bivalirudin and Cardiovascular-Diseases

The direct thrombin inhibitor bivalirudin has gained popularity in cardiovascular medicine over the past decade because, in comparison with unfractionated heparin, it guarantees a predictable dose-related degree of anticoagulation with a low immunogenic profile and, possibly, with reduced rates of major bleeding complications. In the past bivalirudin has been frequently employed in the management of patients with heparin-induced thrombocytopenia. The REPLACE-2, ACUITY and ISAR-REACT4 studies demonstrated bivalirudin non-inferiority in comparison with unfractionated heparin in terms of ischemic end-points with a reduction of the bleeding rate also in patients acute coronary syndrome without ST elevation. Finally the results of the HORIZONS-AMI study positioned this drug as a first choice anticoagulant during percutaneous coronary interventions in patients with ST-elevation myocardial infarction. In fact the bivalirudin alone regimen, compared to unfractionated heparin plus GP2b3a inhibitors, decreased in-hospital bleeding rates and short and long term mortality. Given the body of clinical evidence, bivalirudin is likely to contend to GP2b3a inhibitors the leading place among the proposed anticoagulation strategies in the setting of acute coronary syndromes. The duration of the bivalirudin infusion after PCI and the optimal oral antiplatelet regimen associated to bivalirudin are important issues to be solved in future randomized controlled studies.

Topics: Antithrombins; Cardiovascular Diseases; Chemotherapy, Adjuvant; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins

With femoral access, bivalirudin decreases risks of major bleeding after percutaneous coronary intervention (PCI) and provides better net clinical benefit compared to unfractionated heparin (UFH) plus planned glycoprotein IIb/IIIa inhibitors. Whether this benefit exists compared to UFH monotherapy is less clear. We performed a systematic review and meta-analysis to compare outcomes in patients undergoing transfemoral PCI with UFH or bivalirudin. Randomized trials (n = 3) and observational studies (n = 13) comparing bivalirudin to UFH monotherapy were reviewed. Primary outcomes were 30-day rates of major adverse cardiovascular events (MACEs) including death, myocardial infarction (MI), urgent revascularization, as well as all-cause mortality, MI, major bleeding, and blood transfusion. We collected data from 16 studies involving 32,492 patients undergoing PCI. Most observational studies were performed in the United States, whereas all randomized trials were done in Europe. Compared to UFH monotherapy, bivalirudin was associated with similar risk of MACEs (odds ratios [OR] 0.92, 95% confidence interval [CI] 0.75 to 1.12), a substantial 45% relative decrease in major bleeding (OR 0.55, 95% CI 0.43 to 0.72), and a trend in the decrease of transfusion (OR 0.87, 95% CI 0.70 to 1.08). A decrease in mortality was seen in observational studies (OR 0.62, 95% CI 0.45 to 0.85) but remained inconclusive in randomized trials (OR 0.63, 95% CI 0.20 to 2.01). MI rate was similar with the 2 anticoagulants. In conclusion, in patients undergoing transfemoral PCI, the benefit of bivalirudin over UFH monotherapy is driven by a significant decrease in major bleeding with similar rates of MACE. As PCI practice moves toward other bleeding-avoidance strategies such as the radial approach, future studies should focus on the interaction between anticoagulant strategy and access-site choice.

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Cardiovascular Diseases; Heparin; Hirudins; Humans; Myocardial Ischemia; Peptide Fragments; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins; Treatment Outcome

This meta-analysis was performed to assess the efficacy and safety of bivalirudin compared with unfractionated heparin or enoxaparin plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI).. Pharmacotherapy for patients undergoing PCI includes bivalirudin, heparin, and GP IIb/IIIa inhibitors. We sought to compare ischemic and bleeding outcomes with bivalirudin versus heparin plus GP IIb/IIIa inhibitors in patients undergoing PCI.. A literature search was conducted to identify fully published randomized trials that compared bivalirudin with heparin plus GP IIb/IIIa inhibitors in patients undergoing PCI.. A total of 19,772 patients in 5 clinical trials were included in the analysis (9785 patients received bivalirudin and 9987 patients received heparin plus GP IIb/IIIa inhibitors during PCI). Anticoagulation with bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in no difference in major adverse cardiovascular events (odds ratio [OR] 1.07, 95% confidence interval [CI] 0.96 to 1.19), death (OR 0.93, 95% CI 0.72 to 1.21), or urgent revascularization (OR 1.06, 95% CI 0.86 to 1.30). There is a trend towards a higher risk of myocardial infarction (OR 1.12, 95% CI 0.99 to 1.28) but a significantly lower risk of TIMI major bleeding with bivalirudin (OR 0.55, 95% CI 0.44 to 0.69).. In patients who undergo PCI, anticoagulation with bivalirudin as compared with unfractionated heparin or enoxaparin plus GP IIb/IIIa inhibitors results in similar ischemic adverse events but a reduction in major bleeding.

