hirudin and Coronary-Disease

Topics: Anticoagulants; Catheterization, Peripheral; Coronary Disease; Femoral Artery; Hemorrhage; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Punctures; Radial Artery; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Risk Factors; Treatment Outcome

This meta-analysis is to evaluate the efficacy and safety of bivalirudin in patients with ST-elevation myocardial infarction (STEMI).. PubMed, Cochrane Library, Embase, CNKI, CBMdisc, and VIP database were searched. Randomized controlled trial (RCT) was selected and the meta-analysis was conducted by RevMan 5.1. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) and the primary safety endpoint was the incidence of major bleeding. Secondary efficacy endpoints were myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), stock, mortality, and thrombocytopenia. The pooled risk ratios (RRs) with the corresponding 95% confidence intervals (CI) were used to assess the efficacy and safety of bivalirudin vs heparin.. Seven RCTs met the inclusion criteria, and 16,640 patients were included. We found that bivalirudin associated with lower risk of mortality (RR = 1.05; 95% CI = 0.74-1.49; P = .03; I = 2%), major bleeding (RR = 0.64; 95% CI = 0.54-0.75; P < .00001; I = 70%) and thrombocytopenia (RR = 0.39; 95% CI = 0.25-0.61; P < .0001; I = 0) compared with heparin. However, the use of bivalirudin increase the risk of MI(RR = 1.37; 95% CI = 1.10-1.71; P = .004; I = 25%) and ST(RR = 1.61; 95% CI = 1.05-2.47; P = .03; I = 70%) and has similar risk of MACE (RR = 1.00; 95% CI = 0.90-1.11; P = .97; I = 16%), TVR (RR = 1.43; 95% CI = 0.92-2.22; P = .11; I = 46%) and stock (RR = 1.43; 95% CI = 0.92-2.22; P = .11; I = 46%) compared with heparin used in STEMI patients.. Bivalirudin associated with lower risk of mortality, major bleeding and thrombocytopenia compared with heparin. However, the use of bivalirudin increase the risk of MI and ST and has similar risk of MACE, TVR and stock compared with heparin used in STEMI patients.

Topics: Antithrombins; Coronary Disease; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Randomized Controlled Trials as Topic; Recombinant Proteins; Thrombosis; Treatment Outcome

Transradial approach has significantly decreased the rate of access site bleeding in patients undergoing percutaneous coronary interventions (PCI), therefore potentially mitigating the benefits offered by bivalirudin in lowering major bleeding complications as compared to heparin. However, nonaccess site bleeding, that represent the majority of hemorrhagic complications, still carry negative prognostic consequences for these patients and no study has so far defined the exact impact of bivalirudin on nonaccess site bleeding, that was therefore the aim of present meta-analysis.. Literature archives (Pubmed, EMBASE, Cochrane) and main scientific sessions were scanned comparing bivalirudin vs. heparin in patients undergoing PCI. Primary endpoint was the occurrence of nonaccess site bleeding within 30 days. Secondary endpoints were 30 days mortality and the occurrence of access-site bleeding.. The present meta-analysis shows that bivalirudin can provide a significant reduction of both access and nonaccess site bleeding in patients undergoing PCI. However, these hemorrhagic benefits did not impact on survival, and moreover, were significantly conditioned by the association of heparin with potent antithrombotic strategies, such as glycoprotein IIbIIIa inhibitors, rather than by heparin or bivalirudin alone. Therefore, we could not provide any clinical evidence for the routine use of bivalirudin as preferred anticoagulation strategy for PCI. © 2017 Wiley Periodicals, Inc.

Topics: Adolescent; Adult; Aged; Anticoagulants; Antithrombins; Chi-Square Distribution; Clinical Decision-Making; Coronary Disease; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Odds Ratio; Peptide Fragments; Percutaneous Coronary Intervention; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Time Factors; Treatment Outcome; Young Adult

Bivalirudin has been shown to be safe and efficacious compared with heparin plus glycoprotein IIb/IIIa inhibitor (GPI) in patients undergoing percutaneous coronary intervention (PCI). Whether bivalirudin would have the beneficial effects in female patients undergoing PCI remains unknown. We searched the literature for randomized controlled trials that assessed bivalirudin versus heparin plus GPI therapy in female patients undergoing PCI. The primary efficacy end point was major adverse cardiovascular events (MACE) within 30 days. The secondary efficacy end points were 30-day incidence of all-cause mortality, myocardial infarction (MI), urgent/ischemia-driven revascularization of target vessel. The safety end point was major bleeding up to 30 days. A total of 4,501 female patients were included in five randomized trials. No significant difference in MACE emerged between bivalirudin and heparin plus GPI at 30 days (8.15% vs 8.76%, RR 0.94, 95% CI 0.77-1.16, P = .57). There were no significant differences in rates of mortality (1.28% vs 1.91%, RR 0.74, 95% CI 0.45-1.20, P = .22), MI (5.46% vs 5.25%, RR 1.02, 95% CI 0.79-1.32, p = .88), or target vessel revascularization (2.13% vs 1.65%, RR 1.43, 95% CI 0.88-2.30, P = .15). Compared with heparin plus GPI, bivalirudin was associated with a significant reduction in 30-day major bleeding (5.32% vs 9.20%, RR 0.58, 95% CI 0.47-0.72, P < .0001). In conclusion, bivalirudin is associated with a significant reduction in 30-day major bleeding without increased ischemic events compared with heparin plus GPI in female patients undergoing PCI.

Topics: Antithrombins; Coronary Disease; Drug Therapy, Combination; Female; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins

The anticoagulant of choice during percutaneous coronary intervention (PCI) in women is not well established.. An electronic search was conducted for trials that randomized patients undergoing PCI to bivalirudin versus heparin, and reported outcomes of interest in women. Random effects DerSimonian-Laird risk ratios (RR) were calculated. Main outcome was net adverse clinical events (NACE) at 30-days. Other outcomes included major adverse cardiac events (MACE), all-cause mortality, myocardial infarction (MI), target vessel revascularization (TVR), and major bleeding at 30-days. 1-year all-cause mortality and MACE were also examined.. Nine trials that randomized women undergoing PCI to bivalirudin (n=3960) versus heparin (n=4050) were included. At 30-days, bivalirudin was associated with reduced risk of NACE (RR=0.85; 95% CI 0.73-0.98; p=0.03), mainly driven by reduction in major bleeding (RR=0.59; 95% CI 0.49-0.71; p<0.001) compared with heparin. No difference in MACE (p=0.92), all-cause mortality (p=0.23), MI (p=0.86); or TVR (p=0.53) was demonstrated between both groups. At 1-year, the risk of MACE and all-cause mortality was similar in both groups. On a subgroup analysis, the benefit associated with bivalirudin appeared to be less evident when Glycoprotein IIb/IIIa inhibitors (GPI) was used as bailout therapy with heparin, however without significant interaction. Furthermore, in STEMI population, no difference in NACE, MACE, or major bleeding was observed between both groups.. In women undergoing PCI, bivalirudin is associated with reduced risk of major bleeding and NACE compared with heparin especially when GPI is routinely used.

Topics: Anticoagulants; Antithrombins; Coronary Disease; Female; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Percutaneous coronary intervention (PCI) induces thrombin generation and is associated with the risk of acute, subacute, or long-term ischaemic events. Therefore, intravenous anticoagulation is recommended to minimize thrombotic complications. The intensity and duration of anticoagulation needed are dependent on the clinical presentation (elective PCI for stable coronary artery disease, PCI for non-ST elevation acute coronary syndromes, or primary PCI for ST-segment elevation myocardial infarction) and procedural features. As both ischaemic and periprocedural bleeding complications are associated with acute and long-term mortality, the optimal level of anticoagulation and the best agents are a matter of debate. Despite a number of limitations and the lack of large randomized clinical trials, unfractionated heparin (UFH) is still been used in the majority of interventions. Intravenous enoxaparin, a low-molecular-weight heparin, leads to a more predictable level of anticoagulation and has been compared with UFH in patients with elective PCI and primary PCI with favourable results. The direct thrombin inhibitor bivalirudin has been studied in numerous trials and consistently shown to reduce bleeding complications when compared with UFH with or without glycoprotein IIb/IIIa inhibitors. This review will summarize the current status of anticoagulation for PCI and the results of most recent trials and give recommendations for different clinical scenarios.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Coronary Disease; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins

Diabetes patients undergoing percutaneous coronary intervention (PCI) have more complications than nondiabetes patients, including increased long-term mortality. Use of bivalirudin versus heparin and glycoprotein IIb/IIIa inhibitors (GPI) in diabetes patients undergoing PCI and its effect on long-term mortality were evaluated in few randomized trials, but with conflicting results.. We searched the literature for randomized controlled trials that compared heparin and GPI therapy with bivalirudin in diabetes patients undergoing PCI. The incidence of major adverse cardiovascular events (MACE), death from any cause, myocardial infarction (MI), urgent revascularization, major and minor bleeding (at 30 days), as well as all-cause mortality at 1 year were included, and meta-analysis was performed.. A total of 5,137 patients with diabetes were included in four randomized trials. At 30 days, bivalirudin, compared with heparin and GPI, caused less major bleeding (odds ratio (OR), 0.68; 95% confidence interval (CI), 0.52-0.89; P = 0.005) and less minor bleeding (OR, 0.48; 95% CI, 0.41-0.57; P < 0.00001) and similar rates of MACE (OR, 0.87; 95% CI, 0.70-1.08; P = 0.21), MI (OR, 0.87; 95% CI, 0.68-1.10; P = 0.25), and urgent revascularization (OR, 1.12; 95% CI, 0.76-1.65; P = 0.57). Death from any cause at 30 day was numerically lower with bivalirudin use but not statistically significant (OR, 0.72; 95% CI, 0.46-1.13; P = 0.15). Mortality at 1 year was significantly lower in diabetes patients treated with bivalirudin compared with heparin and GPI (OR, 0.72; 95% CI, 0.52-0.99; P = 0.04). A secondary analysis suggests that the major bleeding benefit with bivalirudin may be driven by mandated use of GPI in heparin arm.. Among patients with diabetes undergoing PCI, bivalirudin caused less major and minor bleeding compared with heparin and GPI, with similar rates of MACE, death, MI, and urgent revascularization at 30 days, but significantly lower mortality rates at 1 year.

Topics: Anticoagulants; Antithrombins; Coronary Disease; Diabetes Complications; Drug Therapy, Combination; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

In 2006, the American College of Cardiology, American Heart Association, and Society for Cardiovascular Interventions published the 2005 update of the evidence-based guidelines for the treatment of patients undergoing percutaneous coronary intervention (PCI). Together with procedural recommendations, these guidelines for percutaneous coronary intervention provide clinicians with guidance in the appropriate use of adjunctive pharmacologic therapy in patients undergoing PCI. However, there remain substantial variations in practice among clinicians and within and across institutions. Furthermore, the guidelines (being a static document) cannot incorporate additional evidence that has accumulated since their publication. Several landmark trials, notably Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT 2) and Acute Catheterization and Urgent Intervention Triage strategY (ACUITY), have added substantially to the knowledge base about pharmacologic therapy since publication of the guidelines. This article is therefore intended to discuss implementation into clinical practice of the revised guidelines for antiplatelet and antithrombotic pharmacologic therapy during PCI and to evaluate recent clinical evidence and make recommendations for revision of the guidelines incorporating the outcomes of recently completed trials.

Topics: American Heart Association; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Clopidogrel; Combined Modality Therapy; Coronary Disease; Drug-Eluting Stents; Hirudins; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Practice Guidelines as Topic; Pyridines; Recombinant Proteins; Societies, Medical; Thrombolytic Therapy; Ticlopidine; United States

The role of adjunctive pharmacology for percutaneous coronary intervention (PCI) has been extensively studied, but controversy remains regarding the optimal regimen. While older studies suggest that glycoprotein IIb/IIIa inhibitors (GPI) should be routinely administered, much of this evidence was collected prior to the era of widespread stenting and thienopyridine use. There is now substantial clinical evidence that bivalirudin monotherapy is the optimal adjunctive pharmacology for the vast majority of patients undergoing elective or urgent percutaneous coronary intervention (PCI), including those presenting with an acute coronary syndrome (ACS). Bivalirudin monotherapy provides similar protection from ischemic complications with a reduced rate of major hemorrhage, resulting in a superior net clinical outcome compared with the use of GPI.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clopidogrel; Combined Modality Therapy; Coronary Disease; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins; Ticlopidine

The standard of care for patients with acute coronary syndrome is antithrombotic and antiplatelet therapies along with early percutaneous coronary intervention. Because of the limitations of heparin, there has been an interest in direct thrombin inhibitors, such as bivalirudin, which is now the anticoagulant of choice in percutaneous coronary intervention.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Disease; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombosis

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

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials as Topic; Coronary Disease; Fibrinolytic Agents; Hemostatics; Heparin; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Thrombin

Direct thrombin inhibitors (DTIs) are a new class of therapeutics possessing theoretic advantages over unfractionated heparin (UFH). In contrast to UFH, DTIs do not activate platelets, have no circulating inhibitors, and bind to both free and clot-bound thrombin. These theoretical advantages have spurred clinical trials investigating DTIs in a variety of cardiovascular indications. Currently, the major role for DTIs in cardiology is as an adjunct during percutaneous coronary intervention (PCI). Such a role stems from the results of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 randomized trial, in which bivalirudin with provisional abciximab was demonstrated to be equivalent to UFH plus planned abciximab with respect to ischemic endpoints, while being associated with less bleeding. Ongoing clinical trials will define the role of bivalirudin as an adjunct to primary PCI for ST-segment elevation myocardial infarction and in non-ST segment elevation acute coronary syndrome as an adjunct to an early invasive strategy.

Topics: Abciximab; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Antithrombins; Coronary Disease; Eptifibatide; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Peptide Fragments; Peptides; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Cohort Studies; Coronary Disease; Heparin; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins

Bivalirudin (Hirulog, Angiomax) is a specific, reversible and direct thrombin inhibitor with a predictable anticoagulant effect. It is cleared by both proteolytic cleavage and renal mechanisms, predominantly glomerular filtration. Bivalirudin inhibits both circulating thrombin and fibrin bound thrombin directly by binding to thrombin catalytic site and anion-binding exosite I in a concentration-dependent manner. Bivalirudin prolongs activated partial thromboplastin time, prothrombin time, thrombin time and activated clotting time (ACT). ACT levels with bivalirudin do not correlate with its clinical efficacy. Bivalirudin with a provisional GpIIb/IIIa inhibitor is indicated in elective contemporary percutaneous coronary intervention (PCI). In respect to combined ischemic and hemorrhagic endpoints of death, myocardial infarction, unplanned urgent revascularization and major bleeding during PCI (including subgroups of patients with renal impairment and diabetes) bivalirudin is not inferior to unfractioned heparin and planned GpIIb/IIIa inhibitors. In addition, bivalirudin has been consistently shown to have significantly less in-hospital major bleeding than heparin alone or heparin in combination with a GpIIb/IIIa inhibitor. Bivalirudin appears to be also safe and effective during PCI in patients with heparin-induced thrombocytopenia. Finally, data from PCI studies support the safety and efficacy of bivalirudin, although its direct randomized comparison with unfractionated heparin is lacking.

Topics: Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Cardiopulmonary Bypass; Coronary Disease; Cost-Benefit Analysis; Hirudins; Humans; Peptide Fragments; Postoperative Complications; Recombinant Proteins; Thrombin

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

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

Lepirudin (Refludan), Berlex Laboratories, USA and Canada; Pharmion, all other countries), a recombinant derivative of the naturally occurring leech anticoagulant hirudin, was the first direct thrombin inhibitor to be approved by the European Agency for the Evaluation of Medicinal Products and the US Food and Drug Administration for the treatment of heparin-induced thrombocytopenia. Since its introduction into Europe and the USA, it has been studied in over 7000 patients requiring anticoagulation in conditions including acute coronary syndromes, percutaneous coronary intervention, cardiopulmonary bypass and heparin-induced thrombocytopenia. Three European clinical trials, designated Heparin-Associated Thrombocytopenia (HAT)-1, -2 and -3, demonstrated the efficacy and safety of lepirudin in the prevention and treatment of thrombosis in patients with antibody-confirmed heparin-induced thrombocytopenia. A postmarketing, observational study, termed the Drug-Monitoring Program, evaluated lepirudin in over 1000 patients with heparin-induced thrombocytopenia in the setting of routine clinical practice. In the Drug-Monitoring Program, adverse events were substantially reduced compared with clinical trials, while clinical efficacy was maintained; suggesting that insight gained through clinical experience was translated into improved safety. Here, pharmacotherapy using lepirudin is reviewed, with particular reference to clinical studies in heparin-induced thrombocytopenia, and some recommendations based on this extensive clinical experience with lepirudin are provided. Although only approved for the treatment of heparin-induced thrombocytopenia, the use of lepirudin in acute coronary syndromes, percutaneous coronary intervention, vascular surgery and coronary artery bypass grafting is also discussed. The review concludes with a discussion of pharmacokinetic and clinical data supporting the potential for subcutaneous administration of lepirudin.

Topics: Anticoagulants; Cardiovascular Surgical Procedures; Coronary Disease; Dose-Response Relationship, Drug; Heparin; Hirudins; Humans; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Thrombin; Thrombocytopenia; Venous Thrombosis

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

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

Native hirudin is the most potent natural direct thrombin inhibitor currently known; it is capable of inhibiting not only fluid phase, but also clot-bound thrombin. Recombinant technology now allows production of recombinant hirudins (r-hirudins), which are available in sufficient purity and quantity with essentially unaltered thrombin-inhibitory potency. As thrombin is known to play a key role in a number of thrombotic disorders, numerous studies focused on the impact of r-hirudins on the clinical course in these diseases. R-hirudins provided significantly more stable anticoagulation than standard heparin, but demonstrated a relatively narrow therapeutic range with relevant bleeding risk even at clinically effective doses. In doses that are not associated with an increased bleeding risk, r-hirudins often failed to demonstrate significant superiority to heparin. To date, r-hirudins have a definite role in the treatment of heparin-induced thrombocytopenia, where they markedly reduce the high risk of thrombosis. For prophylaxis of deep vein thrombosis, r-hirudins have been shown to be superior to both unfractionated and low molecular weight heparin, but are not extensively used in this indication. In acute coronary syndromes, a definite role of r-hirudins has not yet been firmly established. When applied in an appropriate dose as adjunct to thrombolysis in patients with acute myocardial infarction, randomized, controlled trials did not show a consistent benefit of r-hirudins, especially in the long-term. In patients undergoing coronary balloon angioplasty for acute coronary syndromes, promising effects in the early postprocedural phase did not translate to an improved outcome after 6 months. In patients with unstable angina pectoris, efficacy and safety of r-hirudins as primary antithrombotic therapy are still under debate. In the future, r-hirudins are to be compared with alternative or additional potent antithrombotic agents or treatment strategies. This comparison will ultimately lead to their final placement in the management of thrombotic disorders.

Topics: Clinical Trials as Topic; Coronary Disease; Fibrinolytic Agents; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Partial Thromboplastin Time; Recombinant Proteins; Thrombin; Thrombocytopenia; Tissue Distribution; Venous Thrombosis

Most acute coronary syndromes (ACS) are triggered by platelet-rich thrombus superimposed on disrupted atherosclerotic plaque. Thrombin and platelets both play a role in this process. Whereas unfractionated heparin and aspirin have served as cornerstones in the treatment of ACS, several limitations of heparin provide the impetus to seek out better anticoagulants. Direct thrombin inhibitors such as bivalirudin, hirudin, and argatroban offer several pharmacologic advantages over heparin. Additionally, bivalirudin also appears to provide clinical advantages over unfractionated heparin therapy in ACS patients and those undergoing percutaneous coronary intervention.

Topics: Arginine; Coronary Disease; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Thrombin

This review deals with a newly-developed category of antithrombotic drugs - the direct thrombin inhibitors. These agents interact with thrombin and block its catalytic activity on fibrinogen, platelets and other substrates. Heparin and its derivatives (low molecular weight heparins and the active pentasaccharide) inhibit thrombin and/or other coagulation serine proteases indirectly via antithrombin, and the warfarin-type drugs interfere with the synthesis of the precursors of the coagulation serine proteases. The direct thrombin inhibitors approved for clinical use at present (lepirudin, desirudin, bivalirudin, argatroban) and another in the advanced clinical testing stage (melagatran/ximelagatran), are the subject of this review. The chemical structure; kinetics of thrombin inhibition; pharmacokinetics and clinical use of each of these is discussed.

Topics: Antithrombins; Arginine; Coronary Disease; Half-Life; Hirudins; Humans; Metabolic Clearance Rate; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin; Venous Thrombosis

Percutaneous coronary interventions are being used with increasing frequency nowadays for the treatment of patients with coronary heart disease. Acute thrombotic complications remain one of the major limitations of these procedures for which unfractionated heparin has been the standard foundation anticoagulant. It has, however, many limitations and disadvantages that necessitated research and development of alternative anticoagulant therapies. The direct thrombin inhibitor bivalirudin has been approved as a substitute for heparin in patients undergoing angioplasty for unstable angina based on data in higher-risk patients where bivalirudin resulted in lower rates of ischaemic and bleeding complications compared to heparin. This evidence was collected prior to the widespread use of platelet glycoprotein (GP) IIb/IIIa receptor blockers, thienopyridines and intracoronary stents, considered standard practice for such patients today. The REPLACE-2 study was carried out to establish whether, in the current era, bivalirudin used with provisional GP IIb/IIIa blockade if necessary during the procedure could provide equivalent protection from ischaemic events compared with the gold standard of heparin plus routine GP IIb/IIIa blockade. With advantages with regards to bleeding, ease of use and reduced cost, bivalirudin use with provisional GP IIb/IIIa inhibitors in low-to-moderate risk percutaneous coronary interventions allows GP IIb/IIIa receptor antagonists to be used in a selective fashion, rather than in all patients. In this article, background rationale for bivalirudin use in this setting is reviewed as well as past research in this area. Additionally, the implications of the REPLACE-2 study in establishing where bivalirudin fits into our current interventional cardiology practice and future directions are presented.

