bivalirudin and Renal-Insufficiency

Direct thrombin inhibitors have several potential advantages over indirect thrombin inhibitors such as heparin. Bivalirudin, a bivalent direct thrombin inhibitor, is most commonly used in clinical practice and has a proven role in contemporary interventional medicine with elective percutaneous coronary intervention (PCI) as well as in patients with non-ST-elevation acute coronary syndrome (NSTEACS). Results from well-controlled clinical trials have shown that bivalirudin is associated with an approximate 50% reduction in major bleeding while having similar effects on incidence of death and myocardial infarction (MI) compared with herapin or enoxaparin and glycoprotein IIb/IIIa inhibitors. Bivalirudin has been successfully used in off- and on-pump cardiac surgery. Argatroban is the most evaluated among the univalent direct thrombin inhibitors inhibiting only the catalytic site of thrombin. It has been associated with similar rates of major bleeding compared with heparin in patients with acute MI receiving either streptokinase or alteplase with no effects on clinical endpoints. In a meta-analysis of 11 randomised trials where direct thrombin inhibitors (hirudin, bivalirudin, argatroban, efegatan or inogatran) were compared with unfractionated heparin in >35,000 patients with ST-elevation MI (STEMI) or NSTEACS there was no mortality difference between treatment groups but the incidence of MI at 30 days was significantly reduced in patients treated with direct thrombin inhibitors compared with heparin (4.7% vs 5.3%; p < 0.004). The role of direct thrombin inhibitors in both primary angioplasty for STEMI and angioplasty after fibrinolytic therapy needs to be established. Overall, the efficacy and improved safety profile make bivalirudin an attractive first-line anticoagulant for elective PCI and in patients with NSTEACS undergoing an invasive strategy.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Fibrinolysis; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Thrombin; Thrombocytopenia

Bivalirudin (Angiox, Angiomax) is a synthetic 20-amino acid peptide analogue of hirudin. It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin. Intravenous bivalirudin is approved in Europe for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). In the US, bivalirudin is approved in patients with unstable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and has recently been approved for use with provisional glycoprotein (GP) IIb/IIIa inhibition in patients undergoing PCI. Bivalirudin plus provisional GP IIb/IIIa inhibition is effective in patients undergoing PCI. The large, well controlled REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) study showed that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition and that bivalirudin was associated with a reduced risk of bleeding complications. In patients with heparin-induced thrombocytopenia (HIT), bivalirudin was effective against ischaemic events and there was a low incidence of bleeding complications. Bivalirudin should be considered as an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elective PCI, especially in any patient with a high risk of bleeding complications.

Topics: Angioplasty, Balloon, Coronary; Anticoagulants; Brachytherapy; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hirudins; Humans; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Renal Insufficiency

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

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

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

Bivalirudin, a direct thrombin inhibitor, is as effective as unfractionated heparin (UFH), with decreased bleeding in patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI). The aim of this study was to evaluate the effectiveness of bivalirudin versus UFH in selected PCI patients at high bleeding risk. Four hundred one consecutive patients who underwent PCI fulfilling ≥ 1 enrollment criterion (age >75 years, chronic renal failure, and diabetes mellitus) were randomized to bivalirudin (bolus 0.75 mg/kg followed by infusion during the procedure; n = 198) or UFH (75 IU/kg; n = 203). In the overall population, 39% were aged >75 years, 22% had renal failure, 63% had diabetes, and 29% had acute coronary syndromes. The primary efficacy end point was the 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, stent thrombosis, or target vessel revascularization). The primary safety end point was the occurrence of any bleeding or entry-site complications after PCI. All patients were preloaded with clopidogrel 600 mg. Glycoprotein IIb/IIIa inhibitors were used at the operators' discretion. Thirty-day major adverse cardiac event rates were 11.1% in the bivalirudin group and 8.9% in the UFH group (p = 0.56); the primary efficacy end point was reached mainly because of periprocedural myocardial infarction; 1 patient in the bivalirudin group had stent thrombosis. Occurrence of the primary safety end point was 1.5% in the bivalirudin group and 9.9% in the UFH group (p = 0.0001); this benefit was essentially driven by the prevention of entry-site hematomas >10 cm (0.5% vs 6.9%, p = 0.002). In conclusion, Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin (ARMYDA-7 BIVALVE) indicates that bivalirudin, compared with UFH, causes significantly lower bleeding and has a similar incidence of major adverse cardiac events in patients with older age, diabetes mellitus, or chronic renal failure who undergo PCI.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Antithrombins; Coronary Artery Disease; Diabetes Complications; Drug Therapy, Combination; Female; Heart Diseases; Heparin; Hirudins; Humans; Incidence; Male; Myocardial Infarction; Peptide Fragments; Platelet Glycoprotein GPIIb-IIIa Complex; Postoperative Complications; Postoperative Hemorrhage; Recombinant Proteins; Renal Insufficiency; Treatment Outcome