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Diseases; Drug Therapy, Combination; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Anticoagulants; Arginine; Cardiac Surgical Procedures; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sensitivity and Specificity; Sulfonamides; Thrombocytopenia; Thrombosis

Heparin-induced thrombocytopenia/thrombosis is an immunologic reaction to unfractionated heparin characterized by thrombocytopenia, platelet activation and thrombosis. A high index of suspicion is required for timely diagnosis and treatment. Treatment is complex and outcome maybe less then satisfactory.

Topics: Ancrod; Antibodies; Anticoagulants; Arginine; Cardiovascular Diseases; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Practice Guidelines as Topic; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Sulfonamides; Thrombin

Heparin, the most widely used antithrombin, suffers several limitations, including high inter-individual variability of anticoagulant response, a nonlinear dose-response curve, inability to inactivate clot-bound thrombin, a requirement for endogenous cofactors and inactivation by platelet factor 4 and heparinase. These shortcomings may explain its suboptimal efficacy and safety in the prevention of arterial vessel occlusion. Heparin's drawbacks may be overcome by direct thrombin inhibitors. The development of these specific antithrombins has been a major therapeutic goal of the past decade. The high expectations generated by the use of these compounds in experimental models of arterial thrombosis appeared to be confirmed by the initial phase I and II clinical studies. However, large phase III trials have been highly discouraging: three trials with hirudin have been interrupted as a result of a high incidence of serious adverse events. Two of these trials were subsequently restarted at lower doses and did not support an incremental efficacy of hirudin over heparin. Two trials in the setting of angioplasty (one with hirudin and one with hirulog) have also failed to demonstrate the superiority of these compounds over heparin. Is this the result of a very narrow therapeutic range of these agents or the consequence of poor design of the phase II studies leading to the selection of inappropriate doses for the comparative efficacy trials? This review focuses on the clinical development of two specific antithrombins: hirudin and hirulog. The experimental pharmacology and human studies of Argatroban are discussed in a review by Fitzgerald and Murphy.

Topics: Animals; Antithrombins; Cardiovascular Diseases; Drug Evaluation; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin; 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

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Blood Vessel Prosthesis Implantation; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Hirudins; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Stents; Survival Rate

Topics: Anticoagulants; Antithrombins; Cardiovascular Diseases; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Recombinant Proteins; Stents; Thrombosis; Treatment Outcome

Topics: Biomarkers; Biomedical Research; Blood Pressure Determination; Cardiovascular Diseases; Cost-Benefit Analysis; Education, Medical, Graduate; Hemoglobins; Hirudins; Humans; Peptide Fragments; Prognosis; Recombinant Proteins; Survival Analysis; Treatment Outcome

Bivalirudin, a direct thrombin inhibitor, provides similar ischemic outcomes with significantly less major bleeding compared with unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) in patients undergoing percutaneous coronary interventions (PCI). Although the approved labeling for bivalirudin allows for low-dose prolonged postprocedure administration, this practice is not routine. Therefore, we sought to evaluate the safety and efficacy of longer post-PCI infusion.. From our database, we retrospectively compared two groups of patients with acute coronary syndrome undergoing complex PCI, one group treated with UFH+GPI (n = 59) and another with a periprocedural and post-PCI bivalirudin infusion for 4 h (n = 50). Endpoints included periprocedural myocardial infarction (MI), 30-day major adverse cardiac events, and in-hospital major and minor bleeding.. There were no significant differences in the baseline and procedural characteristics of the two groups; most patients (approximately 90%) had complex coronary lesions (the American College of Cardiology/American Heart Association type B2/C). There was no significant difference in the rates of periprocedural MI (11.9 vs. 8.0%, P = NS) or 30-day major adverse cardiac events (8.5 vs. 6.0%, P = NS) among patients treated with UFH+GPI or bivalirudin. However, patients who received bivalirudin had significantly lower rates of minor bleeding (20.3 vs. 4.0%, P<0.05), and a trend toward significantly less major bleeding (8.5 vs. 4.0%, P = 0.07). When we compared the group treated with a prolonged bivalirudin infusion with a historical group treated with peri-PCI-only bivalirudin infusion, we observed in the latter an increased incidence of periprocedural MI and a comparable incidence of bleeding.. A prolonged bivalirudin infusion after urgent PCI seems effective in protecting myocardium without increasing bleeding rates, and represents an attractive alternative to the standard pharmacological treatment of UFH+GPI in the catheterization laboratory.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Cardiovascular Diseases; Drug Administration Schedule; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Retrospective Studies; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

