hirudin and Renal-Insufficiency

Direct thrombin inhibitors (DTIs) are an emerging class of anticoagulants in routine clinical practice, although they have been under investigation for quite some time. Desirudin (Iprivask®, Canyon Pharmaceuticals™) is a recombinant hirudin derivative that directly inhibits free and fibrin-bound thrombin. Desirudin was the first DTI approved for deep vein thrombosis (DVT) prophylaxis in Europe (Revasc®) and is the newest injectable DTI commercially available in the USA. Desirudin is one of the few nonheparin subcutaneous drugs that has demonstrable efficacy for DVT prophylaxis. Subcutaneous desirudin has been shown to be more effective than both subcutaneous unfractionated heparin and enoxaparin, with comparable bleeding rates in the prevention of DVT in patients undergoing elective hip replacement. Desirudin also offers the advantage of a fixed dosing regimen while being less immunogenic than unfractionated heparin. However, owing to its pharmacokinetic properties, patients with renal dysfunction require dosing modifications. The favorable profile shown with desirudin thus far will allow its clinical use to grow and will promote further investigation into broadening its clinical applications.

Topics: Animals; Anticoagulants; Antithrombins; Dose-Response Relationship, Drug; Hemorrhage; Hirudins; Humans; Recombinant Proteins; Renal Insufficiency; Venous Thrombosis

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

Recombinant hirudins (r-hirudins) are potent direct thrombin inhibitors increasingly used for alternative anticoagulation, especially in heparin-induced thrombocytopenia. R-hirudins are almost exclusively eliminated by the kidneys, and a close correlation between r-hirudin clearance and endogenous creatinine clearance has been observed. Accordingly, the pharmacokinetics of r-hirudin are altered in patients with renal insufficiency. A decline of renal r-hirudin clearance is associated with an increase of r-hirudin half-life and the area under the curve (AUC). Therefore, renal impairment necessitates reduction of r-hirudin dose to avoid overdose or inadequate accumulation of the thrombin inhibitor. To this end, close monitoring of r-hirudin anticoagulation is required, which at best is performed by measuring r-hirudin blood levels by ecarin clotting times (ECT) or chromogenic assays, in addition to activated partial thromboplastin time (aPTT). Recent studies showed that r-hirudin anticoagulation is feasible in acute or chronic renal failure treated with continuous or intermittent renal replacement therapy, if appropriate r-hirudin dosing and adequate monitoring are warranted. High-volume hemofiltration with r-hirudin-permeable hemodialyzers constitutes a valuable means to markedly reduce r-hirudin blood concentration and total r-hirudin body content in case of r-hirudin overdose or r-hirudin-associated bleeding. In the future, the hepatically eliminated direct thrombin inhibitor argatroban may facilitate alternative anticoagulation in patients with renal insufficiency.

Topics: Adult; Aged; Anticoagulants; Area Under Curve; Clinical Trials as Topic; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Kidney; Middle Aged; Recombinant Proteins; Renal Dialysis; 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

Critically ill patients often require renal replacement therapy accompanied by thrombocytopenia. Thrombocytopenia during heparin anticoagulation may be due to heparin-induced thrombocytopenia with need for alternative anticoagulation. Therefore, we compared argatroban and lepirudin in critically ill surgical patients.. Following institutional review board approval and written informed consent, critically ill surgical patients more than or equal to 18 years with suspected heparin-induced thrombocytopenia, were randomly assigned to receive double-blind argatroban or lepirudin anticoagulation targeting an activated Partial Thromboplastin Time (aPTT) of 1.5 to 2 times baseline. In patients requiring continuous renal replacement therapy we compared the life-time of hemodialysis filters. We evaluated in all patients the incidence of bleeding and thrombembolic events.. We identified 66 patients with suspected heparin-induced thrombocytopenia, including 28 requiring renal replacement therapy. Mean filter lifetimes did not differ between groups (argatroban 32 ± 25 hours (n = 12) versus lepirudin 27 ± 21 hours (n = 16), mean difference 5 hours, 95% CI -13 to 23, P = 0.227). Among all 66 patients, relevant bleeding occurred in four argatroban- versus eleven lepirudin-patients (OR 3.9, 95% CI 1.1 to 14.0, P = 0.040). In the argatroban-group, three thromboembolic events occurred compared to two in the lepirudin group (OR 0.7, 95% CI 0.1 to 4.4, P = 0.639). The incidence of confirmed heparin-induced thrombocytopenia was 23% (n = 15) in our study population.. This first randomized controlled double-blind trial comparing two direct thrombin inhibitors showed comparable effectiveness for renal replacement therapy, but suggests fewer bleeds in surgical patients with argatroban anticoagulation.. Clinical Trials.gov NCT00798525. Registered 25 November 2008.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Arginine; Critical Illness; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Recombinant Proteins; Renal Insufficiency; Renal Replacement Therapy; Sulfonamides; Surgical Procedures, Operative; Thrombocytopenia

