of heparin in the early 1900s. Hirudin, the naturally occurring anticoagulant of the leech, is a single peptide chain of 65 amino acids with a molecular weight of about 7000. Recombinant technology has developed methods to produce recombinant forms of hirudin (r-hirudin) in sufficient quantities for therapeutic use. Hirudin is a potent thrombin-specific inhibitor that forms equimolar complexes with thrombin. It represents a new anticoagulant agent in a field in which heparin has been the only available drug for many years. In contrast to heparin, hirudin does not require antithrombin III as a cofactor, is not inactivated by antiheparin proteins, has no direct effects on platelets and may also inactivate thrombin bound to clot or the subendothelium. In humans, experience with r-hirudin in preventing or treating venous thromboembolism is very preliminary. However, r-hirudin achieved promising results in patients with unstable angina, or following coronary angioplasty. In patients with acute myocardial infarction, 3 important clinical trials were stopped because of an excess of bleeding complications. At present, the discovery of a r-hirudin regimen that is more efficacious than heparin and at least as safe needs a reappraisal of the drug in further trials.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Thrombolytic Therapy; Thrombophlebitis

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Antithrombin III; Clinical Trials as Topic; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Thrombin; Thrombolytic Therapy

The central role of thrombosis in the pathogenesis of acute myocardial infarction, unstable angina and complications after angioplasty has led to intense interest in developing more effective antithrombotic agents for these disorders. Hirudin, a direct thrombin inhibitor, has undergone extensive testing in experimental models and has recently been evaluated in patients in several pilot trials. Across these three indications, hirudin has been found to achieve a more consistent level of anticoagulation than heparin, as gauged by the activated parital thromboplastin time. Similarly, as an adjunct to thrombolytic therapy in acute myocardial infarction, in the treatment of unstable angina and in support of angioplasty, hirudin appeared to improve indexes of coronary reperfusion and patency. Initial results with clinical end points, including death or myocardial infarction, appeared to favor hirudin over heparin. In several large phase III trials, hirudin is being compared with heparin for all three indications. In the first phases of these trials, the rate of hemorrhagic events, including intracranial hemorrhage, was higher than expected in both the hirudin and heparin arms, which demonstrated that a safety ceiling had been reached. The reformulated Thrombolysis in Myocardial Infarction (TIMI) 9 and Second Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO II) trials are using lower doses of hirudin and heparin, which should allow testing of whether the initial favorable results observed in pilot trials will translate into improved clinical outcome, with an acceptable safety profile, for patients with acute myocardial infarction or unstable angina or those undergoing angioplasty.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Thrombosis; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Thrombolytic Therapy

The initiating event in unstable angina is plaque rupture. It triggers platelet activation and aggregation, leading to the formation of an intracoronary thrombus, which can be detected on autopsy, angiography, and by fiber-optic coronary angioscopy. Biochemical markers of platelet and thrombin activity are usually increased and support the pathophysiologic role of coronary thrombosis in unstable angina. Aspirin and heparin have been shown to be effective, whereas thrombolytic therapy has no beneficial clinical effect. Newer specific antithrombotic drugs (hirudin, hirulog) and GPIIb/IIIa platelet receptor inhibitors are being tested in clinical trials and seem to provide a new dimension for the treatment of acute coronary syndromes.

Topics: Angina, Unstable; Blood Coagulation Disorders; Coronary Thrombosis; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Recombinant Proteins; Thrombin

Most of the clinical evaluation of the direct thrombin inhibitors has been in coronary artery disease. The recent clinical reports suggest that there is a narrower window of safety with recombinant hirudin than initially thought particularly when it is used in conjunction with thrombolytic agents and aspirin in acute myocardial infarction. The efficacy data, however, indicate that the direct thrombin inhibitors have great potential particularly in the initial management of patients with acute unstable angina and non-Q-wave infarction. There is much to learn regarding the mechanism of action, optimal dose, and optimal concomitant therapy in the use of direct thrombin inhibitors in the management of acute coronary ischaemia; and since hirudin and other direct thrombin inhibitors have so much potential in the management of acute coronary ischaemia, it is critical that dose-finding studies be performed to determine safe regimens of these agents to allow their evaluation in large-scale trials with important clinical outcomes. The direct thrombin inhibitors have also shown to have promise in the prevention of deep vein thrombosis in high-risk surgical patients. There is limited clinical data on the other novel anticoagulants which are currently being developed.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Aspirin; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Design; Drug Therapy, Combination; Enzyme Activation; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Hirudin Therapy; Hirudins; Humans; Lipoproteins; Myocardial Infarction; Myocardial Ischemia; Peptide Fragments; Platelet Aggregation Inhibitors; Postoperative Complications; Protein C; Randomized Controlled Trials as Topic; Recombinant Proteins; Thrombolytic Therapy; Thrombophlebitis; Treatment Outcome

Recombinant hirudin and hirudin analogues constitute interesting new antithrombotic agents that have distinct advantages over heparin. These agents specifically inhibit thrombin and all of its actions and also suppress further thrombin generation. As opposed to unfractionated heparin, hirudin and hirulog effectively suppress clot-bound thrombin, making these agents of particular interest in the treatment of arterial thrombosis, for example, following thrombolysis or percutaneous transthoracic angioplasty. The recent data derived from clinical trials supporting the use of hirudin and hirulog in the prevention and treatment of thrombotic diseases are reviewed here.

Topics: Angina, Unstable; Anticoagulants; Cardiovascular Diseases; Clinical Trials as Topic; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Thrombolytic Therapy

Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown.. We enrolled 4570 patients with stable or unstable angina (with normal levels of troponin T and creatine kinase MB) who were undergoing PCI after pretreatment with a 600-mg dose of clopidogrel at least 2 hours before the procedure; 2289 patients were randomly assigned in a double-blind manner to receive bivalirudin, and 2281 to receive unfractionated heparin. The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization.. The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P=0.57). The secondary end point occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P=0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P=0.008).. In patients with stable and unstable angina who underwent PCI after pretreatment with clopidogrel, bivalirudin did not provide a net clinical benefit (i.e., it did not reduce the incidence of the composite end point of death, myocardial infarction, urgent target-vessel revascularization, or major bleeding) as compared with unfractionated heparin, but it did significantly reduce the incidence of major bleeding. (ClinicalTrials.gov number, NCT00262054.)

Topics: Aged; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Clopidogrel; Double-Blind Method; Female; Hemorrhage; Heparin; Hirudins; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Premedication; Recombinant Proteins; Recurrence; Risk; Stents; Thrombosis; Ticlopidine

The relation across anemia, hemorrhagic complications, and mortality associated with percutaneous coronary intervention (PCI) is unclear. We reviewed the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 Trial, which compared bivalirudin plus provisional glycoprotein IIb/IIIa blockade with heparin plus planned glycoprotein IIb/IIIa blockade in patients undergoing urgent or elective PCI. Of the 6,010 patients randomized in REPLACE-2, 1,371 (23%) were anemic. Major bleeding was more common in anemic than in nonanemic patients (4.9% vs 2.8%, p = 0.0001). In anemic patients, treatment with bivalirudin (n = 678) resulted in a lower risk of major bleeding versus heparin plus glycoprotein IIb/IIIa blockade (n = 693, 3.5% vs 6.2%, p = 0.0221). Mortality was higher in anemic patients than in nonanemic patients at 30 days (0.9% vs 0.2%, p <0.0001), 6 months (2.6% vs 0.7%, p <0.0001), and 1 year (4.3% vs 1.5%, p <0.0001). There were no differences between anemic and nonanemic patients with regard to ischemic complications at 30 days. Although anemic patients had higher mortality rates, proportions of cardiovascular and noncardiovascular mortalities were equal in anemic and nonanemic patients. In conclusion, anemic patients undergoing PCI have an increased risk of mortality and major bleeding, but not of ischemic events, and the use of bivalirudin with provisional glycoprotein IIb/IIIa blockade decreases the risk of hemorrhagic complications compared with heparin plus planned glycoprotein IIb/IIIa blockade.

Topics: Aged; Anemia; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Cause of Death; Double-Blind Method; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Hemorrhage; Predictive Value of Tests; Proportional Hazards Models; Recombinant Proteins; Research Design; Risk Factors; Treatment Outcome

Adverse events occur following non-ST elevation acute coronary syndromes (NSTE ACS). However, the timing of these events in relation to index event is less clear.. Accordingly, we evaluated 26,466 NSTE ACS patients from the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb), Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) A and B trials to ascertain the timing of adverse events. Outcomes of interest were death, myocardial infarction (MI), and death or MI at 180 days. Logistic regression modeling for death was used to categorize patients into low-, medium-, and high-risk groups.. At 6 months, 6.2% of patients died, 12.1% had MI, and 15.7% suffered death or MI. From 15% to 40% of these events occurred beyond 30 days. At 6 months, 3%, 4%, and 13% of patients died in low-, medium-, and high-risk groups, respectively. However, the proportion of patients dying beyond 30 days was similar in the three groups (44%, 43%, and 41% of death, respectively). Similarly, whereas death or MI increased with higher risk (11%, 14%, and 23%, respectively), the proportion of patients with this event beyond 30 days did not differ in the three strata (22%, 20%, and 25%, respectively).. Our study provides important insights into the timing of adverse events and suggests that the substantial proportion of patients suffer subsequent adverse events after their index NSTE ACS. Thus, these data call for continuous surveillance for these events and efforts beyond the acute phase at increasing adherence to evidence-based therapies to improve the outcomes of these patients.

Topics: Acute Disease; Aged; Angina, Unstable; Aspirin; Female; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Risk Assessment; Risk Factors; Survival; Time Factors

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

Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients.. We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding.. Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97).. In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].).

Topics: Adult; Aged; Aged, 80 and over; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Artery Bypass; Drug Therapy, Combination; Enoxaparin; Female; Hemorrhage; Heparin; Hirudins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins

Patients with acute coronary syndromes (ACS; unstable angina and non-ST-segment elevation myocardial infarction) are at significant risk for death and myocardial infarction. Early angiography followed by revascularization is considered the treatment of choice for moderate- to high-risk patients with ACS. However, despite the integration of newer therapies including stents, glycoprotein IIb/IIIa inhibitors, and thienopyridines, the rate of adverse ischemic events still remains unacceptably high, and the intensive pharmacologic regimens used to stabilize the disrupted atherosclerotic plaque and support angioplasty and surgical revascularization procedures elicit a high rate of bleeding complications. Pilot trials suggest that the thrombin-specific anticoagulant bivalirudin may improve clinical outcomes in ACS.. In the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial, 13,800 patients with moderate- to high-risk ACS are being prospectively randomly assigned at up to 600 centers to unfractionated heparin or enoxaparin + IIb/IIIa inhibition, versus bivalirudin + IIb/IIIa inhibition, versus bivalirudin + provisional IIb/IIIa inhibition. All patients undergo cardiac catheterization within 72 hours, followed by percutaneous or surgical revascularization when appropriate. In a second random assignment, patients assigned to receive IIb/IIIa inhibitors are subrandomized to upstream drug initiation, versus IIb/IIIa inhibitor administration during angioplasty only. The primary study end point is the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. Clinical follow-up will continue for 1 year.. The ACUITY trial is the largest study yet performed in patients with ACS undergoing an invasive strategy. In addition to evaluating the utility of bivalirudin in ACS, this study will also provide important guidance regarding the necessity for and timing of IIb/IIIa inhibitor administration.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Cardiac Catheterization; Combined Modality Therapy; Coronary Artery Bypass; Enoxaparin; Heparin; Hirudins; Humans; Multicenter Studies as Topic; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design

Topics: Aged; Angina, Unstable; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Endopeptidases; Female; Fibrinolytic Agents; Hirudins; Humans; Male; Peptide Fragments; Point-of-Care Systems; Prothrombin; Recombinant Proteins; Whole Blood Coagulation Time

The Thrombolysis in Myocardial Infarction (TIMI) 8 trial was undertaken to compare the efficacy and safety of bivalirudin versus unfractionated heparin in a double-blind phase III trial of patients with unstable angina/non-ST-elevation myocardial infarction (MI).. All patients received aspirin and were randomized either to unfractionated heparin (bolus of 70 U/kg followed by an infusion of 15 U/kg/h) or bivalirudin (bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/h) for a minimum of 72 hours. The primary efficacy end point was a composite of all cause mortality or nonfatal recurrent MI.. A total of 133 of the planned 5320 patients were enrolled, at which point the study was terminated by the sponsor because of a decision at the time to suspend further development of bivalirudin. Through 14 days, the incidence of death or nonfatal MI was 9.2% in the 65 patients in the unfractionated heparin group and was 2.9% in the 68 patients in the bivalirudin group, odds ratio (95% CI) 0.30 (0.06-1.53). Major hemorrhage occurred in 3 patients in the unfractionated heparin group (4.6%) but in none of the patients in the bivalirudin group (P =.11).. The trend toward a lower rate of death or nonfatal MI in the bivalirudin group is consistent with a therapeutic effect of the drug and is consistent with other trials of bivalirudin in patients with acute coronary syndromes. The potential for clinically meaningful antithrombotic activity without an increased risk of bleeding and availablility of an alternative anticoagulation strategy in patients who cannot tolerate unfractionated heparin are particularly attractive and underscore the need for further evaluation of bivalirudin.

Topics: Aged; Angina, Unstable; Anticoagulants; Antithrombins; Double-Blind Method; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Myocardial Infarction; Odds Ratio; Peptide Fragments; Recombinant Proteins; Recurrence

We sought to evaluate whether oral anticoagulant (AC) therapy given for five months was superior to standard (control) therapy in patients with unstable angina receiving aspirin.. The long-term risk of myocardial infarction (MI) or death remains high in patients with unstable angina, despite the use of aspirin. Therefore, additional treatments are necessary.. Of the 10,141 patients entering the main trial, 3,712 were randomized 12 to 48 h later to receive oral AC therapy (n = 1,848) or standard therapy (n = 1,864).. One-hundred forty patients (7.6%) suffered from cardiovascular death, MI or stroke while receiving oral AC, compared with 155 patients (8.3%) on standard therapy (relative risk [RR] 0.90, 95% confidence interval [CI] 0.72 to 1.14; p = 0.40). The rates of the primary outcomes plus refractory angina were 16.7% (n = 308) versus 17.5% (n = 327) (RR 0.95, 95% CI 0.81 to 1.11; p = 0.53). Countries were divided into good or poor compliers (based on the use of oral AC above or below 70% at 35 days), without knowledge of results by country. In good-complier countries, oral AC was discontinued in only 10.4% of patients at seven days and in 23.6% by five months, compared with 27.6% and 44.9%, respectively, in poor complier countries. There were significant reductions in the risks of both the primary (6.1% vs. 8.9%; RR 0.68, 95% CI 0.48 to 0.95; p = 0.02) and secondary outcomes (11.9% vs. 16.5%; RR 0.70, 95% CI 0.55 to 0.90; p = 0.005) with oral AC in the good-complier countries. There was little difference in the poor-complier countries (9.0% vs. 7.8% for the primary and 21.3% vs. 18.5% for the secondary outcomes, tests for interactions comparing the RRs for the primary and secondary outcomes were p < 0.02 and p = 0.002, respectively, between the two sets of countries). In the overall study, there was an excess of major bleeding (2.7% vs. 1.3%; p = 0.004), which was larger in the good-complier countries (RR 2.71) compared with the poor-complier countries (RR 1.58). There were also reductions in cardiac catheterization (RR 0.80; p = 0.004) and coronary revascularization procedures (RR 0.82; p = 0.06) in the good-complier countries, but not in the poor-complier countries (RR 0.98 and 1.06, respectively, p for interaction of 0.06 and 0.04, respectively).. Overall, oral AC led to a small, nonsignificant reduction in the risk of the primary and secondary outcomes. Stratifying the countries or centers by their rates of compliance to oral AC suggested that good compliance to oral AC could potentially lead to clinically important reductions in major ischemic cardiovascular events.

Topics: Administration, Oral; Adult; Aged; Angina, Unstable; Anticoagulants; Aspirin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Heparin; Hirudins; Humans; Long-Term Care; Male; Middle Aged; Myocardial Infarction; Survival Rate

Novel antithrombotic agents such as hirudin have shown promise in the therapy of acute coronary syndromes. PEG-hirudin (polyethyleneglycol conjugated hirudin) has been developed to provide a longer plasma half-life and more stable antithrombotic plasma levels. Privious trials indicated a narrow therapeutic window for hirudin and a number of aPTT (activated partial thromboplastin time)-monitored trials investigating hirudin in acute coronary syndromes had to be stopped because of intracranial bleeding complications.. The present study evaluates the ecarin clotting time (ECT), a parameter based on the conversion of prothrombin by the snake venom enzyme ecarin, for the monitoring of PEG-hirudin therapy.. Plasma from either healthy volunteers (n=20) or from patients (n=10) suffering from unstable angina pectoris (UAP) was spiked with increasing PEG-hirudin concentrations. In a prospective randomized clinical trial patients with UAP were treated with intravenous PEG-hirudin or heparin over 72 hours. Patients were randomized to the following treatment groups: (1) heparin control group, n=15; (2) PEG-hirudin low dose (0.1 mg/kg bolus, 0.01 mg/kg/h infusion), n=19; (3) intermediate dose (0.15 mg/kg and 0.015 mg/kg/h), n=17; 4) high-dose (0.2 mg/kg and 0.02 mg/kg/h), n=16. Spiked plasma samples and plasma from UAP patients treated with i.v. PEG-hirudin were analyzed for aPTT, ECT, and PEG-hirudin levels.. A linear correlation up to the highest therapeutic concentrations could be observed between PEG-hirudin plasma concentrations and the ECT. This was true for both plasma samples spiked with PEG-hirudin in vitro as well as for samples taken from patients treated with i.v. PEG-hirudin (correlation coefficient 0.9, respect.) In contrast the aPTT did not show a reliable linear correlation to PEG-hirudin concentrations.. Monitoring of PEG-hirudin therapy by ECT may help to avoid inadequate anticoagulation or overdosing. Thus, the safety and efficacy profile of PEG-hirudin therapy is likely to be enhanced by ECT monitoring.

Topics: Angina, Unstable; Antithrombins; Blood Coagulation Tests; Drug Monitoring; Endopeptidases; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Partial Thromboplastin Time; Regression Analysis

We tested the hypothesis that different anticoagulant treatments may produce different platelet effects and von Willebrand factor (vWf) release in unstable angina.. The early increase of vWf has been reported to be a risk factor for adverse outcome in unstable angina. Anticoagulant drugs play a key role in stabilization of unstable angina, but they may not have the same efficacy and the same effects on acute vWf release.. We studied 154 patients enrolled in several clinical trials testing four different anticoagulant treatments in unstable angina or non-Q-wave myocardial infarction. Patients were treated during at least 48 h by either intravenous unfractionated heparin, one of two different low molecular weight heparins (enoxaparin or dalteparin) or the direct thrombin inhibitor PEG-hirudin. All patients received aspirin but no Ib/IIIa inhibitors.. The release of vWf over the first 48 h (delta vWf) did not relate to the baseline clinical characteristics. At 30 days of follow-up, delta vWf was sevenfold higher in patients with an end point (death, myocardial infarction, revascularization) than in patients free of events (+53 +/-7% vs. +7 +/-14%, p = 0.004). The same trend was present for each component of the composite end point with the highest levels for one-month mortality (+87 +/- 32% vs. +26 +/- 8%, p = 0.09). The vWf values did not increase over 48 h in patients receiving either enoxaparin or PEG-hirudin (+10 +/- 9% and -5 +/- 20%, respectively). A serious rise ofvWf was measured in unfractionated heparin-treated patients (+87 +/- 11%), which differed significantly from the enoxaparin group (p = 0.0006) and PEG-hirudin group (p < 0.0001). In dalteparin-treated patients, delta vWf was elevated (+48 +/- 8%) and did not differ from the unfractionated heparin group (NS).. We confirm that, in unstable angina patients, a rise of vWf over the first 48 h is associated with an impaired outcome at 30 days. Moreover, the four different anticoagulant treatments tested here do not provide the same protection with regards to vWf release, which may have important prognostic implications and explain different results observed in recent clinical trials.

Topics: Aged; Angina, Unstable; Anticoagulants; Antithrombins; Aspirin; Biomarkers; Blood Platelets; Dalteparin; Disease-Free Survival; Drug Administration Routes; Drug Therapy, Combination; Enoxaparin; Female; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Survival Rate; Treatment Outcome; von Willebrand Factor

To compare effects of heparin and hirudin on biochemical markers of coagulation.. Patients (n=395) with unstable angina or myocardial infarction without ST elevation were randomized to a 72-h infusion of one of three regimens: unfractionated heparin (bolus of 5000 IU followed by an infusion of 1200 IU. h(-1)), low-dose hirudin (HBW 023; 0.2 mg. kg(-1)bolus followed by 0.10 mg. kg(-1). h(-1)) or medium-dose hirudin (0.4 mg. kg(-1)bolus followed by 0.15 mg. kg(-1). h(-1)). Infusions were adjusted to maintain an activated partial thromboplastin time of between 60-100 s. Activated partial thromboplastin time, prothrombin fragment 1.2 (F1.2), thrombin antithrombin III complex and D-dimer were measured before, during and after the infusion. Median activated partial thromboplastin time was similar in the two groups early on, but was significantly lower in the heparin group than in the combined hirudin group 48 h after starting the infusion (53 s and 75 s, respectively;P<0.001), and 6 h after stopping (31 s and 46 s, respectively;P<0.001). Median F1.2 levels were not significantly different between the groups during the infusion. Median thrombin antithrombin III levels in the heparin and hirudin groups were 2.8 microg. l(-1)and 2.3 microg. l(-1), respectively, at 6 h (P<0.001), and 3.0 microg. l(-1)and 2.3 microg. l(-1), respectively, at 48 h (P<0.001). Median D-dimer levels were 320 ng. ml(-1)and 260 ng. ml(-1)48 h after starting the infusion in the heparin and hirudin groups, respectively (P<0.001), and 415 ng. ml(-1)and 280 ng. ml(-1), respectively (P<0.001) 6 h after stopping. D-dimer levels were significantly elevated above baseline values in both groups 24-48 h after stopping the infusions.. The greater reduction of thrombin antithrombin III and D-dimer during the hirudin infusion supports the hypothesis that hirudin is a more potent antithrombin agent than heparin. Increased D-dimer levels after stopping heparin or hirudin suggest that there is an ongoing pro-coagulant state. These results point to the greater efficacy of hirudin in preventing early clinical events (death, myocardial infarction and refractory ischaemia) compared with heparin that have been observed in large randomized trials. Persistent activation of coagulation afterstopping infusions in our study suggests that a longer course of antithrombotic treatment may be needed to pacify the thrombus.

Topics: Angina, Unstable; Anticoagulants; Antithrombin III; Antithrombins; Biomarkers; Blood Coagulation; Canada; Drug Administration Schedule; Electrocardiography; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Peptide Fragments; Prothrombin; Recombinant Proteins

In patients with unstable angina, intravenous heparin reduces thrombin activity but does not influence thrombin generation. Recombinant hirudin, a direct thrombin inhibitor, may be more effective in inhibiting both thrombin generation and activity. We measured the plasma levels of prothrombin fragment 1+2 (a marker of thrombin generation) and fibrinopeptide A (a marker of thrombin activity) in 67 patients with unstable angina enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial who were receiving either recombinant hirudin (31 patients) or heparin (36 patients). Blood samples were obtained at baseline (before any treatment), after 3 to 5 days of study drug infusion (immediately before discontinuation), and 1 month later. In the patients receiving recombinant hirudin, the prothrombin fragment 1+2 levels measured immediately before drug discontinuation were significantly lower than at baseline (P:=0.0014), whereas they had not changed in the patients receiving heparin; at this time point, the difference between patients receiving hirudin and those receiving heparin was statistically significant (P:=0.032). One month later, the prothrombin fragment 1+2 levels in both groups were similarly persistently high and did not differ from baseline. Fibrinopeptide A plasma levels at the end of infusion were significantly lower than at baseline in both treatment groups (P:=0. 0005 for hirudin and P:=0.042 for heparin) and remained lower after 1 month (P:=0.0001 for both hirudin and heparin). The fibrinopeptide A plasma levels were not different between patients treated with hirudin versus heparin at baseline, at the end of infusion, and after 1 month. Thus, in patients with unstable angina, in vivo thrombin generation and activity are reduced during intravenous infusion of recombinant hirudin. However, the inhibition of thrombin generation is not sustained, and after 1 month, the majority of patients have biochemical signs of increased thrombin generation.