Topics: Administration, Cutaneous; Animals; Coronary Disease; Drugs, Investigational; Hirudins; Humans; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Abciximab; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Aspirin; Clopidogrel; Coronary Disease; Hirudins; Humans; Immunoglobulin Fab Fragments; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Stents; Ticlopidine

The economics of bleeding complications and the role of antithrombotic therapies in percutaneous coronary intervention (PCI) are discussed. More than 1 million PCI procedures are performed annually in the United States, at a mean cost of hospitalization of approximately $9,000 and billions of dollars in total health care costs. Ischemic complications have been reduced to the point that bleeding has become the most common complication. Bleeding complications and transfusions are also among the most costly complications in PCI, accounting for an incremental cost of hospitalization after PCI that may exceed $10,000, due to increased length of stay and the use of additional resources such as ultrasound evaluation and surgical repair of the vascular site. Anemia and transfusions are also associated with increased morbidity and mortality, contributing to additional treatment costs beyond those directly attributable to correcting the bleeding complication. In the past decade, significant reductions in heparin dose and warfarin use were associated with reduced bleeding complications, but glycoprotein IIb/IIIa inhibitors have been shown to increase the clinical and economic costs of bleeding complications. The replacement of heparin with bivalirudin is associated with significant reductions in the costs of antithrombotic therapy and in complications. Reductions in bleeding complications have become a primary target for further improvements in both clinical and economic outcomes.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Disease; Heparin; Hirudins; Hospitalization; Humans; Length of Stay; Peptide Fragments; Postoperative Hemorrhage; Randomized Controlled Trials as Topic; Recombinant Proteins; Stents

The chemistry and pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics of bivalirudin are reviewed; clinical trials of bivalirudin's application in percutaneous coronary intervention (PCI) are also discussed. Bivalirudin is a direct thrombin inhibitor approved for use in PCI. It reversibly binds to thrombin's catalytic site and substrate recognition site and blocks both circulating and fibrin-bound thrombin. Peak concentrations occur in less than 5 minutes after bolus-dose administration, and its half-life is approximately 25 minutes. It is primarily eliminated renally, and dosage reduction may be required in patients with severe renal dysfunction. Two clinical trials have demonstrated that bivalirudin is at least as effective as unfractionated heparin (UFH) in preventing ischemic complications in PCI. Other trials have shown that bivalirudin has beneficial ischemic and hemorrhagic outcomes in a more modern PCI setting (i.e., intracoronary stent placement, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors). Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors was noninferior to UFH with planned glycoprotein IIb/IIIa inhibitors and superior to UFH alone with respect to ischemic and hemorrhagic endopoints in PCI. Major bleeding with bivalirudin has occurred in approximately 3% of patients in clinical trials, and it is not known to have any interactions with the cytochrome P-450 isoenzyme system. The acquisition cost of bivalirudin in one study was less than the combination of UFH and glycoprotein IIb/IIIa inhibitors. Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Coronary Disease; Drug Interactions; Fibrinolytic Agents; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin; Thrombosis

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

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

Among the antithrombotic therapies evaluated to date, the synthetic peptide bivalirudin is unique in its ability to reduce both ischemic and bleeding complications associated with percutaneous coronary intervention (PCI). Bivalirudin is a small peptide consisting of 20 amino acid residues that binds thrombin in a direct, reversible, and bivalent fashion. The agent is approved for use in the United States and New Zealand as an anticoagulant in patients with unstable angina undergoing PCI and may also prove beneficial in patients with acute coronary syndromes (ACS), acute myocardial infarction (AMI) and in patients undergoing coronary artery bypass graft (CABG) procedures. This article examines bivalirudin in more detail.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Coronary Disease; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

To describe heparin-induced thrombocytopenia (HIT or HIT-2), an immune-mediated adverse reaction to heparin or low-molecular-weight heparin. Available treatment options and considerations in developing a therapy approach are discussed.. A search of the National Library of Medicine (1992-June 2001) was done to identify pertinent literature. Additional references were reviewed from selected articles.. Articles related to laboratory recognition and treatment options of HIT, including the use of agents in selected clinical conditions, were reviewed and included.. HIT is a rare but potentially severe adverse reaction to heparin that was, until recently, poorly understood and had limited treatment options. Recent advances describing the recognition and clinical manifestations of immune-mediated HIT, including recently available antithrombotic treatment options, have dramatically changed outcomes for patients having this syndrome.

Topics: Animals; Anticoagulants; Arginine; Chondroitin Sulfates; Clinical Trials as Topic; Coronary Disease; Dermatan Sulfate; Drug Combinations; Female; Heparin; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Pregnancy; Rabbits; Recombinant Proteins; Sulfonamides; Thrombocytopenia

Heparin is a commonly used anticoagulant in patients with coronary artery disease but its use does not always result in low rates of ischaemic and bleeding events, so the search for new anticoagulants continues. Thrombin plays a key role in both thrombosis and haemostasis and direct thrombin inhibitors modelled on the hirudin molecule found in the saliva of the medicinal leech, Hirudo medicinalis, have recently been developed. To date, the only direct thrombin inhibitor shown to reduce both the ischaemic and the bleeding complications associated with percutaneous coronary intervention (PCI) is bivalirudin, which is approved for this indication in the US and New Zealand. This agent is currently being studied in patients undergoing PCI with or without glycoprotein IIb/IIIa inhibitors and stenting. Bivalirudin has been shown to significantly reduce the risk of reinfarction in patients with acute myocardial infarction (MI) treated with streptokinase, but its use for this indication is not approved in the US. It may also prove to be beneficial in patients with acute MI treated with other fibrinolytic regimens or with primary or facilitated PCI. Bivalirudin is suitable for use as an alternative to heparin in the majority of patients undergoing PCI and in patients receiving streptokinase for acute MI.

Topics: Acute Disease; Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Clinical Trials as Topic; Coronary Artery Disease; Coronary Disease; Coronary Thrombosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins

Acute coronary syndromes encompass a spectrum of conditions, including myocardial infarction and unstable angina. These syndromes are related to the formation and disruption of atherosclerotic plaque. Rupture of plaque leads to thrombin generation, fibrin deposition, and platelet aggregation, ultimately resulting in restriction of blood flow and ischemia of cardiac tissue. Percutaneous coronary intervention (PCI), including angioplasty and coronary stent placement, has been developed to open occluded arteries. The frequency with which these procedures are performed speaks to their largely successful outcomes. However, the mechanical manipulations of PCI result in additional plaque rupture and damage to the vessel wall, exposing subendothelial components to blood and resulting in the initiation of the clotting cascade and in platelet activation. Left unchecked, these intertwined processes lead to formation of arterial thrombi at the site of endothelial damage, and potentially to abrupt vessel closure or embolization of thrombi into the distal microcirculation. Thrombin plays a central role in thrombus formation and platelet activation, and its inhibition significantly reduces thrombus-related sequelae. Current antithrombotic strategies during PCI are based on the traditional indirect thrombin inhibitor heparin. Heparin has several limitations in efficacy and safety, due in part to its indirect mechanism of action. Bivalirudin, a direct thrombin inhibitor, offers significant improvement over heparin in the clinical outcomes and risks associated with PCI.

Topics: Angioplasty, Balloon, Coronary; Arginine; Clinical Trials as Topic; Coronary Disease; Coronary Thrombosis; Fibrinolytic Agents; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin

Bivalirudin (Angiomax, The Medicines Company) is a synthetic 20 amino acid peptide rationally designed on the basis of structural studies of hirudin, a naturally occurring anticoagulant. Bivalirudin represents a new class of anticoagulant drugs that directly inhibits thrombin, a key component in blood clot formation and extension. With its high binding affinity and specificity for thrombin, bivalirudin acts directly on thrombin, rather than via other clotting factors. The compound has a variety of potential uses as an alternative to heparin in the management of cardiovascular disease and related medical procedures i.e., unstable angina (UA), myocardial infarction (MI) and percutaneous transluminal coronary angioplasty (PTCA).

Topics: Animals; Coronary Disease; Drug Approval; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

The majority of patients with acute coronary syndromes have renal impairment from either the aging process or from underlying disease, such as nephrosclerosis or diabetes. For example, in the phase 3 studies of bivalirudin use in PTCA, only 25% of patients had normal renal function: 46% had mild renal impairment, 28% had moderate renal impairment and about 1% had severe renal impairment. In patients with normal renal function, the intravenous pharmacokinetics of bivalirudin are dose proportional (linear) and are characterized by rapid plasma clearance (4.58 ml/minute/kg), a small volume of distribution (0.2 L/kg), and an elimination half-life of about 30 minutes. Renal clearance is the primary route of elimination of bivalirudin. As for other small polypeptides, bivalirudin is filtered at the glomerulus, secreted in the proximal convoluted tubule, reabsorbed in the distal convoluted tubule and degraded within intracellular lysosomes to constituent amino acids. There is a direct positive relationship between the dose of bivalirudin, plasma concentrations and the activated partial thromboplastin time (aPTT) or activated clotting time (ACT). A study comparing the pharmacokinetics and pharmacodynamics of bivalirudin with normal renal function (GFR greater than or = 90 ml/minute; n = 8), mild (GFR 60-89 ml/minute; n = 8), moderate (GFR 30-59 ml/minute; n = 7), or severe (GFR < 30 ml/minute; n = 10) renal impairment showed that while clearance was similar in the normal (4.58 ml/minute/kg) and mildly impaired (4.94 ml/minute/kg) groups, the clearance rate was reduced 45% in the moderate impairment (2.50 ml/minute/kg) group and about 68% in the severe impairment (1.46 ml/minute/kg) group. Clearance was further reduced (77%) in a group of 12 dialysis dependent patients (1.04 ml/minute/kg). There was a strong positive correlation between plasma bivalirudin concentrations and aPTT. The derived maximal effect (Emax) was similar for the normal (58.3 seconds), mildly impaired (44.7 seconds) and moderately impaired (56.8 seconds) groups, but prolonged in the severely renally impaired (79.4 seconds) and dialysis dependent (84.4 seconds) patients. These kinetic and dynamic results have recently been substantially confirmed in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), where reduced plasma clearance (20%) and elevated ACTs were observed in patients with moderate renal impairment. The bleeding results of the phase 3 PTCA clinical trial (invol

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Coronary Disease; Hirudin Therapy; Hirudins; Humans; Kidney Function Tests; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency; Safety; Treatment Outcome

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

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

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

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Clinical Trials as Topic; Coronary Disease; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Risk Factors

To compare bivalirudin to heparin during non-primary percutaneous coronary intervention (PCI).. The optimal anticoagulant to support PCI remains uncertain.. We performed a propensity score-based analysis comparing clinical outcomes of patients receiving heparin to those receiving bivalirudin during non-primary PCI.. Of 18,867 patients in the Cardiovascular Patient Outcomes Research Team Non-Primary PCI (CPORT-E) trial, we selected 7,913 patients undergoing non-staged PCI of whom 57.3% received heparin and 42.7% received bivalirudin. In-hospital myocardial infarction occurred in 4.4% of patients receiving bivalirudin and 3.0% of patients receiving heparin (relative risk [RR] 1.5, 95% confidence interval [CI] 1.1-2.1, P = 0.022); this difference persisted at 6 weeks (5.0% vs. 3.6%, RR 1.4, 95% CI 1.0-1.8, P = 0.041). There was no difference in all-cause mortality either in-hospital (0.2% vs. 0.1% for heparin vs. bivalirudin, P = 0.887) or at 6 weeks (0.5% vs. 0.7%, P = 0.567). In-hospital bleeding requiring transfusion occurred in 0.9% of patients receiving bivalirudin and 1.9% of patients receiving heparin (RR 0.4, 95% CI 0.3-0.7, P <0.001), but there was no difference at 6 weeks (2.7% for heparin vs. 1.9% for bivalirudin, RR 0.7, 95% CI 0.5-1.0, P = 0.062).. In patients undergoing non-primary PCI at hospitals without on-site cardiac surgery, bivalirudin was associated with a decreased risk of in-hospital bleeding requiring transfusion and an increased risk of in-hospital MI compared to heparin. © 2017 Wiley Periodicals, Inc.

Topics: Aged; Anticoagulants; Antithrombins; Blood Transfusion; Coronary Disease; Female; Hemorrhage; Heparin; Hirudins; Hospital Mortality; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Peptide Fragments; Percutaneous Coronary Intervention; Propensity Score; Recombinant Proteins; Risk Factors; Time Factors; Treatment Outcome

Previous studies have compared bivalirudin and unfractionated heparin (UFH) plus the routine use of glycoprotein IIb/IIIa inhibitors. They have demonstrated that bivalirudin can decrease bleeding complications without a significant increase in ischemic complications, resulting in a better net clinical outcome, as defined by the efficacy (ischemic complications) or safety (bleeding complications) end point. The aim of the present study was to compare bivalirudin and UFH plus protamine in patients undergoing elective percutaneous coronary intervention and pretreated with clopidogrel and aspirin. We randomly assigned 850 patients with stable or unstable coronary artery disease to bivalirudin or UFH followed by protamine at the end of the percutaneous coronary intervention. The primary end point was in-hospital major bleeding. The main secondary end points were the 1-month composite of death, myocardial infarction, unplanned target vessel revascularization; and the 1-month net clinical outcome. The rate of major bleeding (primary end point) was 0.5% in patients randomized to bivalirudin and 2.1% in patients randomized to UFH (p = 0.033). At 30 days, the rate of major bleeding was 0.9% in the bivalirudin arm and 2.8% in the UFH arm (p = 0.043). The composite of death, myocardial infarction, and target vessel revascularization rate and the net clinical outcome rate was 2.8% and 6.4% (p = 0.014) and 3.3% and 7.8% (p = 0.004), respectively, in the bivalirudin and UFH arms. In conclusion, in percutaneous coronary intervention patients pretreated with clopidogrel and aspirin, bivalirudin was associated with less major bleeding and fewer ischemic complications and a better net clinical outcome than UFH.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electrocardiography; Female; Follow-Up Studies; Hemorrhage; Hemostasis; Heparin; Heparin Antagonists; Hirudins; Humans; Incidence; Infusions, Intravenous; Italy; Male; Peptide Fragments; Protamines; Recombinant Proteins; Retrospective Studies; Treatment Outcome

The aim of this study was to identify a subset of patients at high risk of bleeding or myocardial infarction from a percutaneous coronary intervention and to investigate whether such high-risk subsets derive preferential benefit from heparin or bivalirudin.. This study included 4570 patients with coronary artery disease enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment trial and randomized to receive bivalirudin or heparin. Primary outcomes were in-hospital incidence of major bleeding and 30-day incidence of myocardial infarction. Major bleeding, myocardial infarction, and bleeding plus myocardial infarction occurred in 140, 204, and 34 patients, respectively. Older age, female sex, lower body weight, low cholesterol, multi-lesion intervention, complex lesions, and heparin therapy were independent correlates of increased risk of bleeding. Multi-lesion intervention, unstable angina, and lower body weight correlated independently with increased risks of myocardial infarction. Compared with heparin, bivalirudin was associated with a reduction in major bleeding (3.1 vs. 4.6%, P = 0.008), but mostly in low-risk patients. A reduction in the bleeding risk inversely correlated with an increase in the risk of myocardial infarction with bivalirudin (R = -0.61).. Bivalirudin and unfractionated heparin have a differential effect on risk of bleeding and myocardial infarction across various subsets of patients.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Disease; Double-Blind Method; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Radiography; Recombinant Proteins; Risk Factors

Topics: Aged; Anticoagulants; Aprotinin; Blood Loss, Surgical; Coronary Artery Bypass; Coronary Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Probability; Prospective Studies; Recombinant Proteins; Reference Values; Risk Assessment; Single-Blind Method; Survival Analysis; Treatment Outcome

Patients undergoing percutaneous coronary intervention (PCI) have a significant risk of hemorrhagic complications. Predictors of major hemorrhage and its relation to mortality in PCI are not well defined. Baseline and periprocedural predictors of major hemorrhage and its impact on mortality in patients undergoing elective or urgent PCI randomly assigned to heparin plus planned glycoprotein IIb/IIIa inhibitor (GPI) versus bivalirudin plus provisional GPIs in the REPLACE-2 Trial were determined. Of 6,001 patients, 3.2% experienced a major hemorrhage. Independent baseline predictors of major hemorrhage included advanced age, female gender, impaired creatinine clearance, and anemia. Independent periprocedural predictors of major hemorrhage included treatment with heparin plus GPI, increased procedural duration, provisional use of GPI, increased time to sheath removal, length of intensive care unit stay, and use of an intra-aortic balloon pump (all p <0.05). Mortality rates were higher in patients with than without major hemorrhage at 30 days (5.1% vs 0.2%), 6 months (6.7% vs 1.0%), and 1 year (8.7% vs 1.9%; p <0.001 for all). Furthermore, major hemorrhage was an independent predictor of 1-year mortality (odds ratio 2.66, 95% confidence interval 1.44 to 4.92, p = 0.002). In conclusion, in patients undergoing elective or urgent PCI, major hemorrhage was an independent predictor of 1-year mortality. A number of baseline and periprocedural factors independently predicted major hemorrhage, including treatment with heparin plus GPI.

Topics: Aged; Angioplasty, Balloon, Coronary; Antithrombins; Coronary Disease; Female; Fibrinolytic Agents; Hemorrhage; Hirudins; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; Prospective Studies; Recombinant Proteins

Postmortem and angiographic studies have demonstrated that thrombosis is the primary cause of coronary artery occlusion in smokers. Further, smokers have high levels of fibrinogen, increased platelet aggregation, and more platelet-dependent thrombin generation than do nonsmokers, suggesting that glycoprotein (GP) IIb/IIIa inhibitor use during percutaneous coronary intervention (PCI) may be especially useful among smokers. We evaluated a subpopulation of active smokers in the REPLACE-2 trial to assess the effect of treating smokers with bivalirudin and provisional GP IIb/IIIa blockade compared with heparin and planned GP IIb/IIIa blockade. The REPLACE-2 trial enrolled 1,558 smokers and 4,305 nonsmokers. Smokers who were treated with bivalirudin had an absolute 3.2% increase in the composite end point of death and myocardial infarction at 48 hours compared with smokers who were treated with heparin and GP IIb/IIIa inhibitors (7.7% vs 4.5%, p=0.008, interaction p=0.016). This difference was ameliorated when GP IIb/IIIa inhibitors were used consistently in a previous trial that compared bivalirudin with heparin during PCI (4.6% vs 6.7%, p=0.322). In conclusion, these results suggest that smokers may derive particular benefit with GP IIb/IIIa inhibitors for decreasing myocardial infarction and death after PCI. These findings require further validation from other large, randomized trials.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Disease; Double-Blind Method; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Smoking; Survival Analysis

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

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

Percutaneous coronary interventions (PCI) of coronary artery bypass grafts (CABG) are associated with worse outcomes compared with those of native coronary PCI. Little is known concerning the use of direct thrombin inhibition during CABG intervention. The objective of this report is to examine the safety and efficacy of bivalirudin with GPIIb/IIIa blockade inhibition in patients undergoing CABG PCI. GP IIb/IIIa use was provisional in REPLACE-2 and planned in REPLACE-1.. A post hoc analysis of patients undergoing CABG PCI in the REPLACE-1 and -2 trials was performed. In REPLACE-1, patients were randomized to either heparin or bivalirudin, with GP IIb/IIIa inhibitor use at the operator's discretion. In REPLACE-2, patients were randomized to heparin plus GP IIb/IIIa inhibition versus bivalirudin with provisional GP IIb/IIIa blockade. In both studies, randomized treatment groups were well matched. In unadjusted and logistic regression analysis, there were no significant differences in the combined endpoint of death, myocardial infarction, urgent revascularization, or major bleeding when patients were treated with either heparin or bivalirudin. Individual safety and efficacy endpoints were also similar. Minor bleeding was significantly reduced in patients treated with bivalirudin (14.8% vs. 22.7%, P = 0.037). Follow-up data available from the REPLACE-2 trial at 12 months found similar efficacy between groups with a trend towards decreased 12 month mortality in the bivalirudin vs. heparin groups (4.2% vs. 7.8%, P = 0.16).. CABG PCI using bivalirudin with provisional GPIIb/IIIa inhibition appears to provide similar safety and efficacy to heparin with GPIIb/IIIa inhibition.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Combined Modality Therapy; Coronary Artery Bypass; Coronary Disease; Endpoint Determination; Female; Follow-Up Studies; Heparin; Hirudins; Humans; Logistic Models; Male; Middle Aged; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Retrospective Studies; Survival Analysis; Thrombin; Time Factors; Treatment Outcome

The purpose of this study was to assess if clopidogrel pretreatment affects the relative efficacy of bivalirudin versus heparin with glycoprotein (GP) IIb/IIIa blockade for percutaneous coronary interventions (PCI).. Although thienopyridine pretreatment may improve clinical outcomes with PCI, it is unknown if bivalirudin's efficacy compared with heparin is dependent upon such pretreatment.. The Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE-2) trial was a double-blind, triple-dummy, randomized-controlled trial comparing heparin plus routine GP IIb/IIIa blockade (heparin group) with bivalirudin plus provisional GP IIb/IIIa blockade (bivalirudin group) during PCI. The primary end point was a composite of death, myocardial infarction (MI), urgent revascularization at 30 days, and major in-hospital bleeding. The secondary end point was a 30-day composite of death, MI, and urgent revascularization. Clopidogrel pretreatment was encouraged (300 mg loading, 75 mg/day).. Of 6,010 patients enrolled, 5,893 received clopidogrel, with 85.8% in the bivalirudin and 84.6% in the heparin group receiving clopidogrel pretreatment. Bivalirudin (provisional GP IIb/IIIa blockade 7.2%) was noninferior to the heparin group for both primary and secondary end points. Clopidogrel pretreatment did not affect the relative efficacy of bivalirudin versus heparin with GP IIb/IIIa blockade, irrespective of pretreatment duration. Pretreatment was associated with significantly lower primary end point with bivalirudin (8.7% pretreatment vs. 12.9% no pretreatment, p = 0.007), and nonsignificantly with heparin (9.7% vs. 11.7%, respectively, p = 0.20). Multivariable models showed a trend toward lower primary and secondary end points with clopidogrel pretreatment.. Clopidogrel pretreatment at the doses and time administered in this trial did not influence the relative efficacy of bivalirudin versus heparin plus GP IIb/IIIa blockade for PCI. However, pretreatment was associated with a trend towards lower clinical events after PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Clopidogrel; Coronary Disease; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Survival Analysis; Ticlopidine; Treatment Outcome

The purpose of this study was to compare the cost of percutaneous coronary intervention (PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with that of heparin + routine GP IIb/IIIa inhibition.. Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad range of patients undergoing PCI, many patients currently do not receive such therapy because of concerns about bleeding complications or cost. Recently, bivalirudin with provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin + routine GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this novel strategy is unknown.. In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to receive bivalirudin with provisional GP IIb/IIIa (n = 2,319) versus heparin + routine GP IIb/IIIa (n = 2,332). Resource utilization data were collected prospectively through 30-day follow-up on all U.S. patients. Medical care costs were estimated using standard methods including bottom-up accounting (for procedural costs), the Medicare fee schedule (for physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based approaches for the remaining hospitalizations.. Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic outcomes including death or myocardial infarction were similar for the bivalirudin and GP IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p = 0.002) and minor bleeding (15.1% vs. 28.1%, p < 0.001). Compared with routine GP IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI] $37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p < 0.001 for both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants themselves, hospital savings were due primarily to reductions in major bleeding (cost savings = $107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient).. Compared with heparin + routine GP IIb/IIIa inhibition, bivalirudin + provisional GP IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to $400/patient depending on the analytic perspective.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Combined Modality Therapy; Coronary Disease; Costs and Cost Analysis; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Heparin; Hirudins; Hospitalization; Humans; Male; Middle Aged; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Treatment Outcome; United States

The direct antithrombin, bivalirudin, did not reduce angiographic restenosis measured either as the dichotomous restenosis rate of 62% for bivalirudin and 58% for heparin (p = 0.70), or as the late loss in lumen diameter of 0.44 +/- 0.47 mm for bivalirudin and 0.39 +/- 0.53 mm for heparin (p = 0.62). Direct thrombin inhibition with bivalirudin neither reduces angiographic restenosis nor alters the impact of several established risk factors for restenosis.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Antithrombins; Coronary Disease; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Linear Models; Male; Middle Aged; Peptide Fragments; Radiography; Recombinant Proteins; Recurrence; Risk Factors; Treatment Outcome

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

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

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

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.

Topics: Amino Acid Sequence; Aspirin; Blood Coagulation; Blood Coagulation Tests; Cardiac Catheterization; Coronary Disease; Female; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Molecular Sequence Data; Peptide Fragments; Recombinant Proteins; Thrombin

Topics: Anticoagulants; Antithrombins; Coronary Disease; Heparin; Hirudins; Humans; Peptide Fragments; Percutaneous Coronary Intervention; Recombinant Proteins; Treatment Outcome

The efficacy and safety of bivalirudin in percutaneous coronary intervention (PCI) has always been a hot topic in perioperative antithrombotic therapy, but there are still some controversies. So studies are needed to provide more evidence, especially the real world study which includes patients excluded from previous RCT studys. Our study aimed to investigate these information and analyze the independent predictors of postoperative adverse events.A retrospective study enrolled 1416 patients underwent PCI in Tianjin Chest Hospital from May 2016 to October 2017. The incidence of stent-thrombosis and net clinical adverse events, including all-cause death, myocardial infarction, stroke, urgent target-vessel revascularization and bleeding, were followed up for 30 days and 1 year. Logistic regression and COX regression were respectively used to analyze independent predictors of bleeding events within 30-days, and independent predictors of Major adverse cardiovascular and cerebrovascular events (MACCE) in patients with stent implantation within 1-year.Seven hundred six patients were treated with bivalirudin while 710 with unfractionated heparin (UFH). The proportions of diabetes, hypertension, anemia, myocardial-infarction history, PCI history, moderate-to-severe renal-impairment, gastrointestinal-bleeding history in the bivalirudin group were significantly higher (P < .05). Women, anemia were independent risk factors for bleeding within 30-days (P < .05). Among 682 patients with stent implantation in bivalirudin group, anemia, Body Mass Index (BMI) >25 kg/m2, KILLIP ≥2, ejection fraction (EF) <45%, eGFR <60 ml/minutes were independent risk factors for MACCE, while Statins, proton pump inhibitor (PPI) were independent protective factors for MACCE with-in 1-year (P < .05).Bivalirudin have good anticoagulant effect and lower bleeding risk during PCI, especially in patients with higher bleeding risk. In patients treated with bivalirudin, female, anemia were independent predictors of bleeding within 30-days, BMI >25 kg/m2, anemia, KILLIP ≥2, EF <45%, eGFR <60 ml/minutes were independent risk factors and Statins, PPI were independent protective factors of MACCE within 1-year.

Topics: Aged; Aged, 80 and over; Antithrombins; Coronary Disease; Female; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Percutaneous Coronary Intervention; Perioperative Care; Postoperative Hemorrhage; Recombinant Proteins; Retrospective Studies; Risk Factors; Sex Factors; Stents; Thrombosis; Treatment Outcome

To observe the efficacy and safety of bivalirudin use in Chinese patients with coronary heart disease (CHD) during the peri-percutaneous coronary intervention(PCI) period.. A total of 3 271 patients who underwent PCI and received periprocedural bivalirudin treatment between July 2013 and October 2015 from 88 centers of China were involved in this study. The primary outcome was 30-day net adverse clinical events (NACE a composite of major adverse cardiac or cerebral events (MACE, all-cause death, reinfarction, urgent target vessel revascularization, or stroke) or bleeding), the secondary outcome was stent thrombosis at 30 days.. The mean age of enrolled patients was (65.12±12.44) years old, 27.4%(889/3 244) of them were female. Percent of stable coronary disease (SCD), non-ST segment elevation acute coronary syndrome (NSTE-ACS) and ST elevation myocardial infarction (STEMI) was 5.0%(162/3 248), 44.6%(1 450/3 248) and 50.4%(1 636/3 248) respectively. Radial access was performed in 89.5% (2 879/3 271) patients, and 9.7% (316/3 271) and 34.1% (1 115/3 271) patients also received ticagrelor and tirofiban medication. 69.3% (2 266/3 271) patients received post-procedural bivalirudin infusion, in which 46.3% (1 050/2 266) was treated at PCI-does, with a median duration of 2.5(1.0, 4.0) h. During the 30-day follow-up, NACE occurred in 3.45% (103/2 988) patients, the incidence of MACE, death was 2.17% (65/2 994) and 1.03% (31/3 017), respectively and bleeding events were recorded in 1.37% (41/2 996) patients. Four cases (0.13%) of stent thrombosis (3 acute stent thrombosis) were recorded.. Peri-PCI Bivalirudin use is safe and related with low bleeding risk in Chinese CHD patients.

Topics: Aged; China; Coronary Disease; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Peptide Fragments; Percutaneous Coronary Intervention; Recombinant Proteins; Retrospective Studies; Stroke; Tirofiban; Tyrosine

This study sought to assess whether incorporation of routine bleeding risk estimates affected the utilization of bivalirudin during percutaneous coronary intervention (PCI).. Bivalirudin use during PCI has been shown to reduce bleeding complications. However, a risk-treatment paradox exists, in which patients at highest risk for bleeding are least likely to receive bivalirudin. Whether routine estimation of individualized bleeding risk can affect physicians' use of bivalirudin is unknown.. PCI data from a single health system between 2007 and 2011 were analyzed. Beginning in July 2009, individualized bleeding risk estimates were provided immediately preceding PCI. Using a pre-post design, we compared bivalirudin use before and after this implementation, for patients across 3 strata of bleeding risk (<1%, 1% to 3%, and >3%).. Data from 6,491 PCI procedures were analyzed. Overall, bivalirudin use increased in the post-implementation period (26.9% vs. 34.2%, p < 0.001). Bivalirudin use increased in intermediate (27% to 35%, p < 0.001) and high bleeding risk patients (25% to 43%, p < 0.001), and decreased in low-risk patients (30% to 25%, p = 0.014). During the same period, bleeding complications decreased in intermediate-risk (3.4% to 1.8%, p = 0.009) and high-risk (6.9% to 3.7%, p = 0.005) patients and remained unchanged in low-risk patients (1.1% to 1.0%, p = 0.976).. There was an increase in bivalirudin use and a lower incidence of bleeding after the incorporation of individualized bleeding risk estimates into clinical practice. This implementation led to a reversal of the risk-treatment paradox, through a rational increase in bivalirudin use in patients at intermediate and high bleeding risk and decreased use in lower-risk patients.

Topics: Aged; Antithrombins; Clinical Competence; Coronary Disease; Female; Hemorrhage; Hirudins; Humans; Incidence; Male; Middle Aged; Missouri; Peptide Fragments; Percutaneous Coronary Intervention; Preoperative Period; Recombinant Proteins; Retrospective Studies; Risk Assessment; Risk Factors

Topics: Angioplasty, Balloon, Coronary; Coronary Disease; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins

The association between obesity and bleeding after percutaneous coronary intervention (PCI) is not well defined. We investigated the impact of body mass index (BMI) on PCI-related bleeding, and whether bivalirudin, compared to heparin, used as PCI anticoagulant modifies this relationship.. From 2000 to 2009, 16,783 patients who underwent PCI were grouped according to 6 BMI groups: underweight (<18.5 kg/m(2)), "normal" weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), class I (30-34.9 kg/m(2)), class II (35-39.9 kg/m(2)), and class III obesity (> or =40 kg/m(2)). Bivalirudin was used in 11,433 patients and heparin in 5,350. In-hospital major bleeding (hematocrit drop > or =15% or gastrointestinal bleeding) and need for transfusion rates were collected.. The incidence of major bleeding varied significantly throughout the BMI spectrum (5.6% vs 2.5% vs 1.9% vs 1.6% vs 2.1% vs 1.9%, respectively, from underweight to class III obese patients, P < .001). The incidence of transfusion across BMI followed the same reverse J-shape curve (10.9% vs 6.6% vs 3.6% vs 3.4% vs 3.8% vs 5.6%, P < .001). After adjustment for potential confounding factors, underweight patients had neither an increased risk for major bleeding nor an increased risk for transfusion compared with "normal" weight patients. Class I obese patients had a lower risk of major bleeding (odds ratio [OR] 0.68 [95% CI 0.48-0.97]). Overweight, class I, and II obese patients had a lower risk of transfusion (respectively, OR 0.68 [0.55-0.84], 0.68 [0.53-0.87], and 0.66 [0.48-0.92]). The highest BMI patients had neither an increased risk for major bleeding (class II and III obesity) nor an increased risk for transfusion (class III obesity). The same reverse J-shaped relationship to BMI seen in the overall population for the raw incidence of major bleeding was found when the population was divided according to type of anticoagulant used as follows: bivalirudin or heparin. Likewise, the "need for transfusion" relationship to BMI is not altered by bivalirudin use.. The better outcome for bleeding seen in patients in the middle of the BMI spectrum suggests the existence of a "bleeding obesity paradox," which persists after adjustment by confounding factors and exists irrespective of the anticoagulant used.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Body Mass Index; Coronary Disease; Female; Follow-Up Studies; Hirudins; Humans; Incidence; Male; Middle Aged; Obesity; Odds Ratio; Peptide Fragments; Postoperative Hemorrhage; Prognosis; Recombinant Proteins; Retrospective Studies; Risk Factors; Thrombosis

To describe data and insights from a national quality improvement initiative known as Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines (CRUSADE), for managing non-ST-segment elevation acute coronary syndrome (ACS), as well as the findings and implications of Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), a study of bivalirudin with or without a glycoprotein (GP) IIb/IIIa inhibitor in patients with non-ST-segment elevation ACS who were undergoing an invasive intervention, and the results of two recent studies of clopidogrel in patients with ST-segment elevation myocardial infarction (MI) that are not reflected in current ACC/AHA guidelines for managing ST-segment elevation MI.. Data from the CRUSADE registry suggest that there is room for improvement in the use of GP IIb/IIIa inhibitors and clopidogrel during the first 24 hours of hospitalization in patients with non-ST-segment elevation ACS who undergo early invasive cardiac procedures, and in the prescribing of angiotensin converting-enzyme (ACE) inhibitors at the time of discharge. Adherence to ACC/AHA guidelines for non-ST-segment elevation ACS has improved over time but further improvement is needed. Failure to reduce the dose of a GP IIb/IIIa for patients with renal insufficiency resulting in excessive dosing of GP IIb/IIIa inhibitors increases the risk of major bleeding and is particularly common among the elderly, women, and patients with renal insufficiency. The ACUITY study suggests that bivalirudin plus a GP IIb/IIIa inhibitor is a suitable alternative to standard therapy for moderate- to high-risk patients with non-ST-segment elevation ACS who are undergoing early invasive intervention, and bivalirudin alone may be preferred because of a lower risk of major bleeding. However, interpretation of the ACUITY results is complicated by numerous methodologic concerns, so the role of bivalirudin in managing non-ST-segment elevation ACS is still evolving. In patients with ST-segment elevation, clopidogrel provides an early benefit in reopening occluded coronary arteries and a late benefit in reducing cardiovascular mortality and morbidity without increasing the risk of bleeding. Clopidogrel treatment is warranted before as well as after percutaneous coronary intervention in patients with ST-segment elevation MI who receive fibrinolytic therapy. Adding clopidogrel to fibrinolytic therapy and other standard therapy reduces mortality without increasing the risk of bleeding.. Evidence-based guidelines provide recommendations for the management of ACS, but the pace of clinical research is rapid and current guidelines do not reflect the latest research findings. Pharmacists need to stay abreast of new developments and ensure that clinical practice reflects these developments.