Among patients who undergo percutaneous coronary intervention, renal impairment is associated with an excessive risk of bleeding and ischemic events. Bivalirudin provides comparable suppression of ischemic events with a decrease in bleeding events compared with heparin and glycoprotein IIb/IIIa inhibition. We examined the relation between adverse events, renal impairment, and antithrombotic therapy within a randomized comparison. The Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events per-protocol study population was assessed. Renal function was defined as calculated creatinine clearance <60 ml/min. Events within the overall study population and within each study arm were assessed. Thirty-day events by renal function were compared by chi-square test and logistic regression. Late mortality was compared by log-rank test. Interaction analyses were performed. Among 5,710 patients, renal impairment was associated with increased ischemic events (hazard ratio 1.45, 95% confidence interval 1.13 to 1.88, p = 0.004), bleeding complications (hazard ratio 1.72, 95% confidence interval 1.06 to 2.80, p = 0.028), and excessive 12-month mortality (hazard ratio 3.85, 95% confidence interval 2.67 to 5.54, p <0.001). Bivalirudin provided suppression of ischemic events that was comparable to heparin and glycoprotein IIb/IIIa inhibition regardless of renal impairment. Fewer bleeding events with bivalirudin were also evident irrespective of renal dysfunction. No interaction between treatment assignment, bleeding or ischemic complications, and renal impairment was observed. The safety and efficacy of bivalirudin compared with heparin and planned glycoprotein IIb/IIIa inhibition in this high-risk group are comparable and consistent with the results of the overall trial.

Topics: Abciximab; Aged; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Atherectomy, Coronary; Chi-Square Distribution; Double-Blind Method; Drug Therapy, Combination; Eptifibatide; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Intraoperative Complications; Ischemia; Logistic Models; Male; Middle Aged; Peptide Fragments; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Renal Insufficiency; Stents; Survival Analysis; Treatment Outcome

Bivalirudin offers several important advantages of relevance to the management of extracorporeal membrane oxygenation (ECMO) patients. This multicenter retrospective analysis evaluated the bivalirudin dosing in pediatric ECMO and correlated these doses with the severity of renal dysfunction. A total of 75 patients were included in this analyses: estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m 2 (n = 29), eGFR 30-60 (n = 18), eGFR < 30 (n = 28), and of those 23 were on renal replacement therapy (RRT). The initial bivalirudin dose used to reach therapeutic anticoagulation in patients with eGFR > 60 was significantly higher than the dose required in those with renal impairment (0.25 mg/kg/hr in patients with eGFR > 60 and 0.19 mg/kg/hr in patients on RRT, 0.18 mg/kg/hr in patients with eGFR 30-60 and 0.13 mg/kg/hr in patients with eGFR < 30 with no RRT). Progressive dose escalations (two to threefold increase) were required to maintain therapeutic range over the initial 4 days of ECMO that coincided with improving renal creatinine clearance during that same time period. Establishing an initial starting dose of bivalirudin contingent upon eGFR is essential for the rapid achievement of target anticoagulation intensity. Further dose adjustments guided by laboratory monitoring is necessary given the dynamic changes in creatinine clearance following ECMO initiation.

Topics: Anticoagulants; Child; Creatinine; Extracorporeal Membrane Oxygenation; Humans; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Renal Replacement Therapy; Retrospective Studies