Topics: Aged; Angina Pectoris; Angina, Unstable; Female; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Middle Aged; Recombinant Proteins; Thrombin

The objective of this study was to identify predictors of major adverse cardiac events after successful coronary angioplasty.. The acute complications of angioplasty are related to baseline clinical and angiographic variables, and early complications adversely affect long-term outcome. However, the predictors of enduring success after uncomplicated angioplasty are less well defined.. Of 4,098 patients undergoing angioplasty in the Hirulog Angioplasty Study, 3,899 (95%) had a successful procedure without in-hospital death, emergent bypass surgery or clinical evidence of myocardial infarction. Baseline and procedural variables for these 3,899 patients were examined.. Major adverse cardiac events occurred in 22% of the patients with initially successful procedures at 6 months: death in 1%, myocardial infarction in 2% and repeat revascularization in 21%. Univariable predictors of increased events included successful salvage from abrupt vessel closure (p < 0.001), emergency stenting (p < 0.001), multilesion angioplasty (p < 0.001), diabetes (p=0.02), target lesion in the left anterior descending artery (p=0.02), unstable angina (p=0.03) and smaller final luminal diameter (p=0.04). There was a trend toward increased events among patients with prior angioplasty (p=0.08), but asymptomatic elevation of the creatine kinase was not predictive (p=0.5). In a multivariable model, abrupt vessel closure was the strongest independent predictor of major adverse cardiac events at 6 months (p < 0.001; odds ratio [95% confidence interval]=3.6 [2.5 to 5.1]), while multivessel angioplasty, target lesion in the left anterior descending artery and diabetes also remained independent predictors (all p < or = 0.02).. This analysis suggests that "uncomplicated" abrupt vessel closure is a powerful predictor of adverse clinical outcome following successful angioplasty. Improved techniques to reduce abrupt closure during angioplasty are thus urgently needed, and patients who experience "uncomplicated" closure require closer surveillance during follow-up.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Female; Follow-Up Studies; Heparin; Hirudins; Hospital Mortality; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Recurrence; Stents; Survival Rate

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Female; Follow-Up Studies; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Recurrence; Stents; Survival Rate; Treatment Outcome

Despite the use of heparin and aspirin, 5-10% of patients with unstable angina develop myocardial infarction or refractory angina in hospital. We tested the hypothesis that recombinant hirudin (lepirudin), a direct thrombin inhibitor, would be superior to heparin, an indirect thrombin inhibitor, in patients with acute ischaemic syndromes who were receiving aspirin.. 10,141 patients with unstable angina or suspected acute myocardial infarction without ST elevation were randomly assigned heparin (5000 units bolus then 15 units kg(-1) h(-1); n=5058) or hirudin (0.4 mg/kg bolus then 0.15 mg kg(-1) h(-1) infusion; n=5083) for 72 h in a double-blind trial. The primary outcome measure was cardiovascular death or new myocardial infarction at 7 days. Analysis was by intention to treat.. At 7 days, 213 (4.2%) patients in the heparin group and 182 (3.6%) in the hirudin group had experienced cardiovascular death or new myocardial infarction (relative risk 0.84 [95% CI 0.69-1.02]; p=0.077). The numbers with cardiovascular death, new myocardial infarction, or refractory angina at 7 days were 340 (6.7%) with heparin and 284 (5.6%) with hirudin (0.82 [0.70-0.96]; p=0.0125). These differences were primarily observed during the 72 h treatment period (cardiovascular death or myocardial infarction relative risk 0.76 [0.59-0.99], p=0.039: cardiovascular death, myocardial infarction, or refractory angina 0.78 [0.63-0.96], p=0.019). Although there was an excess of major bleeding requiring transfusion with hirudin (59 [1.2%] vs 34 [0.7%] with heparin; p=0.01), there was no excess in life-threatening episodes (20 in each group) or strokes (14 in each group).. The data from OASIS-2 suggest that recombinant hirudin is superior to heparin in preventing cardiovascular death, myocardial infarction, and refractory angina with an acceptable safety profile in patients with unstable angina or acute myocardial infarction without ST elevation. Thus, a direct thrombin inhibitor is more effective than an indirect thrombin inhibitor.

Topics: Angina, Unstable; Cardiovascular Diseases; Double-Blind Method; Electrocardiography; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Recombinant Proteins; Risk Factors; Treatment Outcome

Despite use of heparin and aspirin, 5-10% of patients with unstable angina develop myocardial infarction (MI) or refractory angina in the hospital. We tested the hypothesis that recombinant hirudin (lepirudin), a direct thrombin inhibitor, is superior to heparin, an indirect thrombin inhibitor, in patients with acute ischemic syndromes who were receiving aspirin. Patients (n = 10,141) with unstable angina or suspected acute MI without ST-segment elevation were randomly assigned heparin (5,000-U bolus, then 15-U/kg per hour infusion; n = 5,058) or hirudin (0.4-mg/kg bolus, then 0.15-mg/kg per hour infusion; n = 5,083) for 72 hours in a double-blind trial. The primary outcome measure was cardiovascular death or new MI at 7 days. Analysis was by intention to treat. At 7 days, 213 patients (4.2%) in the heparin group and 182 (3.6%) in the hirudin group had experienced cardiovascular death or new MI (relative risk = 0.84; 95% CI = 0.69-1.02; p = 0.077). The number of patients with cardiovascular death, new MI, or refractory angina at 7 days was 340 (6.7%) with heparin and 284 (5.6%) with hirudin (relative risk = 0.82; 95% CI = 0.70-0.96; p = 0.0125). These differences were primarily observed during the 72-hour treatment period (cardiovascular death or MI relative risk = 0.76; 95% CI = 0.59-0.99; p = 0.039; cardiovascular death, MI, or refractory angina relative risk = 0.78; 95% CI = 0.63-0.96; p = 0.019). Although there was an excess of major bleeding with hirudin requiring transfusion (59 [1.2%] vs 34 [0.7%] with heparin; p = 0.01), there was no excess in life-threatening episodes (20 in each group) or strokes (14 in each group). Data from the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-2 trial suggest that a direct thrombin inhibitor, recombinant hirudin, is more effective than an indirect thrombin inhibitor, heparin, in preventing cardiovascular death, MI, or refractory angina. Recombinant hirudin also has an acceptable safety profile in patients with unstable angina or acute MI without ST-segment elevation.

Topics: Adult; Angina, Unstable; Anticoagulants; Aspirin; Death, Sudden, Cardiac; Double-Blind Method; Drug Administration Schedule; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Recurrence; Risk; Treatment Outcome

The objectives of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (phase 2) were (1) to compare the efficacy, safety, and feasibility of recombinant hirudin versus unfractionated heparin as short-term therapy in patients with acute coronary syndromes without ST elevation and (2) to compare the efficacy and safety of long-term therapy with warfarin and aspirin versus standard therapy with aspirin alone in the same patient population. Investigators at 31 Canadian centers randomized 909 patients to receive either medium-dose hirudin, low-dose hirudin, or unfractionated heparin. The incidence of the 7-day primary composite outcome of cardiovascular death, new myocardial infarction (MI), or refractory angina was significantly lower among patients who received hirudin than among those assigned to unfractionated heparin. A subset of these patients was subsequently randomized to long-term, low-intensity (international normalized ratio [INR] < 1.5) or moderate-intensity (INR 2-2.5) anticoagulant treatment with warfarin or to standard therapy. In this substudy, promising results were observed in favor of moderate-intensity warfarin. These findings provided the rationale for the design and conduct of the large-scale, phase III OASIS-2 trial.

Topics: Acute Disease; Aged; Angina, Unstable; Anticoagulants; Aspirin; Canada; Death, Sudden, Cardiac; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Electrocardiography; Feasibility Studies; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Pilot Projects; Recombinant Proteins; Recurrence; Registries; Treatment Outcome; Warfarin

Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies.. In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5+/-0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1. 66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5. 1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.004).. Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.