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Clinical Protocols; Clopidogrel; Coronary Disease; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Outcome Assessment, Health Care; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Practice Guidelines as Topic; Recombinant Proteins; Ticlopidine

The direct thrombin inhibitor bivalirudin has been found to be noninferior to heparin plus planned glycoprotein (GP) IIb/IIIa blockade in the prevention of acute ischemic end points and 1-year mortality after percutaneous coronary intervention (PCI) with bare metal stents. We investigated whether long-term outcomes after bivalirudin use remained comparable to heparin plus GP IIb/IIIa blockade in current clinical practice of drug-eluting stent use.. Using the 2004-2005 Cornell Angioplasty Registry, we studied 2504 consecutive patients undergoing urgent or elective PCI with periprocedural use of bivalirudin or heparin plus GP IIb/IIIa platelet inhibitors. Patients presenting with an acute ST-elevation myocardial infarction (MI) < or = 24 hours, thrombolytic therapy < or = 7 days, hemodynamic instability/shock, or renal insufficiency were excluded.. Of the study cohort, 1340 patients (54%) received bivalirudin and 1164 patients (46%) received heparin plus GP IIb/IIIa blockade. The incidence of inhospital mortality (0.3% vs 0.2%, P = .692), MI (6.6% vs 8.1%, P = .191), and combined end point of death, stroke, emergent coronary artery bypass graft/PCI, and MI (6.9% vs 8.3%, P = .199) was similar in the bivalirudin and heparin plus GP IIb/IIIa inhibitor groups. There was a lower incidence of major (0.7% vs 1.9%, P = .012) and minor bleeding (9.6% vs 15.6%, P < .001) in the bivalirudin versus heparin plus GP IIb/IIIa inhibitor group. Mean clinical follow-up was 24.8 +/- 7.7 months. At follow-up, there were 87 (6.5%) deaths in the bivalirudin group versus 42 (3.6%) in the heparin plus GP IIb/IIIa inhibitor group (hazard ratio 1.87, 95% CI 1.30-2.71, P = .001). After a propensity score adjusted multivariate Cox analysis, bivalirudin use was associated with a nonsignificant trend toward increased long-term mortality (hazard ratio 1.45, 95% CI 0.98-2.16, P = .065).. Compared with heparin plus GP IIb/IIIa inhibition, routine use of bivalirudin as the procedural anticoagulant in contemporary PCI with drug-eluting stents was associated with lower rates of inhospital complications and similar long-term all-cause mortality.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Coronary Disease; Creatine Kinase, MB Form; Drug Therapy, Combination; Female; Heparin; Hirudins; Humans; Intraoperative Complications; Logistic Models; Male; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Hemorrhage; Recombinant Proteins; Registries; Retrospective Studies; Stents; Treatment Outcome; Troponin I

To perform a cost-effectiveness analysis comparing three treatment approaches during nonurgent percutaneous coronary intervention (PCI): bivalirudin with provisional glycoprotein (GP) IIb-IIIa inhibitor therapy, unfractionated heparin (UFH) with eptifibatide, and UFH with abciximab.. Literature-based decision model from an institutional perspective.. Patient data from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 study and three other randomized controlled trials that included UFH and routine GP IIb-IIIa inhibitor (eptifibatide or abciximab) therapy. All included studies were comparable based on patient population, procedural techniques, and general treatment approaches.. We included patient populations undergoing contemporary nonurgent PCI to identify probabilities of success or complications (myocardial infarction, urgent revascularization, thrombocytopenia, and major or minor bleeding at 30 days). Costs were assigned to each outcome by incorporating diagnosis-related group-- and/or Current Procedural Terminology--associated costs, institutional drug acquisition costs, and unit replacement costs of platelets and red blood cells. In the base-case analysis, the use of bivalirudin with provisional GP IIb-IIIa inhibitor therapy dominated the UFH and planned GP IIb-IIIa inhibitor approach: UFH with eptifibatide was 74 US dollars more expensive and 1.2% less effective, and UFH with abciximab was 777 US dollars more expensive and 2.3% less effective. Sensitivity analyses indicated that the model results were robust, but also revealed that bivalirudin lost its cost-effectiveness, resulting in UFH with eptifibatide becoming more cost-effective, when two or more vials of bivalirudin were necessary in greater than 27% of cases or when the use of provisional GP IIb-IIIa inhibitor therapy exceeded 20%.. This analysis indicates that bivalirudin with provisional GP IIb-IIIa inhibitor therapy is the most cost-effective antithrombotic treatment strategy in nonurgent PCI when its use and dosing are consistent with the REPLACE-2 trial.

Topics: Abciximab; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Antithrombins; Coronary Disease; Cost-Benefit Analysis; Databases, Factual; Decision Support Techniques; Drug Costs; Eptifibatide; Fibrinolytic Agents; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Peptide Fragments; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

The REPLACE-2 trial demonstrated the noninferiority of bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) blockade as compared with heparin plus planned GPIIb/IIIa blockade among patients undergoing percutaneous coronary revascularization. Provisional drug was used in 374 (6%) of the 6010 patients. We sought to analyze the predictors for provisional drug use and to assess the outcomes in this cohort.. Outcome among the 5.2% of patients in the heparin plus GPIIb/IIIa blockade group and the 7.2% of patients in the bivalirudin group who received provisional placebo or GPIIb/IIIa inhibitor, respectively, was compared against patients without provisional drug use and between randomized arms. Multivariate models identified predictors of provisional drug use and outcome at 30 days, 6 months, and 1 year.. Myocardial infarction, repeat revascularization, and bleeding events occurred more frequently among patients who required provisional drug than those who did not, but there were no differences in 1-year mortality. Ischemic and hemorrhagic end points occurred at similar rates among patients receiving provisional drug in either the heparin plus GPIIb/IIIa group compared with the bivalirudin group. Independent predictors of provisional drug use were randomization to bivalirudin, recent infarction, multilesion intervention, impaired pretreatment coronary flow, and lesion complexity. Provisional drug use, but not randomization to bivalirudin, independently predicted 30-day and 6-month ischemic events.. Provisional administration of a GPIIb/IIIa inhibitor is associated with more frequent ischemic and bleeding events, reflecting the procedural complications that led to the use of provisional drug. The proportion of bivalirudin-treated patients who will require provisional GPIIb/IIIa blockade, however, is not large enough to have a significant deleterious impact on the overall incidence of ischemic end points or to invalidate the strategy of bivalirudin plus provisional GPIIb/IIIa blockade.

Topics: Aged; Angioplasty, Balloon, Coronary; Antithrombins; Coronary Disease; Drug Therapy, Combination; Female; Heparin; Hirudins; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Stroke Volume; Treatment Outcome

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

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

Chronic kidney disease is associated with an increased risk of ischemic and bleeding complications after percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, has been shown to reduce adverse bleeding events compared to unfractionated heparin in patients undergoing PCI. However, the effect of diminished renal function on the safety and efficacy of bivalirudin for PCI is unknown. We aimed to test the safety of bivalirudin in routine practice and to assess whether this benefit was influenced by renal function.. The interaction between renal impairment and benefit from bivalirudin was assessed in 115 consecutive patients (age 68.5+/-12.1, 45% female) undergoing PCI. Bivalirudin dosing was adjusted based on renal function. Creatinine clearance (CrCl) was calculated using the Cockroft-Gault formula. The composite endpoints of in-hospital death, myocardial infarction or revascularization and bleeding events were assessed. Overall, these events occurred in 10 (8.7%) patients. Patients with a CrCl<60 ml/min had a significantly increased risk for in-hospital complications (18.6 versus 2.78%, P = 0.011). Univariate analysis for MACE and bleeding were significant for CrCl<60 ml/min OR: 2.54 (95% CI: 1.61-39.7, P = 0.011), age OR: 3.29 (95% CI: 1.07-1.39, P<0.001) and female gender OR: 2.1 (95% CI: 0.036-0.89, P = 0.036). Risk of complications increased with decreasing renal function: 2.7, 14.2, and 37.5% for CrCl of >60, 30-60 or <30 ml/min, respectively, P = 0.002).. Advanced age, renal dysfunction, and female gender remain important risk factors for ischemic and bleeding complications in patients undergoing PCI with bivalirudin.

Topics: Aged; Angioplasty, Balloon, Coronary; Antithrombins; Comorbidity; Coronary Disease; Creatinine; Female; Hemorrhage; Hirudins; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Peptide Fragments; Prospective Studies; Recombinant Proteins; Risk Factors

Sirolimus-eluting stents (SESs) reduce restenosis compared with bare metal stents. Safety issues with drug-eluting stents are particularly important given concerns of possible increased thrombogenicity. Compared with heparin plus glycoprotein IIb/IIIa inhibitors, the direct thrombin inhibitor bivalirudin has been shown to reduce the risk of hemorrhagic complications in patients receiving bare metal stents, with similar efficacy in preventing ischemic complications. The safety and efficacy of percutaneous coronary intervention (PCI) with SESs and bivalirudin anticoagulation have not been prospectively studied. This prospective study performed at 9 United States hospitals evaluated 1,182 patients referred for PCI with SESs in whom the procedural anticoagulant was bivalirudin. Clopidogrel was administered before PCI in 79% of patients, and only 5.3% received procedural glycoprotein IIb/IIIa inhibitors. At 30 days, major adverse cardiac events occurred in 7.1% of patients, including 0.3% mortality, 4.4% myocardial infarction (defined as creatine kinase-MB >3x normal), 1.7% target vessel revascularization, and 0.6% stent thrombosis. Major bleeding occurred in only 0.8% of patients. Thus, use of bivalirudin as the procedural anticoagulant to support SES implantation in a "real world" population of patients undergoing PCI results in low rates of major adverse cardiac events, stent thrombosis, and major bleeding.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Coated Materials, Biocompatible; Coronary Disease; Coronary Restenosis; Follow-Up Studies; Hirudins; Hospital Mortality; Humans; Immunosuppressive Agents; Middle Aged; Peptide Fragments; Prospective Studies; Recombinant Proteins; Risk Factors; Safety; Sirolimus; Stents; Treatment Outcome; United States

Bivalent direct thrombin inhibitors reduce ischemic risk compared to heparin. Results from randomized, double-blind clinical trials have demonstrated that bivalirudin is superior to heparin alone and as effective as heparin plus routine glycoprotein (GP) IIb/IIIa therapy for the prevention of ischemic events with a statistically significant reduction in the rate of in-hospital major bleeding.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Antithrombins; Clinical Trials as Topic; Coronary Disease; Costs and Cost Analysis; Diabetic Angiopathies; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Risk Assessment; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Coronary Disease; Cost-Benefit Analysis; Embolism; Heparin; Hirudins; Hospitalization; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Recombinant Proteins; Saphenous Vein

The number of patients with coexisting chronic kidney disease (CKD) and cardiovascular disease is growing rapidly. Treatment of these patients is challenging, primarily because of a lack of pharmacokinetic and clinical trial data associated with these combined disease entities. In this report, we discuss the cardiovascular disease risk associated with CKD and review the use of anticoagulation for acute cardiovascular disease in patients with CKD. We evaluate the potential role of direct thrombin inhibitors in patients with renal disease who have acute coronary syndromes, with particular focus on the clinical efficacy of bivalirudin. We conclude that direct thrombin inhibitors, including bivalirudin and argatroban, may be promising alternatives to heparin in patients who have renal insufficiency and are therefore at an increased risk for bleeding. In the treatment of patients with advanced renal insufficiency and cardiovascular disease, however, these agents should be used with dose modification to account for altered excretion.