Acute heparin-induced thrombocytopenia (HIT) patients present a myriad of anticoagulation management challenges, in clinical settings where unfractionated heparin (UFH) is the traditional drug of choice. UFH use in cardiac surgery is a known entity that has been subject to rigorous research. Research has, thus, led to its unparalleled use and the development of well-established protocols for cardiac surgery. In comparison to UFH, bivalirudin use for acute HIT patients requiring urgent cardiac surgery with cardiopulmonary bypass (CPB) is still in its infancy. We describe the tailored post-CPB management of refractory bleeding in a 65-year-old infective endocarditis, acute HIT patient with renal failure who underwent urgent aortic valve replacement and mitral valve repair with bivalirudin anticoagulation. A management approach that entailed a combination of continuous venovenous haemofiltration (CVVH), 4-Factor prothrombin complex concentrate (PCC) (Beriplex), recombinant factor VIIa (rFactor VIIa) and desmopressin (DDAVP) were consecutively used post-operatively in theatre. Based on this case study experience, two modifications to institutional protocols are recommended. The first is the use of CVVH in theatre to eliminate bivalirudin in renal failure patients or in patients where bivalirudin elimination is prolonged. Secondly, a 'rescue therapy/intervention' algorithm for the swift identification of refractory bleeding post-CPB is also recommended. Rescue therapy agents, such as a 4-Factor PCCs and rFactor VIIa, should be incorporated into the protocol after a robust evidence-based search and agreement with the haematologist. The aim of these recommendations is to reduce the risk of bleeding associated with bivalirudin use for inexperienced institutions and experienced institutions alike, until larger randomized, controlled studies provide more in-depth knowledge to expand our clinical practice.

Topics: Acute Disease; Aged; Anticoagulants; Aortic Valve; Blood Coagulation Factors; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Deamino Arginine Vasopressin; Factor VIIa; Hemorrhage; Hemostatics; Heparin; Hirudins; Humans; Male; Mitral Valve; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia

Topics: Heart Ventricles; Heart-Assist Devices; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia

Limited data are available regarding adverse bleeding events associated with antithrombotic agents incorrectly dosed based on renal function in patients receiving percutaneous coronary intervention (PCI).. To compare the incidence of bleeding during their hospital stay in patients with reduced renal function receiving incorrect doses of bivalirudin or eptifibatide to the incidence of correct doses, based on manufacturer recommendations; secondary objectives were to determine the incidence of correct dosing based on manufacturer recommendations and the incidence of TIMI (Thrombolysis in Myocardial Infarction) major bleeding.. A chart review over a 32-month period showed that patients with reduced renal function who received either eptifibatide or bivalirudin during PCI were evaluated for correct dosing based on manufacturer recommendations, bleeding incidence according to the TIMI criteria, and extent of bleeding according to the TIMI and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) criteria.. One hundred ninety patients met inclusion criteria, 56 who received eptifibatide and 134 who received bivalirudin. Eptifibatide was dosed incorrectly in 64% of the patients. Patients receiving incorrectly dosed compared to correctly dosed eptifibatide experienced significantly more bleeding (64% vs 35%, respectively, p = 0.04), a greater extent of bleeding based on the TIMI and GUSTO criteria (p = 0.03 and p = 0.009, respectively), and had more TIMI major bleeding (19% vs 5%, respectively). Bivalirudin was dosed incorrectly in 28% of the patients. Patients receiving incorrectly dosed compared to correctly dosed bivalirudin experienced a significantly greater extent of bleeding based on the GUSTO criteria (p = 0.01). There was no significant difference between the incidence of bleeding (37% vs 21%, respectively; p = 0.06), extent of bleeding based on the TIMI criteria (p = 0.058), or incidence of TIMI major bleeding (5% vs 3%).. Patients receiving incorrectly dosed eptifibatide and bivalirudin are susceptible to adverse bleeding events. The occurrence of incorrect dosing offers an opportunity for pharmacist-driven institutional improvement.

Topics: Aged; Angioplasty, Balloon, Coronary; Antithrombins; Eptifibatide; Female; Glomerular Filtration Rate; Hemorrhage; Hirudins; Humans; Incidence; Male; Medical Records Systems, Computerized; Medication Errors; Middle Aged; Peptide Fragments; Peptides; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency; Thrombosis

Bivalirudin, a direct thrombin inhibitor, is indicated for patients with suspected heparin-induced thrombocytopenia (HIT) with anticipated percutaneous coronary intervention (PCI). Data is limited on dose selection among patients with renal insufficiency, particularly with prolonged infusion durations. The study cohort comprised 73 patients with renal dysfunction who received bivalirudin for suspected HIT with or without acute coronary syndrome. We reviewed individual pharmacy and medical records for laboratory and bivalirudin dosing information, medical comorbidities, and adverse clinical outcomes during administration. When estimated glomerular filtration rate (eGFR) was calculated by the Cockcroft-Gault (CG; ml/min) formula, the average bivalirudin dose (mg/kg/h) achieving a therapeutic activated partial thromboplastin time (aPTT) was 0.07 ± 0.04, 0.15 ± 0.08, and 0.16 ± 0.07 for patients with eGFR between 15-30, 31-60, and >60, respectively. When eGFR was calculated by the modification of diet in renal disease (MDRD; ml/min/1.73 m(2)) formula, the average bivalirudin dose achieving a therapeutic aPTT was 0.07 ± 0.04, 0.12 ± 0.07, and 0.20 ± 0.07 for patients with eGFR between 15-30, 31-60, >60, respectively. The difference between the dose achieving a therapeutic aPTT for patients with eGFR >60 when calculated by MDRD versus CG was completely abolished when obese patients were excluded from the CG cohort. The results of our series of patients with renal dysfunction receiving prolonged duration of bivalirudin in the setting of acute coronary syndrome (ACS) suggests that dose adjustment is safe and should be considered for patients with moderate to severe renal impairment (eGFR < 60 ml/min/1.73 m(2)).