Topics: Administration, Oral; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Aspirin; Coronary Artery Bypass; Electrocardiography; Hemorrhage; Hirudins; Humans; Infusions, Intravenous; Myocardial Infarction; Myocardial Ischemia; Patient Compliance; Pilot Projects; Platelet Aggregation Inhibitors; Warfarin

Percutaneous transluminal coronary angioplasty is often complicated by thrombotic abrupt vessel closure in patients with unstable angina pectoris. The present multicentre trial was performed to determine the feasibility of two-dose regimens of recombinant hirudin (r-hirudin) compared to standard heparin in patients undergoing coronary angioplasty for unstable angina, and to investigate the effects of the different treatment regimen on markers of coagulation activation. At five participating centres, 61 patients were randomly enrolled in one of two sequential groups of r-hirudin (group 1: 0.3 mg.kg-1 i.v. bolus, 0.12 mg.kg-1.h-1 i.v. infusion; 21 patients; group 2: 0.5 mg.kg-1 i.v. bolus, 0.24 mg.kg-1.h-1 i.v. infusion; 19 patients) or in a heparin control group (150 IU.kg-1 i.v. bolus, 20 IU.kg-1.h-1 i.v. infusion; 21 patients). Antithrombotic therapy was started immediately before coronary angioplasty and continued for 24 h. This was followed by a low-dose anticoagulant infusion for another 24 h (r-hirudin: 0.04 mg . kg-1 . h-1; heparin: 7 IU . kg-1 . h-1). Activated partial thromboplastin time, r-hirudin plasma concentrations by both immunological and functional assay, thrombin-hirudin complex, thrombin-antithrombin III complex, soluble fibrin, and prothrombin fragment 1 + 2 were closely monitored. The median partial thromboplastin time prolongations at 24 h vs baseline were found to be 1.9-fold and 2.3-fold in r-hirudin group 1 and dose group 2, respectively, and 3.0-fold in the heparin group. There was a dose-dependent correlation between partial thromboplastin time and the r-hirudin plasma levels (r = 0.61). In five of 21 patients of dose group 1, three of 19 patients of dose group 2, and 10/21 patients of the heparin group, partial thromboplastin time values exceeding the predefined target range prompted an interruption of the infusion. One major bleeding complication occurred in dose group 2. The functional assay for the estimation of r-hirudin plasma concentrations showed excellent correlations to the immunological technique (r = 0.99). Differences between the thrombin-hirudin complex levels could not be observed. Increased concentrations of thrombin-antithrombin III complex, soluble fibrin, and prothrombin fragment 1 + 2 were seen 4-8 h after coronary angioplasty and after reduction of the high-dose therapy in dose group 1 when compared with dose group 2 and the heparin group, respectively. Based on coagulation tests the present study showed the

Topics: Adult; Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Biomarkers; Blood Coagulation; Dose-Response Relationship, Drug; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Fibrinolytic Agents; Heparin; Hirudins; Humans; Infusions, Intravenous; Middle Aged; Partial Thromboplastin Time; Recombinant Proteins; Thrombin

Thrombin plays an important role in the pathogenesis of acute coronary thrombosis. We studied the effects of a direct thrombin inhibitor, recombinant desulfatohirudin, and heparin on plasma levels (at 0, 4, 12, and 24 hours) of fibrinopeptide A (FPA), which reflects thrombin action, and prothrombin fragment F1.2, which reflects thrombin generation, in patients with unstable angina.. Patients were randomized to one of two doses of heparin (n = 50) (target activated partial thromboplastin time, 65 to 90 seconds or 90 to 110 seconds) or one of four doses of r-hirudin (n = 113) (0.05, 0.10, 0.20, or 0.30 mg.kg-1.h-1 by infusion). r-Hirudin induced a dose-dependent decline in plasma FPA. At 24 hours, FPA levels with 0.1- to 0.3-mg.kg-1.h-1 r-hirudin regimens were significantly lower than with 0.05 mg.kg-1.h-1 r-hirudin; levels with 0.1- to 0.2-mg.kg-1.h-1 r-hirudin regimens were lower than with both heparin regimens. Plasma F1.2 did not decline significantly during therapy with heparin or hirudin except at 0.3 mg.kg-1.h-1 hirudin. At 24 hours, they were higher with the 0.05-mg.kg-1.h-1 r-hirudin regimen than with other regimens. For comparable levels of thrombin generation (F1.2 levels), FPA levels were higher in heparin patients than in hirudin patients. For the same FPA values, the corresponding F1.2 values were higher in the hirudin group.. Our findings provide evidence for distinct in vivo effects of the two agents and suggest that r-hirudin is a relatively more potent inhibitor of thrombin action but a less effective inhibitor of thrombin generation than heparin. The lower FPA levels in hirudin patients may reflect its ability to inactivate clot-bound thrombin. The relative clinical efficacies of the two agents need to be defined by clinical trials in progress.

Topics: Angina, Unstable; Antithrombin III; Coronary Angiography; Fibrinolytic Agents; Fibrinopeptide A; Heparin; Hirudin Therapy; Hirudins; Humans; Partial Thromboplastin Time; Peptide Fragments; Peptide Hydrolases; Prothrombin; Recombinant Proteins

This study was performed to evaluate the efficacy of peri-interventional treatment with recombinant hirudin (r-hirudin [HBW 023]) compared with heparin in the prevention of troponin T release in patients with unstable angina.. Percutaneous transluminal coronary angioplasty in patients with unstable angina is associated with a high risk of acute thrombotic complications.. Serial troponin T measurements were performed in 61 patients with unstable angina during the 48-h observation period after coronary angioplasty of the ischemia-related lesion. Patients were randomly assigned to peri-interventional intravenous treatment with either r-hirudin (dosage group I: 0.3-mg/kg body weight bolus, 0.12 mg/kg per h for 24 h; dosage group II: 0.5-mg/kg bolus, 0.24 mg/kg per h for 24 h) or heparin (150-IU/kg bolus, 20 IU/kg per h for 24 h). All patients received acetylsalicylic acid before coronary angiography. After 24 h, patients received a constant low dose infusion of either hirudin (0.04 mg/kg per h) or heparin (7 IU/kg per h) for another 24 h. The power of the study to detect a decrease in abnormal troponin T levels from 60% (heparin group) to 20% (combined r-hirudin groups) was 88%.. Serial troponin T measurements revealed two peaks within the 48 h after coronary angioplasty in the heparin but not the hirudin groups. An elevated serum troponin T concentration (> 0.2 ng/ml) within 48 h of coronary angioplasty was found in 9 (24%) of 38 patients in the hirudin groups (5 [25%] of 20 in dosage group I; 4 [22%] of 18 in dosage group II) compared with 11 (58%) of 19 in the heparin group (p = 0.01). We observed major cardiac events (death, myocardial infarction, abrupt vessel closure) in 1 (4.8%) of 21 patients in dosage group I, 1 (5.3%) of 19 in dosage group II and 3 (14.3%) of 21 in the heparin group (p = 0.33).. In this pilot trial, hirudin appears to be superior to heparin in preventing troponin T release after coronary angioplasty.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Coronary Angiography; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardium; Necrosis; Pilot Projects; Premedication; Recombinant Proteins; Thrombosis; Troponin; Troponin T

Direct thrombin inhibitors are a new class of drugs that may offer a more effective and potentially simpler alternative to heparin. Hirulog is a synthetic peptide based on the leech-derived compound hirudin and, like hirudin, is a highly specific, direct inhibitor of free and clot-bound thrombin.. TIMI 7 was a randomized, double-blind study of Hirulog, given with 325 mg/d aspirin to 410 patients with unstable angina. Patients received a constant infusion of Hirulog for 72 hours at one of four doses: 0.02 (n = 160), 0.25 (n = 81), 0.5 (n = 88), and 1.0 (n = 81) mg.kg-1.h-1. The primary efficacy end point was "unsatisfactory outcome," defined as death, nonfatal myocardial infarction (MI), rapid clinical deterioration, or recurrent ischemic pain at rest with ECG changes by 72 hours. Unsatisfactory outcome was not different among the four dose groups: 8.1%, 6.2%, 11.4%, and 6.2% (P = NS). However, the secondary end point of death or nonfatal MI through hospital discharge occurred in 10.0% of patients treated with 0.02 mg.kg-1.h-1 compared with 3.2% of patients treated with the three higher doses of Hirulog (0.25, 0.5, and 1.0 mg.kg-1.h-1, P = .008). Only 2 of 410 patients (0.5%) experienced a major hemorrhage attributed to Hirulog.. The direct thrombin inhibitor Hirulog is a promising new antithrombotic agent that deserves further study. The results of TIMI 7 lend support to the use of an antithrombin agent with aspirin in patients with unstable angina.

Topics: Adult; Aged; Angina, Unstable; Aspirin; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardial Revascularization; Peptide Fragments; Pilot Projects; Recombinant Proteins; Thrombin

The likelihood of restenosis is a major limitation of coronary angioplasty. We studied whether hirudin, a highly selective inhibitor of thrombin with irreversible effects, would prevent restenosis after angioplasty. We compared two regimens of recombinant hirudin with heparin.. We randomly assigned 1141 patients with unstable angina who were scheduled for angioplasty to receive one of three treatments: (1) a bolus dose of 10,000 IU of heparin followed by an intravenous infusion of heparin for 24 hours and subcutaneous placebo twice daily for three days (382 patients), (2) a bolus dose of 40 mg of hirudin followed by an intravenous infusion of hirudin for 24 hours and subcutaneous placebo twice daily for three days (381 patients), or (3) the same hirudin regimen except that 40 mg of hirudin was given subcutaneously instead of placebo twice daily for three days (378 patients). The primary end point was event-free survival at seven months. Other end points were early cardiac events (within 96 hours), bleeding and other complications of the study treatment, and angiographic measurements of coronary diameter at six months of follow-up.. At seven months, event-free survival was 67.3 percent in the group receiving heparin, 63.5 percent in the group receiving intravenous hirudin, and 68.0 percent in the group receiving both intravenous and subcutaneous hirudin (P = 0.61). However, the administration of hirudin was associated with a significant reduction in early cardiac events, which occurred in 11.0, 7.9, and 5.6 percent of patients in the respective groups (combined relative risk with hirudin, 0.61; 95 percent confidence interval, 0.41 to 0.90; P = 0.023). The mean minimal luminal diameters in the respective groups on follow-up angiography at six months were 1.54, 1.47, and 1.56 mm (P = 0.08).. Although significantly fewer early cardiac events occurred with hirudin than with heparin, hirudin had no apparent benefit with longer-term follow-up.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Cardiovascular Diseases; Coronary Disease; Disease-Free Survival; Double-Blind Method; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Recurrence; Regression Analysis

Heparin is often administered during and after coronary angioplasty to prevent closure of the dilated vessel. However, ischemic or hemorrhagic complications occur in 5 to 10 percent of treated patients. We studied whether these complications could be prevented when the direct thrombin inhibitor bivalirudin (Hirulog) was used in place of heparin.. We performed a double-blind, randomized trial in 4098 patients undergoing angioplasty for unstable or postinfarction angina. Patients were assigned to receive either heparin or bivalirudin immediately before angioplasty. The primary end point were death in the hospital, myocardial infarction, abrupt vessel closure, or rapid clinical deterioration of cardiac origin.. In the total study group, bivalirudin did not significantly reduce the incidence of the primary end point (11.4 percent, vs. 12.2 percent for heparin) but did result in a lower incidence of bleeding (3.8 percent vs. 9.8 percent, P < 0.001). In the prospectively stratified subgroup of 704 patients with postinfarction angina, bivalirudin therapy resulted in a lower incidence of the primary end point (9.1 percent vs. 14.2 percent, P = 0.04) and a lower incidence of bleeding (3.0 percent vs. 11.1 percent, P < 0.001), but in a similar cumulative rate of death, myocardial infarction, and repeated revascularization in the six months after angioplasty (20.5 percent vs. 25.1 percent, P = 0.17).. Bivalirudin was at least as effective as high-dose heparin in preventing ischemic complications in patients who underwent angioplasty for unstable angina, and it carried a lower risk of bleeding. Bivalirudin, as compared with heparin, reduced the risk of immediate ischemic complications in patients with postinfarction angina, but this difference was no longer apparent after six months.

Topics: Aged; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Double-Blind Method; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Ischemia; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Postoperative Complications; Recombinant Proteins; Serine Proteinase Inhibitors

Several new anticoagulants and antiplatelet agents have been developed for use in coronary angioplasty, but almost all have been associated with an increased incidence of bleeding complications. Hirulog, a direct thrombin inhibitor, has several theoretical advantages over heparin. It is unclear, however, whether the use of hirulog as a substitute for heparin in angioplasty would result in a higher incidence of bleeding or other side effects. The safety profile of hirulog was compared with that of heparin in a randomized, double-blind trial in 4312 patients who were scheduled to undergo angioplasty for unstable or postinfarction angina. The goal of anticoagulation was to achieve an activated clotting time of approximately 350 seconds with hirulog (bolus dose of 1.0 mg/kg body weight followed by a 4-hour infusion of 2.5 mg/kg per hour and a 14- to 20-hour infusion of 0.2 mg/kg per hour) or heparin (bolus dose of 175 units/kg followed by an 18- to 24-hour infusion of 15 units/kg per hour). Adverse events were recorded prospectively by study personnel and confirmed independently by clinical monitors blinded to treatment assignment. Compared with heparin in an intention-to-treat analysis, hirulog therapy was associated with either equivalent or lower rates of side effects. Most of the side effects of hirulog and heparin were related to hemorrhagic complications such as intravascular puncture site hemorrhage (29.1% vs 61.6%; p < 0.001), hematuria (16.6% vs 20.6%; p = 0.001), bleeding requiring red cell transfusion (3.7% vs 8.6%; p < 0.001), or hematemesis (0.8% vs 1.9%; p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Prospective Studies; Recombinant Proteins; Safety; Time Factors

Coronary artery thrombosis plays an important pathophysiological role in unstable angina and non-Q-wave myocardial infarction. To date, heparin and thrombolytic therapy has not provided complete or consistent benefit. We hypothesized that recombinant hirudin, a direct thrombin inhibitor, would prevent accumulation of coronary artery thrombus in a manner superior to heparin.. Patients with rest ischemic pain, abnormal ECG, and baseline angiogram indicating a > or = 60% stenosis of a culprit coronary artery or saphenous vein graft with visual appearance of thrombus were randomized to one of two different doses of heparin (either a target activated partial thromboplastin time [aPTT] of 65 to 90 or 90 to 110 seconds) or one of four doses of hirudin (0.05, 0.10, 0.20, or 0.30 mg.kg-1.h-1 infusion) in a dose-escalating protocol. After 72 to 120 hours of study drug, a repeat coronary angiogram was obtained, and the paired studies underwent quantitative analysis. The primary end point was change in the average cross-sectional area of the culprit lesion. Other efficacy end points also involved changes in culprit lesion dimensions and TIMI flow grade. Recombinant hirudin led to a dose-dependent elevation of aPTT that appeared to plateau at the 0.2-mg/kg dose. A higher proportion of hirudin-treated patients had their aPTT within a 40-second range (16% heparin versus 71% hirudin, P < .001). Overall, the 116 patients treated with hirudin tended to show more improvement than the 50 patients receiving heparin relative to the primary efficacy variable--the average cross-sectional area (P = .08)--as well as minimal cross-sectional area (P = .028), minimal luminal diameter (P = .029), and percent diameter stenosis (P = .07).. Recombinant hirudin appears to be a promising antithrombotic intervention compared with heparin for inhibition of coronary artery thrombus. Large-scale comparative trials are warranted.

Topics: Angina, Unstable; Coronary Angiography; Coronary Thrombosis; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Recombinant Proteins

Currently available antithrombotic therapy for unstable angina is unwieldy and occasionally ineffective. This study was designed to investigate the potential of Hirulog, a new synthetic specific antithrombin agent, for the management of this condition.. A total of 55 patients in the acute phase of unstable angina received intravenous Hirulog according to one of two protocols. In an acute dose-escalating study, 0.02, 0.05, 0.1, 0.25, and 0.5 mg.kg-1 x h-1, each for 30 minutes, were infused in 15 patients. Prolongation of activated partial thromboplastin time (aPTT) (r = .95), fibrinopeptide A inhibition (r = .96), and Hirulog plasma levels (r = .91) correlated closely with the dose infused, with significant changes compared with baseline appearing at doses of 0.25 mg.kg-1 x h-1 and higher. The purposes of the second protocol were to determine whether the anticoagulant and antithrombotic effects of the drug were sustained during a 72-hour infusion and to assess whether such treatment prevented the complications of unstable angina. Based on the initial study, we planned to give a dose of 0.25 mg.kg-1 x h-1 to each patient until 2 patients failed therapy, then successively higher doses until a 95% success rate was achieved or adverse effects intervened, increasing the dose after two failures had occurred at each level. Five patients received the 0.25-mg.kg-1 x h-1 dose and 14 the 0.5-mg.kg-1 x h-1 dose before two failures occurred. Failure was observed in only one of 21 patients at the dose of 1 mg.kg-1 x h-1. aPTT (+/- SEM) levels increased to 62 +/- 5, 76 +/- 2, and 98 +/- 3 seconds at the three doses, with minimal intraindividual variation, and Hirulog plasma levels to 1050, 2100, and 4200 mg/mL, respectively. Fibrinopeptide A plasma levels decreased at all doses but more consistently at the dose of 1 mg.kg-1 x h-1. The overall clinical success rate was 87.5%: 60% (3/5) at the low dose, 86% (12/14) at the intermediate dose, and 95% (20/21) at the high dose. No deaths, myocardial infarctions, or bleeding complications occurred.. In unstable angina patients, Hirulog infusions quickly and reproducibly yield stable, dose-dependent anticoagulant and antithrombotic effects with a favorable clinical efficacy profile.

Topics: Angina, Unstable; Dose-Response Relationship, Drug; Female; Fibrinopeptide A; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Thrombin

Bleeding risk stratification is an unresolved issue in older adults. Anemia may reflect subclinical blood losses that can be exacerbated after percutaneous coronary intervention . We sought to prospectively determine the contribution of anemia to the risk of bleeding in 448 consecutive patients aged 75 or more years, treated by percutaneous coronary interventions without concomitant indication for oral anticoagulation. We evaluated the effect of WHO-defined anemia on the incidence of 1-year nonaccess site-related major bleeding. The prevalence of anemia was 39%, and 13.1% of anemic and 5.2% of nonanemic patients suffered a bleeding event (hazard ratio 2.75, 95% confidence interval 1.37 to 5.54, p = 0.004). Neither PRECISE-DAPT nor CRUSADE scores were superior to hemoglobin for the prediction of bleeding. In conclusion, anemia is a powerful predictor of bleeding with potential utility for simplifying tailoring therapies.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Anemia; Angina, Unstable; Anticoagulants; Antithrombins; Aspirin; Cause of Death; Clopidogrel; Comorbidity; Coronary Artery Disease; Drug-Eluting Stents; Female; Gastrointestinal Hemorrhage; Hemorrhage; Heparin; Hirudins; Humans; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Care; Postoperative Hemorrhage; Prasugrel Hydrochloride; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Risk Assessment; Stents; Ticagrelor; Urologic Diseases

We aimed to construct a predictive model for one-year mortality in patients undergoing invasive coronary evaluation and to examine the impact of bivalirudin on survival according to the level of baseline risk.. Compared to heparin plus GP IIb/IIIa inhibitors (HEP/GPI), bivalirudin decreases bleeding complications in a range of clinical presentations. The impact of preprocedural risk assessment on survival and whether this is modified by bivalirudin, has not been investigated in detail.. We examined patient-level data from the REPLACE-2, ACUITY, and HORIZONS-AMI trials (n = 18,819) to construct a risk-adjusted mortality model using baseline clinical variables.. One-year mortality occurred in 287 patients (3.1%) assigned to bivalirudin and 336 patients (3.6%) assigned to HEP/GPI (HR 0.85; 95% CI, 0.73-1.00; P = 0.048). Using 11 highly significant predictors of mortality, we developed an integer-risk score to classify patients into risk tertiles. High-risk patients had a rate of 1-year mortality over 9-fold greater than low-risk patients. Consequently, the absolute mortality reduction attributed to bivalirudin was more marked in high-risk patients: 3.1% (-0.8% to 7.0%) in the overall cohort, 4.8% (0.5% to 9.2%) in the PCI cohort (P-interaction versus intermediate and low risk categories, 0.09 and P = 0.02, respectively).. In patients undergoing invasive coronary evaluation, 1-year mortality can be predicted using baseline variables. Bivalirudin treatment (versus HEP/GPI) conferred a survival benefit.

Topics: Aged; Angina, Stable; Angina, Unstable; Anticoagulants; Antithrombins; Coronary Artery Disease; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

The prospective EUROVISION Registry was designed to capture patterns of use and short term outcomes in consecutive patients undergoing PCI with bivalirudin (BIV) in European centres.. A total of 2018 consecutive BIV-treated patients were included from 58 sites in 5 countries (Germany, Italy, France, Austria, United Kingdom). In-hospital and 30-day outcomes were prospectively collected and included: death, myocardial infarction (MI), stroke, urgent revascularization (URV), major and minor bleeding, stent thrombosis (ST) and thrombocytopenia (TCP).. In this all-comer population, indication for PCI included STEMI (34%), NSTEMI (25%), unstable angina (16%) and stable angina (26%). Diabetes was present in 24% of patients and 30% of cases were performed via radial access. Preloading with a P2Y12 inhibitor was frequent (74%) while procedural glycoprotein inhibitor (GPI) use was low at 4.2%. Almost half (45%) of patients had received at least one additional anticoagulant prior to receiving BIV for PCI. The overall 30-day mortality was 1.0%, with low rates of MI (1.1%), URV (0.8%), ST (0.3%) and stroke (0.2%). The rate of ACUITY major bleeding was 1.6% and no TCP was reported. Dosing variations representing possible under- or over-dosing of BIV were frequent at 35%.. In this prospective registry of consecutive patients intended for PCI, use of BIV was associated with low rates of ischemic complications and excellent safety.

Topics: Aged; Angina, Stable; Angina, Unstable; Anticoagulants; Antithrombins; Coronary Thrombosis; Europe; Female; Hemorrhage; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Outcome Assessment, Health Care; Peptide Fragments; Percutaneous Coronary Intervention; Recombinant Proteins; Registries; Risk Factors; Stents; Stroke

To summarize key changes in the 2007 American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations for pharmacologic therapy as they relate to antiplatelets and anticoagulants, and to evaluate the evidence from several landmark trials that was used to support the guideline updates for these agents.. Literature was accessed through MEDLINE (1950-January 2008) using the search terms acute coronary syndromes, unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), antiplatelet, and anticoagulant. All papers were cross-referenced to identify additional studies.. ACC/AHA guidelines, relevant original research articles, and review articles were evaluated. Studies with more than 1000 patients were the focus of the review.. UA and NSTEMI are the most common presentations of acute coronary syndrome. The recently updated ACC/AHA guidelines for management of this condition were based on significant advances in pharmacotherapy including expanded use of drug-eluting stents, pretreatment with clopidogrel, and newer anticoagulants such as bivalirudin and fondaparinux. Landmark trials have been published that describe advances in the use of antiplatelets and anticoagulants. According to the guidelines, unfractionated heparin (UFH) and enoxaparin are preferred options for both invasive and conservative management. Enoxaparin was noninferior to UFH for invasive management in the SYNERGY trial, although it was associated with a higher incidence of bleeding. Other alternatives for an invasive strategy per the guidelines include bivalirudin and fondaparinux. Bivalirudin (alone or with glycoprotein [GP] IIb/IIIa inhibitor) was compared with heparin plus GP IIb/IIIa inhibitor in the ACUITY trial of patients undergoing early invasive management. The bivalirudin groups were noninferior to standard of care, although bivalirudin alone was associated with less bleeding. Fondaparinux was found to be noninferior to enoxaparin and was associated with fewer bleeding events in the OASIS-5 study of patients who were not treated with an early invasive approach. Accordingly, the guidelines 1list fondaparinux as an alternative for a conservative strategy or in patients at increased risk of bleeding.. Clinicians should be familiar with the updated 2007 ACC/AHA guidelines and the clinical trial evidence that serves as the basis for these recommendations. It is paramount for institutions to outline a preferred and consistent treatment approach. These decisions should involve a review of established efficacy, bleeding risk, need for anticoagulant reversal, costs, and clinician familiarity with different treatment regimens.