Topics: Anticoagulants; Antithrombins; Arginine; Chronic Disease; Coronary Disease; Heparin; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Kidney Diseases; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; United States

Antithrombotic therapy has become the cornerstone of the treatment for atherosclerotic cardiovascular disease. Unfractionated heparin (UFH) has been the thrombin inhibitor of choice for decades. UFH, however, has its deficiencies. To overcome these problems several direct thrombin inhibitors (DTIs) have been developed. These agents are capable of inactivating clot-bound thrombin more efficiently, and provide more predictable and safer anticoagulation in patients with of acute coronary syndromes (ACS). The initial studies of hirudin and bivalirudin in the clinical settings of acute myocardial infarction (AMI), unstable angina (UA) and percutaneous coronary interventions (PCI) conducted in the early 1990s proved to be disappointing. As the knowledge of more appropriate use of these drugs progressed, there is a renewed interest in DTIs. Herein we will review the clinical studies assessing hirudin, bivalirudin and argatroban in the settings of AMI, UA and PCI.

Topics: Acute Disease; Arginine; Coronary Disease; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin

Topics: Clinical Trials as Topic; Coronary Disease; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thrombin

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Chemotherapy, Adjuvant; Coronary Disease; Decision Making; Hirudin Therapy; Hirudins; Humans; Informed Consent; Peptide Fragments; Publications; Randomized Controlled Trials as Topic; Recombinant Proteins

The poor biocompatibility of metallic coronary stents which leads to un-satisfying restenosis rates is mainly caused by contact activation of blood cells, smooth muscle cells and endothelial cells. Mimicking a metal surface with a biocompatible coating that actively suppresses mechanisms leading to restenosis may overcome today's limitations regarding the complications of metal stents. Nitinol coronary stents were coated by CVD polymerization of functionalized [2.2]paracyclophanes. The monomers 4-amino [2.2]paracyclophane, 4-hydroxy methyl [2.2]paracyclophane and [2.2]paracyclophane-4,5,12,13-tetracarboxylic acid dianhydride were previously synthesized. A suitable installation for the CVD polymerization procedure was designed and used for the polymerization procedures. Physical and chemical properties of the polymers were shown to fulfill the requirements regarding the application as a stent coating material. The functional groups of the polymer coatings were used for the immobilization of the thrombin inhibitor r-hirudin. In vitro results indicate that the bioactively coated stents are less thrombogenic than virgin metallic stents. Surface-bound r-hirudin decreases platelet adhesion drastically due to interactions between platelets and r-hirudin.

Topics: Biocompatible Materials; Coronary Disease; Hirudins; Humans; In Vitro Techniques; Materials Testing; Metals; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Platelet Adhesiveness; Polymers; Prostheses and Implants; Stents; Surface Properties; Thrombin; Volatilization

Topics: Angioplasty, Balloon, Coronary; Antithrombins; Clinical Trials as Topic; Coronary Disease; Cost-Benefit Analysis; Data Interpretation, Statistical; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Odds Ratio; Peptide Fragments; Radiography; Recombinant Proteins; Recurrence; Research Design; Treatment Outcome

To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers.. In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-microm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (P<0.02) in the standard-pressure model (sheep) and by 24.8% (P<0.02) in the overstretch pig model compared with uncoated control stents without inducing a local inflammatory response.. The results from this study demonstrate beneficial effects of a polymeric stent coating with polylactic acid releasing r-PEG-hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury. Future studies are proposed to investigate the integration of other substances to further enhance the potential of the stent coating on reducing neointimal formation.

Topics: Absorbable Implants; Animals; Antithrombins; Coronary Disease; Coronary Vessels; Drug Delivery Systems; Hirudins; Iloprost; Lactic Acid; Polyesters; Polymers; Recurrence; Sheep; Stents; Swine; Tunica Intima

Direct thrombin inhibitors may offer advantages over indirect thrombin inhibitors in the management of patients with acute coronary syndromes (ACS). Two direct thrombin inhibitors, hirudin and bivalirudin, have been investigated in Phase II and Phase III clinical trials. Based on the results of a meta-analysis of study data from 25,000 patients, hirudin appears to be more effective than unfractionated heparin (UFH) in the treatment of patients with ACS, but it is associated with an increased rate of major bleeding. A meta-analysis of a smaller patient population has suggested that bivalirudin, too, may be more efficacious than UFH and may also be safer.

Topics: Animals; Antithrombins; Coronary Disease; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins

Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA.. Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolus + 0.7 mg/kg per day for 2 days), and long-term (bolus + 0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58+/-3% versus 35+/-3%; P<.001). No differences were observed among the bolus and short-term hirudin groups and the control group.. Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach.

Topics: Angioplasty, Balloon, Coronary; Animals; Antithrombins; Coronary Disease; Coronary Vessels; Hirudins; Partial Thromboplastin Time; Recombinant Proteins; Recurrence; Swine; Thrombin

Adhesion and aggregation of platelets at sites of intimal injury are accompanied by local thrombin generation and conversion of fibrinogen to insoluble fibrin. As the long-acting thrombin inhibitor, polyethylene glycol-coupled hirudin (PEG-hirudin), would be expected to interrupt this process by inhibiting the action of thrombin on platelets and fibrinogen, its effect on intracoronary thrombus formation, coagulation, platelet function, and duration and intensity of bleeding events was investigated.. Cyclic coronary flow reductions (CFRs) were induced in the left anterior descending coronary artery of 24 anaesthetised mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. There were four treatment regimens (six dogs per group): Control (isotonic saline); PEG 0.08 (0.15 mg/kg bolus + 0.08 mg/kg.h infusion); PEG 0.15 (0.30 mg/kg bolus + 0.15 mg/kg.h infusion); PEG 0.30 (0.60 mg/kg bolus + 0.30 mg/kg.h infusion).. A linear increase in steady-state plasma concentrations to 35.4 +/- 1.6 antithrombin units (ATU)/ml, 59.2 +/- 3.0 ATU/ml and 112.7 +/- 8.4 ATU/ml was achieved with the three doses of PEG-hirudin. The activated partial thromboplastin time (APTT) was increased 1.7-fold with PEG 0.08, 1.9-fold with PEG 0.15 and 2.2-fold with PEG 0.30. The frequency of CFRs during the first hour after drug administration was diminished by about 20% with all three doses of PEG. During the second hour, CFRs were decreased by 61% in all treated groups. Thrombin-induced platelet aggregation was completely abolished by all PEG-hirudin regimens. Buccal bleeding time and blood loss were not increased after either treatment.. In this canine model of coronary artery stenosis, the thrombin inhibitor, PEG-hirudin, effectively reduces platelet-dependent thrombus formation without interfering with primary haemostasis.

Topics: Animals; Antithrombins; Coronary Circulation; Coronary Disease; Coronary Thrombosis; Coronary Vessels; Dogs; Endothelium, Vascular; Hirudin Therapy; Hirudins; Partial Thromboplastin Time; Platelet Aggregation

Air desiccation endothelial injury followed by cholesterol feeding is known to induce focal femoral atherosclerosis in rabbits. We previously demonstrated the effectiveness of hirudin in limiting restenosis after balloon angioplasty (BA) in this double instrumentation injury (DI) model. In the present study, we sought to determine whether BA without prior air desiccation endothelial injury (single instrumentation injury (SI)) would lead to similar femoral lesions, and whether the response to this injury might also be limited by hirudin. Accordingly, 38 femoral arteries of cholesterol-fed rabbits underwent BA with (n = 18, DI group) or without (n = 20, SI group) prior air desiccation endothelial injury. Animals were killed 24 hours or 28 days after BA. Twenty-four hours after BA, the SI group (n = 10) had a significantly smaller percentage of cross-sectional area narrowing by plaque than the DI group (n = 8) (0% versus 42% +/- 9%, p = 0.008). However, 28 days after BA, the percentages of cross-sectional area narrowing by plaque in the SI (n = 10) and DI (n = 10) groups were similar (59% +/- 6% versus 68% +/- 1%, p = NS). The percentages of intima (16% +/- 3% versus 16% +/- 3%, p = NS) and media occupied by foam cells were also similar in the two groups. To test whether hirudin administration would limit arterial narrowing after injury in the SI model, we randomly assigned cholesterol-fed rabbits that had not undergone air desiccation injury to either bolus hirudin followed by repeat dosing 24 hours after BA or bolus heparin (150 U/kg) at the time of BA. The hirudin-treated group showed significantly less angiographic and histologic restenosis 28 days after BA, despite no difference in early (0 to 72 hours) cumulative cellular proliferation between the two groups. Thus, in the cholesterol-fed rabbit, plaque formation and foam cell accumulation are similar after BA of a non-air-desiccated (SI) or focally atherosclerotic (DI) artery. Thrombin inhibition with hirudin limits arterial narrowing after SI, further emphasizing the role of thrombin in neointimal growth after injury.

Topics: Angioplasty, Balloon; Animals; Cell Division; Cholesterol, Dietary; Coronary Disease; Disease Models, Animal; Endothelium, Vascular; Fibrinolytic Agents; Hirudins; Male; Models, Biological; Rabbits

Topics: Aged; Anticoagulants; Blood Coagulation Tests; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Female; Hirudins; Humans; Recombinant Proteins

Topics: Animals; Coronary Disease; Drug Costs; Fibrinolytic Agents; Hirudin Therapy; Hirudins; Humans; Stents; Thrombin; Thrombosis

Because the specific antithrombin hirudin prevents platelet-rich arterial thrombus and accelerates thrombolysis in a variety of animal models, it has promise as antithrombotic therapy. We therefore studied the half-life, effect on anticoagulant parameters, and safety of hirudin in patients with coronary artery disease.. Thirty-eight men and 1 woman (age [mean +/- SD], 60.4 +/- 6.9 years) with angiographic coronary disease were allocated in a single-blind ascending dosage study to a 6-hour i.v. infusion of recombinant hirudin (CGP 39,393) or matching placebo. The median terminal half-life for hirudin, measured by ELISA, was 2.7, 2.3, 2.9, 3.1, and 2.0 hours for the 0.02, 0.05, 0.1, 0.2, and 0.3 mg.kg-1 x h-1 groups, respectively. Activated partial thromboplastin times (aPTT) at 3, 4, and 6 hours were averaged into a plateau value. The aPTT plateau-to-baseline ratios were 1.5 +/- 0.1, 2.0 +/- 0.1, 2.3 +/- 0.1, 2.7 +/- 0.1, and 2.9 +/- 0.1, respectively, with hirudin infused at 0.02, 0.05, 0.1, 0.2, and 0.3 mg.kg-1 x h-1. From 62% to 77% of the aPTT plateau value was seen within 30 minutes of starting the infusions and was directly related to dose. The aPTT-to-baseline ratios correlated well with plasma hirudin levels (r = .88), whereas poor correlation and sensitivity were observed between plasma hirudin levels and activated coagulation time (ACT)-to-baseline ratios (r = .44). Plasma levels of hirudin and ACT in seconds correlated overall well (r = .80), but considerable overlap occurred between baseline ACT and ACT at plasma hirudin concentrations < 1000 ng/mL. Prothrombin times were significantly prolonged only at a dosage of > or = 0.05 mg.kg-1 x h-1 and were 11.8 +/- 0.5 (INR = 1.0), 12.3 +/- 0.7 (INR = 1.1), 13.3 +/- 1.2 (INR = 1.4), 14.2 +/- 0.4 (INR = 1.7), and 15.8 +/- 0.9 (INR = 2.3) seconds for each respective hirudin dosage. Thrombin times were beyond range (> 600 seconds) at 6 hours in all except 2 patients who received the lowest dosage. All parameters returned to baseline between 8 and 18 hours after the infusion. Bleeding times were not significantly prolonged. No side effects occurred. No antibodies to hirudin were detected 2 weeks after the infusion.. Recombinant hirudin has a terminal half-life of 2 to 3 hours. The aPTT correlates well with plasma levels of hirudin and allows close titration over a wide range of anticoagulation, while ACT and prothrombin time are relatively insensitive for monitoring hirudin administration. At anticoagulant levels effective in experimental thrombosis, a 6-hour infusion of hirudin is well tolerated and safe in a predominantly male group of patients with stable coronary atherosclerosis.