The current standard of care for anti-thrombotic therapy with primary PCI for acute ST elevation myocardial infarction (STEMI) is aspirin, clopidogrel, unfractionated heparin and platelet glycoprotein IIb/IIIa inhibitors. However, heparin and glycoprotein IIb/IIIa inhibitors are associated with a high incidence of bleeding, and many of the trials documenting benefit with this therapy were performed before the widespread use of stents and clopidogrel. Bivalirudin is a direct thrombin inhibitor which has been found to have similar efficacy with less bleeding compared with heparin plus glycoprotein IIb/IIIa inhibitors when used with elective PCI and with PCI for unstable angina and non-ST elevation myocardial infarction. The HORIZONS trial evaluated bivalirudin compared with unfractionated heparin and IIb/IIIa inhibitors in patients with STEMI treated with primary PCI and found similar MACE (major adverse cardiac events) with less bleeding and a lower incidence of net adverse clinical events (MACE or major bleeding) at 30 days. Mortality at 30 days was also significantly less with bivalirudin. These results make a strong case for the use of bivalirudin with primary PCI in the great majority of patients with STEMI, with the possible exception of patients with cardiogenic shock or stent thrombosis, and patients with a large thrombus burden or no re-flow following PCI. In the latter case, platelet glycoprotein IIb/IIIa inhibitors would be used as a bail-out strategy.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Cardiovascular Diseases; Clopidogrel; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Myocardial Infarction; Patient Selection; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Stents; Thrombin; Thrombosis; Ticlopidine; Treatment Outcome

Patients with an acute anterior ST-segment elevation myocardial infarction and right bundle-branch block (RBBB) have a high mortality risk, which may be stratified by early ECG changes.. In the Hirulog Early Reperfusion Occlusion (HERO-2) trial, 17 073 patients with acute myocardial infarction (AMI) within 6 hours of symptom onset were treated with streptokinase and randomized to receive bivalirudin or heparin. There was no difference in the primary end point of 30-day mortality. ECGs were recorded at randomization and 60 minutes after fibrinolytic therapy was begun. The 30-day mortality rate was 31.6% in the 415 patients with RBBB and anterior AMI at randomization and 33% in the 100 patients who developed new RBBB at 60 minutes from normal baseline conduction accompanying an anterior AMI. An increase in QRS duration by 20-ms increments was associated with increasing 30-day mortality rate in both RBBB groups on multivariable analyses with covariates of age, Killip class, systolic blood pressure, pulse, and prior infarction. Patients with QRS duration > or = 160 ms had higher 30-day mortality rate than those with QRS duration < 160 ms (37.2% versus 27.2%, P = 0.03, and 46.2% versus 24.5%, P = 0.025, in the 2 groups, respectively). For the patients with RBBB and anterior MI at randomization, RBBB resolved at 60 minutes in 40 patients, but 30-day mortality rate was unchanged. For those with persisting RBBB at 60 minutes, 30-day mortality rate was lower if ST-segment elevation had resolved by > or = 50% (20.4% versus 35.3%, P = 0.006).. In patients with anterior AMI and RBBB, increasing QRS duration is associated with increasing 30-day mortality. Early ST-segment resolution after fibrinolytic therapy despite persisting RBBB is associated with lower mortality rate.

Topics: Aged; Anticoagulants; Bundle-Branch Block; Cardiovascular Diseases; Electrocardiography; Female; Fibrinolytic Agents; Functional Laterality; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Streptokinase; Survival Analysis