Topics: American Heart Association; Angina, Unstable; Anticoagulants; Clopidogrel; Drug-Eluting Stents; Enoxaparin; Fondaparinux; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Practice Guidelines as Topic; Recombinant Proteins; Ticlopidine; United States

For patients undergoing elective percutaneous coronary intervention (PCI), procedural anticoagulation with bivalirudin was previously shown to significantly reduce bleeding complications at the cost of a modest increase in ischemic events compared with unfractionated heparin (UFH) and glycoprotein IIb/IIIa inhibitors (GPIs). However, the excess bleeding in patients treated with UFH and GPIs may have been caused by excessively high UFH doses and increased activated clotting times. This study sought to determine the bleeding risk of targeted low-dose UFH with GPIs compared with bivalirudin in patients undergoing elective PCI. Of 1,205 patients undergoing elective PCI, 602 underwent PCI with adjunctive UFH and GPIs with the UFH dose targeted to an activated clotting time of approximately 250 seconds, and 603 patients matched for baseline characteristics underwent PCI with bivalirudin. Outcomes were analyzed for major bleeding (hematocrit decrease >15%, gastrointestinal bleed, or major hematoma) and 6-month major adverse cardiac events (death, myocardial infarction, and target-lesion revascularization). The maximum activated clotting time achieved was 261.7 +/- 61.6 seconds in the UFH/GPI group and 355.4 +/- 66.6 in the bivalirudin group (p <0.001). In-hospital major bleeding rates were similar between groups (1.8% UFH/GPI vs 1.7% bivalirudin; p = 0.83), as were transfusion requirements (1.2% UFH/GPI vs 0.5% bivalirudin; p = 0.61). The 6-month major adverse cardiac event rate was also similar between groups (9.5% UFH/GPI vs 9.0% bivalirudin; p = 0.81). In conclusion, there were no significant differences in major bleeding and 6-month major adverse cardiac events for patients undergoing elective PCI treated with targeted low-dose UFH and GPIs compared with those treated with bivalirudin.

Topics: Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Recombinant Proteins; Risk Assessment; Risk Factors; Treatment Outcome

Maintaining a therapeutic level of anticoagulation with unfractionated heparin remains a major challenge for clinicians because of the wide variability of patient responses, which may be explained by variable binding of heparin to plasma proteins. Direct thrombin inhibitors may offer an advantage in more predictable anticoagulation.. Plasma samples from normal volunteers, stable coronary artery disease (CAD) patients, unstable angina patients, and acute myocardial infarction patients were obtained. A fixed concentration of heparin (.13 U/ml) or bivalirudin (1.6 microg/ml) was added to plasma from each of the four study groups and measurement of the APTT was performed. In addition, a pool of plasma from patients with acute MI was diluted in pooled normal plasma, and heparin or bivalirudin was added to the plasma preparation and APTT measurements performed.. In heparin-treated plasma samples, mean APTT values were 443 +/- 137% baseline for normal volunteers, 347 +/- 116% for patients with stable CAD, 290 +/- 124% for patients with unstable angina (p < 0.05), and 230 +/- 120% for patients with acute MI (p < 0.05). APTT did not differ across the four groups treated with bivalirudin. There was a much higher degree of variability in APTT values in heparin treated controls (272%-671%, SD approximately 30%) compared to bivalirudin treated controls (284-499%, SD approximately 12%). When the "acute MI pool" was diluted in pooled normal plasma at fixed concentrations of either bivalirudin (1.6 mug/ml) or heparin (0.13 U/ml), there was a sharp decrease in heparin activity from 407% baseline (at 0% acute MI pool) to values as low as 126% baseline (at 100% acute MI pool). A markedly different pattern was seen in the bivalirudin treated samples, where a trend towards decreased APTT values was seen only at the 100% acute MI pool.. Both heparin variability and resistance may limit optimal antithrombotic therapy with heparin in patients with ACS and constitutes a potential advantage of direct antithrombin blockade with bivalirudin.

Topics: Aged; Angina, Unstable; Anticoagulants; Case-Control Studies; Coronary Artery Disease; Drug Resistance; Female; Heparin; Hirudins; Humans; In Vitro Techniques; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins

Topics: Angina, Unstable; Anticoagulants; Cardiac Catheterization; Drug Therapy, Combination; Femoral Artery; Hemorrhage; Hirudins; Humans; Peptide Fragments; Radial Artery; Recombinant Proteins

Topics: Anaphylaxis; Angina, Unstable; Antibody Formation; Anticoagulants; Cross Reactions; Drug Therapy, Combination; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Antithrombins; Coronary Circulation; Eptifibatide; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Peptides; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins

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

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Drug Therapy, Combination; Hemorrhage; Heparin; Hirudins; Humans; Myocardial Ischemia; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins

Bivalirudin is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. Cases of intracoronary thrombosis have been reported with beta-radiation when bivalirudin is used as an anticoagulant. We report two cases of intracoronary thrombosis with gamma-radiation when bivalirudin is used.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Antithrombins; Brachytherapy; Coronary Angiography; Coronary Restenosis; Coronary Thrombosis; Female; Gamma Rays; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Swine

Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05 10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50 109/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.

Topics: Aged; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Prospective Studies; Recombinant Proteins; Thrombocytopenia; Treatment Outcome

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Botulinum Toxins; Botulinum Toxins, Type A; Dermatitis, Atopic; Dermatologic Agents; Eczema; Hirudin Therapy; Hirudins; Humans; Immunosuppressive Agents; Neuromuscular Agents; Peptide Fragments; Recombinant Proteins; Tacrolimus; Torticollis; United States; United States Food and Drug Administration

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anti-Bacterial Agents; Anticoagulants; Antifungal Agents; Aspergillosis; Caspofungin; Contraindications; Drug Information Services; Drug Interactions; Echinocandins; Female; Hirudin Therapy; Hirudins; Humans; Lipopeptides; Male; Peptide Fragments; Peptides; Peptides, Cyclic; Recombinant Proteins

This study was a reanalysis of the Bivalirudin Angioplasty Study, which compared bivalirudin with high-dose heparin during coronary angioplasty for unstable angina.. Differences in rates of death, myocardial infarction, or repeat revascularization were compared at 7, 90, and 180 days after angioplasty with intention-to-treat analysis.. The combined end point occurred in 135 of 2161 patients (6.2%) in the bivalirudin group and in 169 of 2151 patients (7.9%) in the heparin group at 7 days (P =.039). Differences persisted between the groups at 90 days (P =.012) and 180 days (P =.153). Bleeding occurred in 76 patients (3.5%) in the bivalirudin group versus 199 (9.3%) in the heparin group (P <.001).. This analysis supports the hypothesis that bivalirudin reduces ischemic complications and bleeding after angioplasty. Further trials are needed to evaluate bivalirudin versus heparin in conjunction with platelet-glycoprotein IIb/IIIa inhibitors and for coronary stenting.

Topics: Actuarial Analysis; Adult; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Aspirin; Female; Follow-Up Studies; Heparin; Hirudin Therapy; Hirudins; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate

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

A 68-year-old woman with unstable angina and an episode of ventricular fibrillation developed a persistent and recurrent rash due to heparin. Medical therapy was continued with danaproid. For cardiopulmonary bypass and coronary artery grafting, r-hirudin was used as the anticoagulant. There were no thrombotic or coagulopathic complications. There is still no ideal alternative to unfractionated heparin for anticoagulation for cardiopulmonary bypass. The use of r-hirudin was successful and we describe our anticoagulant strategy.

Topics: Aged; Angina, Unstable; Anticoagulants; Coronary Artery Bypass; Coronary Artery Disease; Female; Hirudin Therapy; Hirudins; Humans; Preoperative Care; Recombinant Proteins; Treatment Outcome

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clinical Trials as Topic; Drug Approval; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Multicenter Studies as Topic; Peptide Fragments; Recombinant Proteins; United States; United States Food and Drug Administration

Topics: Angina, Unstable; Anticoagulants; Antithrombins; Arginine; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Pipecolic Acids; Platelet Activation; Platelet Aggregation Inhibitors; Sulfonamides; Thrombolytic Therapy

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Electrocardiography, Ambulatory; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin

In an open-label pilot study of 20 patients with unstable angina (Braunwald class I-IIIB), hirulog was administered as a continuous intravenous infusion for 5 days in a dose of 0.2 mg/kg/hour to produce an activated partial thromboplastin time of approximately 200% of control. The primary end points of the study were: death, development of a transmural myocardial infarction, and intractable angina needing interventions such as an intraaortic balloon pump insertion, angioplasty and surgery. The secondary end points were the presence of an intracoronary thrombus detected on angiography and hemorrhagic complications during therapy. There was no death or transmural infarction in this study cohort; however, 1 patient developed intractable angina. Intracoronary thrombus was documented in 2 patients. Infusion of hirulog resulted in a steady prolongation of the activated partial thromboplastin time without any hemorrhagic or other adverse effect. Hirulog appears to be an effective antithrombotic agent that is tolerated well and may have advantages over heparin in the management of patients with unstable angina.

Topics: Aged; Angina, Unstable; Coronary Angiography; Female; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Pilot Projects; Recombinant Proteins; Thrombin