Topics: Aged; Bleeding Time; Blood Coagulation; Blood Coagulation Tests; Chronic Disease; Coronary Disease; Dose-Response Relationship, Drug; Female; Half-Life; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins

This study was designed to determine whether maintenance of patency in coronary arteries with high grade stenosis after thrombolysis with tissue-type plasminogen activator requires inhibition of thrombin or platelets, or both.. Activation of both thrombin and platelets has been implicated in delaying coronary recanalization induced with fibrinolytic drugs and in predisposing to reocclusion.. Hirudin (1.5 mg/kg body weight) or aspirin (5 mg/kg), or both, was given conjunctively with tissue-type plasminogen activator in 28 conscious dogs with coronary thrombosis induced by electrical stimulation of the vessel wall in the presence of a previously placed high grade distal stenosis (85 +/- 12% [SEM] area reduction).. Among 22 dogs exhibiting coronary recanalization, hirudin plus aspirin, but neither agent alone, modestly shortened the interval to recanalization (31 +/- 4 min with saline solution, n = 6; 29 +/- 4 min with aspirin, n = 5; 23 +/- 9 min with hirudin, n = 6; 21 +/- 7 min with hirudin+aspirin, n = 5). Reocclusion occurred promptly and persisted in five of six dogs given only saline solution plus tissue-type plasminogen activator, in four of six dogs given hirudin and five of five dogs given aspirin; however, reocclusion was prevented in all five of the dogs given both hirudin and aspirin with tissue-type plasminogen activator (p < 0.05 compared with saline-treated dogs). In dogs given both hirudin and aspirin, the partial thromboplastin time was 2.4 +/- 0.3 times baseline, and the template bleeding time was prolonged only modestly (1.6 +/- 0.3 times baseline).. Thus, the combination of hirudin and aspirin in doses that do not markedly perturb hemostasis prevents early reocclusion after thrombolysis despite the presence of severe stenosis. Accordingly, conjunctive administration of both anti-thrombin and antiplatelet agents appears to be necessary for optimal maintenance of patency after thrombolysis induced in the presence of high grade coronary stenosis.

Topics: Animals; Aspirin; Blood Platelets; Coronary Disease; Dogs; Drug Therapy, Combination; Hirudin Therapy; Hirudins; Male; Recurrence; Thrombin; Thrombolytic Therapy; Tissue Plasminogen Activator; Vascular Patency

The changes in blood coagulative properties, which occur in the treatment with medical leeches, were studied in 57 patients with coronary heart, rheumatic and chronic pulmonary diseases. Hirudin therapy was established to affect blood coagulation. The leech salina penetrated into the skin wound to block hemostasis. Having entered the circulating blood, some part of the saliva normalized its impaired coagulative properties. The correction of the above abnormalities and related bleeding indicate it beneficial to use hirudin therapy in secondary coagulopathies and circulatory decompensation.

Topics: Blood Coagulation; Cardiovascular Diseases; Coronary Disease; Hirudin Therapy; Hirudins; Humans; Middle Aged; Pulmonary Heart Disease; Rheumatic Heart Disease

The objectives of this study were to test the hypotheses that thrombin inhibitors 1) enhance tissue-type plasminogen activator (t-PA)-induced coronary thrombolysis and 2) prevent or delay coronary artery reocclusion. Seventy-one dogs developed occlusive coronary thrombi after introducing a copper coil into the left anterior descending coronary artery (LAD). Coronary blood flows were monitored by an externally positioned pulsed Doppler flow probe. t-PA was given with or without heparin at different times after LAD occlusions. In some experiments, hirugen, a synthetic hirudin-based peptide and specific thrombin inhibitor, was given as 4 mg/kg i.v. bolus and 3 mg.kg-1.h-1 i.v. infusion at 30 min after LAD occlusion with t-PA and a bolus of heparin. Thrombolysis times were significantly shorter in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Reocclusion times were significantly longer in t-PA- and heparin-treated dogs than in dogs treated with t-PA alone. Continuous heparin infusions prolonged reocclusion times to greater than 180 min in all treated dogs. The addition of hirugen to t-PA plus one bolus heparin prolonged reocclusion times to 90 +/- 6 min in dogs with 30-min thrombi. Thus heparin enhances t-PA-induced thrombolysis and delays reocclusion. Addition of a specific thrombin inhibitor, such as hirugen, to heparin enhances its effect on delaying reocclusion.

Topics: Animals; Blood Coagulation; Coronary Disease; Dogs; Fibrinolytic Agents; Heparin; Hirudins; Peptide Fragments; Platelet Aggregation; Recurrence; Thrombin; Time Factors; Tissue Plasminogen Activator

Effective thrombolytic recanalization of an occluded coronary vessel is often limited by acute thrombotic reocclusion, which has galvanized the search for effective adjunctive or conjunctive antithrombotic agents.. Recombinant versions of tick anticoagulant peptide (rTAP) and hirudin (rHIR) are highly selective and potent polypeptide inhibitors of factor Xa and thrombin, respectively. The comparative antithrombotic efficacies of rTAP, rHIR, and heparin, administered conjunctively with recombinant tissue-type plasminogen activator (rt-PA), on thrombolytic reperfusion and reocclusion, were determined in a canine model of occlusive coronary artery thrombosis with a superimposed critical stenosis. In this model, a platelet-rich occlusive thrombus was formed after damage to the intimal surface of the left circumflex coronary artery induced by electrolytic injury. Fifteen minutes after occlusion, the dogs received a systemic intravenous administration of either saline (control), heparin (200 units/kg bolus + 2 units/kg/min, heparin (HEP) 200 or 100 units/kg bolus + 1 unit/kg/min, HEP 100), rHIR (50 or 100 micrograms/kg/min, rHIR 50 or 100, respectively), or rTAP (100 micrograms/kg/min, rTAP 100) followed 15 minutes later by rt-PA (100 micrograms/kg bolus + 10 micrograms/kg/min over 90 minutes). Infusions of the conjunctive agents were discontinued 60 minutes after termination of rt-PA. The incidence and time (mean +/- SEM) to thrombolytic reperfusion were determined for control (five of 12; 68.0 +/- 7.8 minutes), HEP 100 (six of eight; 40.1 +/- 8.3 minutes), HEP 200 (six of eight; 39.8 +/- 9.5 minutes), rHIR 50 (six of eight; 51.7 +/- 14.6 minutes), rHIR 100 (eight of eight; 19.5 +/- 4.2 minutes), and rTAP 100 (eight of eight; 22.8 +/- 10.0 minutes). The incidence and time to reocclusion after rt-PA were determined for control (four of five; 45.7 +/- 12.5 minutes), HEP 100 (four of six; 18.2 +/- 10.7 minutes), HEP 200 (five of six; 26.2 +/- 20.7 minutes), rHIR 50 (four of six; 47.3 +/- 21.6 minutes), rHIR 100 (six of eight; 89.8 +/- 5.9 minutes), and rTAP 100 (three of eight; 54.0 +/- 16.3 minutes). All of the dogs that reoccluded in the rHIR 100 group did so after termination of the inhibitor infusion, whereas two of the three dogs in the rTAP 100 group that reoccluded did so during the inhibitor infusion. Coronary artery blood flow was characterized by intermittent periods of reocclusion and recanalization in all groups except rTAP 100.. The potent antithrombotic effects of rTAP in this model directly implicate de novo thrombin formation as a major source of thrombin activity within the highly thrombogenic residual thrombus. These findings suggest that direct inhibition of prothrombinase activity may be an effective strategy in the development of a new class of conjunctive agents.

Topics: Animals; Arthropod Proteins; Coronary Circulation; Coronary Disease; Dogs; Drug Synergism; Factor Xa Inhibitors; Female; Hemodynamics; Hemostasis; Heparin; Hirudins; Intercellular Signaling Peptides and Proteins; Male; Myocardial Reperfusion; Peptides; Recombinant Proteins; Recurrence; Tissue Plasminogen Activator

The antithrombotic activity of hirudin was studied in a rat coronary thrombosis model. The thrombus formation was induced by external application of silver nitrate solution onto the left anterior descending coronary artery. Following subcutaneous injection, hirudin in doses of 0.25, 0.5 and 1.0 mg/kg reduced the development of coronary thrombosis in a dose-dependent manner. The most pronounced antithrombotic effect of hirudin in the described model was related with plasma concentrations between 0.20 and 0.35 microgram hirudin/ml.

Topics: Animals; Coronary Disease; Coronary Thrombosis; Disease Models, Animal; Female; Fibrinolytic Agents; Hirudins; Injections, Subcutaneous; Male; Rats; Rats, Inbred Strains

To investigate the clinical implications and mechanisms of spontaneous platelet aggregation (SPA) in man, 150 normal subjects, 22 patient controls and 130 patients with vascular insufficiency were studied. SPA was negative in normal subjects and patient controls whereas it was positive in 36 of 66 (54%) patients with transient ischemic attacks, 6 of 32 (19%) patients with stable angina, 7 of 10 (70%) patients with acute myocardial infarction and 11 of 14 (80%) patients with acute peripheral arterial insufficiency. The SPA was inhibited with aspirin in vivo, and inhibited competitively in vitro by low concentrations of aspirin, 2-chloroadenosine, prostaglandin E1 or apyrase but only by high concentrations of heparin or hirudin. Addition of platelet-poor plasma from patients with positive SPA did not cause normal platelets to aggregate. Treatment of patients who had acute peripheral arterial insufficiency with aspirin and dipyridamole prevented SPA with notable clinical improvement of the ischemic changes.

Topics: Adenosine; Adult; Aged; Angina Pectoris; Apyrase; Arterial Occlusive Diseases; Aspirin; Coronary Disease; Dipyridamole; Heparin; Hirudins; Humans; Ischemic Attack, Transient; Middle Aged; Myocardial Infarction; Platelet Aggregation; Prostaglandins E

A new device for the direct assessment of spontaneous platelet aggregation in human venous blood is described: the Filtragometer. The principle of the method is based on measurement of the pressure difference across a filter with pores of 20 mum diameter through which blood from a forearm vein is drawn. Platelet aggregates, obstructing the filter, cause a change in the pressure difference which is proportional to the degree of platelet aggregation. The measurement takes only a short time and a small amount (5-10 ml) of blood. Platelet aggregation as measured with the Filtragometer depends on the type of anticoagulant used. The Filtragometer response decreases on inhibition of platelet stickiness in vitro by prostaglandin E1 and in vivo by aspirin ingestion. Moreover it appeared to be higher in a group with a high thrombosis tendency than in a group less susceptible to fatal arterial thrombosis. The Filtragometer seems especially useful in monitoring the results of diet and/or drug therapy.

Topics: Aspirin; Citrates; Coronary Disease; Female; Heparin; Hirudins; Humans; Male; Methods; Micropore Filters; Microscopy, Electron, Scanning; Platelet Aggregation; Prostaglandins E; Thromboembolism; Ultracentrifugation; Ultrafiltration; Venous Pressure

Topics: Animals; Arginine; Benzamides; Cattle; Coronary Disease; Coumarins; Factor VIII; Fibrinogen; Hirudins; Humans; Hydrolysis; Naphthalenes; Protein Binding; Prothrombin; Serum Albumin; Thrombin; Thromboplastin