Topics: Aged; Aged, 80 and over; Cohort Studies; Dose-Response Relationship, Drug; Drug Evaluation; Female; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Insufficiency; Retrospective Studies; Thrombocytopenia

While not approved by the Food and Drug Administration for treatment of heparin-induced thrombocytopenia (HIT), except in patients undergoing percutaneous interventions, the direct thrombin inhibitor bivalirudin is a treatment option that is gaining use. An initial dose of bivalirudin 0.15-0.2 mg/kg/h, adjusted to an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the baseline value, has been suggested. Initial dosing in patients with renal dysfunction, including those on hemodialysis, is unclear.. To evaluate initial bivalirudin dosing requirements in patients with and without renal dysfunction, including patients on different forms of dialysis.. A retrospective analysis of 135 patients treated with bivalirudin for HIT between June 2004 and October 2009 was conducted at a tertiary care medical center. The patients were divided into groups, based on renal function. Patients receiving dialysis were divided into 3 subgroups based on the mode of hemodialysis: intermittent hemodialysis (IHD, n = 24), sustained low-efficiency daily diafiltration (SLEDD, n = 12), or continuous renal replacement therapy (CRRT, n = 5). Patients not receiving dialysis were separated into 3 subgroups based on calculated creatinine clearance (CrCl): CrCl >60 mL/min (n = 52), CrCl 30-60 mL/min (n = 26), and CrCl <30 mL/min (n = 16).. Compared with patients with normal renal function (CrCl >60 mL/min), patients with differing degrees of renal dysfunction (CrCl 30-60 and <30 mL/min) required lower doses of bivalirudin to achieve aPTT goal (0.13 vs 0.08 vs 0.05 mg/kg/h, respectively; p < 0.001). Patients on dialysis (IHD, SLEDD, CRRT) also required dose reductions (0.07, 0.09, and 0.07 mg/kg/h) compared with patients with normal renal function, but higher dosing requirements than patients not receiving dialysis with CrCl <30 mL/min.. Patients with renal dysfunction require a reduced dose of bivalirudin to reach a therapeutic aPTT goal. Slightly higher doses may be observed in patients receiving hemodialysis.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Creatinine; Drug Monitoring; Female; Heparin; Hirudins; Humans; Male; Medical Records; Middle Aged; Peptide Fragments; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Severity of Illness Index; Thrombocytopenia; Young Adult

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

Topics: Anesthetics, Intravenous; Anticoagulants; Aortic Valve Insufficiency; Cardiopulmonary Bypass; Heart Valve Prosthesis Implantation; Heparin; Hirudins; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Middle Aged; Peptide Fragments; Propofol; Recombinant Proteins; Renal Insufficiency; Sufentanil; Thrombocytopenia; Whole Blood Coagulation Time

Despite advances in percutaneous coronary intervention (PCI) techniques and adjunctive therapies, the risks of ischemic and bleeding complications with PCI remain significant. These complications are associated with significant morbidity and mortality, as well as substantially higher costs. Bivalirudin is the only antithrombotic agent that has been shown to reduce both ischemic and hemorrhagic complications associated with PCI. Cost models drawn from the results of three clinical trials of bivalirudin have estimated its potential impact on total medical costs. In addition, the number needed to treat to avoid a bleeding complication has been calculated based on patients shown to have a heightened risk of bleeding in the Bivalirudin Angioplasty Trial. In all models assessed, the use of bivalirudin offset most of its own cost through reductions in bleeding and ischemic complications.

Topics: Aged; Angioplasty, Balloon, Coronary; Anticoagulants; Blood Transfusion; Costs and Cost Analysis; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency; Reoperation