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

The recommended dose (bolus 0.4 mg/kg followed by 0.15 mg/kg per hour) of lepirudin, a direct thrombin inhibitor licensed for treatment of heparin-induced thrombocytopenia (HIT), is too high. Starting in 2001, we omitted the bolus and reduced maintenance dose by at least one-third. Analyzing 53 HIT patients treated between January 2001 and February 2007, we observed that therapeutic anticoagulation intensity already 4 hours after lepirudin start had been reached with the following initial lepirudin doses (median): 0.078 mg/kg per hour [creatinine clearance (CrCl) more than 60 mL/min], 0.040 mg/kg per hour (CrCl 30-60 mL/min), and 0.013 mg/kg per hour (CrCl < 30 mL/min). The efficacy of this treatment was documented by increasing platelets and decreasing D-dimers. Based on this experience, we derived a lepirudin dosing regimen, which was prospectively evaluated treating 15 HIT patients between March 2007 and February 2008. We show that omitting the initial lepirudin bolus and administering 0.08 mg/kg per hour in patients with CrCl more than 60 mL/min, 0.04 mg/kg per hour in patients with CrCl 30-60 mL/min, and 0.01 to 0.02 mg/kg per hour in those with CrCl less than 30 mL/min is efficacious and safe, as documented by increasing platelet counts, decreasing D-dimer levels, and rare thrombotic (1 of 46) and major bleeding (4 of 46) complications.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Cell Count; Blood Platelets; Creatine; Dose-Response Relationship, Drug; Female; Heparin; Hirudins; Humans; Kidney; Male; Metabolic Clearance Rate; Middle Aged; Recombinant Proteins; Renal Insufficiency; Retrospective Studies; Thrombocytopenia; 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

To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function.. Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg.. Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four.. A dose reduction by a factor of six is recommended for persons with severe renal failure.

Topics: Adult; Aged; Anticoagulants; Creatinine; Female; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Severity of Illness Index

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

Desirudin is a renally eliminated direct thrombin inhibitor approved to prevent venous thromboembolism. Empiric dosage adjustment and activated partial thromboplastin time (aPTT) monitoring in patients with moderate renal impairment are recommended, but supportive data are lacking. The objective of this study was to evaluate appropriate desirudin dosing in moderate renal impairment and the effect of desirudin on aPTT in moderate renal impairment. Desirudin plasma concentration and aPTT data were extracted from 6 studies. Participants with normal renal function or moderate renal impairment (creatinine clearance [ClCr] 31-60 mL/min) were included. Pharmacokinetic and Monte Carlo simulations were done. After administration of desirudin 15 mg every 12 hours subcutaneously (SC) to steady state, peak desirudin concentrations were 35 and 47 nmol/L in the normal and moderate renal function groups, respectively. Monte Carlo simulations found median 2-hour C(max) concentrations of 51.7 nmol/L in normal renal function and 52.4 nmol/L in moderate renal impairment. Desirudin exhibits a linear relationship when the square root of desirudin concentration is plotted versus the aPTT ratio (r(2) = 0.76). These analyses support the dosing of desirudin at 15 mg every 12 hours SC without aPTT monitoring in patients with moderate renal impairment.

Topics: Anticoagulants; Drug Administration Schedule; Drug Monitoring; Hirudins; Humans; Injections, Subcutaneous; Monte Carlo Method; Partial Thromboplastin Time; Recombinant Proteins; Renal Insufficiency

Topics: Anticoagulants; Antiphospholipid Syndrome; Cerebral Hemorrhage; Drug Administration Schedule; Half-Life; Heparin; Hirudins; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia; Treatment Outcome

Lepirudin, a recombinant DNA derivative of hirudin, is used to prevent thromboembolic complications caused by heparin-induced thrombocytopenia type II. Anaphylactic and anaphylactoid reactions have been reported with its use in patients both with and without known previous exposure to lepirudin. We describe the case of a 57-year-old woman who received five uneventful courses of lepirudin therapy before having a severe anaphylactic reaction during administration of the intravenous bolus dose that began her sixth course. The patient experienced cardiorespiratory arrest but recovered from the reaction. The decision to administer lepirudin to a patient who has previously received it should be reached with due consideration of the risk:benefit ratio and strategies to manage risk resulting from readministration. Risk factors for an anaphylactic reaction to lepirudin may include use of an initial bolus dose, intravenous rather than subcutaneous administration, length of any single course of therapy beyond 3 days, and repeat administration of lepirudin within 100 days.

Topics: Anaphylaxis; Antibodies; Anticoagulants; Female; Heart Arrest; Hirudins; Humans; Injections, Intravenous; Middle Aged; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency; Respiratory Insufficiency; Risk Factors; Risk Management

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

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

We report a patient who developed type II heparin-induced thrombocytopenia (HIT) and accidentally received a recombinant hirudin (r-hirudin) overdosage. Treatment with hemodialysis (HD) using high-flux polysulfone dialyzer and hemofiltration was performed. Length of treatment was adjusted, monitoring activated partial thromboplastin time (aPTT) to 1.5-2.5 times the mean of the normal range. She developed deep venous thrombosis and occlusion of vascular access. Only after cessation of heparin lock catheter, platelet count began to increase. After one year of treatment with acenocoumarol and additional low-dose r-hirudin, neither bleeding nor thrombotic episodes have been reported.

Topics: Aged; Drug Overdose; Female; Hemofiltration; Heparin; Hirudin Therapy; Hirudins; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; 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

Topics: Aged; Anticoagulants; Dose-Response Relationship, Drug; Heparin; Hirudins; Humans; Recombinant Proteins; Renal Insufficiency; Thrombocytopenia; United States

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

An 81-year-old woman with a history of prior coronary artery bypass surgery, heparin-induced thrombocytopenia with "white clot" syndrome, and renal insufficiency presented with unstable angina. She was referred for cardiac catheterization. Complex percutaneous revascularization of the native circumflex coronary artery was performed using stents. A combination of tirofiban and lepirudin was used with dosing adjusted for renal insufficiency. The hospital course was uncomplicated and the patient was discharged on the fourth hospital day. This is only the second report of the combination use of direct thrombin inhibitor and glycoprotein IIb/IIIa receptor inhibitor.

Topics: Aged; Aged, 80 and over; Anticoagulants; Combined Modality Therapy; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Platelet Aggregation Inhibitors; Recombinant Proteins; Renal Insufficiency; Stents; Thrombocytopenia; Tirofiban; Tyrosine

Lepirudin is a direct thrombin inhibitor indicated for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. In patients with normal renal function, a bolus dose of 0.4 mg/kg is injected over 15-20 seconds, followed by a continuous infusion of 0.15 mg/kg/hour adjusted to prolong the activated partial thromboplastin time (aPTT) to 1.5-2.5 times the patient's baseline. Because renal function directly influences lepirudin elimination, patients with renal impairment require significant adjustments in the initial infusion rate. Current recommendations suggest that patients with dialysis-dependent renal failure should receive an initial bolus of 0.2 mg/kg, followed by 0.1 mg/kg every other day if the aPTT falls below the lower limit of the therapeutic range; however, this dosing may result in significant and prolonged overanticoagulation. A review of available literature regarding pharmacokinetics of lepirudin in renal failure suggests considerable variability in patient response over a narrow creatinine clearance range. Because there is no antidote for lepirudin if significant bleeding occurs, lower and less frequent dosing, guided by aPTT results, is recommended.

Topics: Anticoagulants; Female; Hirudins; Humans; Middle Aged; Partial Thromboplastin Time; Platelet Aggregation; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Recently heparin-induced thrombocytopenia type II has been diagnosed more frequently and does not exclude hemodialysis patients. Up to now, recombinant hirudin is the only available anticoagulant showing no immunologic cross reactions with heparin. However, the use of r-hirudin in hemodialysis patients with different degrees of residual renal functions is impossible using standard dosages because elimination of r-hirudin varies depending on the degree of residual renal function. Therefore the first study was carried out using consecutive r-hirudin anticoagulated hemodialyses to determine the appropriate dose of r-hirudin. Ten hemodialysis patients with creatinine clearance values ranging between 0 and 13 mL/min/1.73m2 were anticoagulated with r-hirudin. An initial bolus of 0.1 mg/kg bwt before the first hemodialysis, resulted in an average r-hirudin blood concentration of 305 ng/mL at the end of treatment. The dose for each of the following four hemodialyses was adjusted individually to reach the minimum therapeutic r-hirudin blood concentration. At the end of these treatments the mean blood r-hirudin concentration was 422 ng/mL. The necessary mean doses ranged between 0.008 and 0.125 mg/kg bwt correlating to the creatinine clearance values of the patients. All hemodialyses of the study were effective and safe. Bleeding times determined during r-hirudin anticoagulation were significantly lower than control values measured 2 days after a heparin administration. The study proved that r-hirudin may be an efficient and safe heparin alternative as a hemodialysis anticoagulant when the individual's residual renal function is noted for dosage and dose adjustment and is controlled by drug monitoring using the ecarin clotting time.

Topics: Adult; Bleeding Time; Fibrinolytic Agents; Hirudins; Humans; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency