hirudin and Angina-Pectoris

The anticoagulant properties of heparin were discovered in 1916, and by the 1930s researchers were evaluating its therapeutic use in clinical trials. Treatment of unstable angina with unfractionated heparin (UFH), in addition to aspirin, was introduced into clinical practice in the early 1980s. UFH was combined with aspirin to suppress thrombin propagation and fibrin formation in patients presenting with acute coronary syndromes (ACS) or patients undergoing percutaneous coronary intervention (PCI). However, UFH stimulates platelets, leading to both activation and aggregation, which may further promote clot formation. Clinical trials have demonstrated that newer agents, such as the low-molecular-weight heparins (LMWHs), are superior to UFH for medical management of unstable angina or non-ST-segment elevation myocardial infarction. Increasingly, the LMWHs have been used as the anticoagulant of choice for patients presenting with ACS. For patients undergoing PCI, LMWH provides no sub-stantial benefit over UFH for anticoagulation; however, direct thrombin inhibitors (DTIs) have demonstrated safety and efficacy in this setting. UFH is likely to be replaced by more effective and safer antithrombin agents, such as DTIs. DTIs have antiplatelet effects, anticoagulant action, and most do not bind to plasma proteins, thereby providing a more consistent dose-response effect than UFH. The FDA has approved 4 parenteral DTIs for various indications: lepirudin, argatroban, bivalirudin, and desirudin. The antiplatelet, anticoagulant, and pharmacokinetic properties of bivalirudin support its use as the anticoagulant of choice for both lower- and higher-risk patients, including those undergoing PCI.

Topics: Acute Disease; Angina Pectoris; Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Models, Molecular; Molecular Structure; Myocardial Ischemia; Peptide Fragments; Pipecolic Acids; Platelet Activation; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thrombosis

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

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Coronary Thrombosis; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Safety; Thrombocytopenia; Treatment Outcome

Topics: Amino Acid Sequence; Angina Pectoris; Antithrombins; Clinical Trials as Topic; Hirudin Therapy; Hirudins; Humans; Molecular Sequence Data; Myocardial Infarction; Thrombin

The combination of glycoprotein IIb/IIIa inhibitors and heparin has not been compared with bivalirudin in studies specifically involving patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compared the two treatments in this patient population.. Immediately before PCI, we randomly assigned, in a double-blind manner, 1721 patients with acute non-ST-segment elevation myocardial infarction to receive abciximab plus unfractionated heparin (861 patients) or bivalirudin (860 patients). The study tested the hypothesis that abciximab and heparin would be superior to bivalirudin with respect to the primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days. Secondary end points included the composite of death, any recurrent myocardial infarction, or urgent target-vessel revascularization (efficacy end point) and major bleeding (safety end point) within 30 days.. The primary end point occurred in 10.9% of the patients in the abciximab group (94 patients) and in 11.0% in the bivalirudin group (95 patients) (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P=0.94). Death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the patients in the abciximab group (110 patients) and in 13.4% in the bivalirudin group (115 patients) (relative risk, 0.96; 95% CI, 0.74 to 1.25; P=0.76). Major bleeding occurred in 4.6% of the patients in the abciximab group (40 patients) as compared with 2.6% in the bivalirudin group (22 patients) (relative risk, 1.84; 95% CI, 1.10 to 3.07; P=0.02).. Abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary end point and increased the risk of bleeding among patients with non-ST-segment elevation myocardial infarction who were undergoing PCI. (Funded by Nycomed Pharma and others; ISAR-REACT 4 ClinicalTrials.gov number, NCT00373451.).

Topics: Abciximab; Adult; Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Antibodies, Monoclonal; Anticoagulants; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Hirudins; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Recurrence; Thrombin

Bivalirudin, with provisional GP IIb/IIIa inhibitor use allows the same protection against ischemic complications while reducing the hemorrhagic complications compared with the systematic association of a GP IIb/IIIa inhibitor plus heparin (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 [Replace-2]). In clinical practice, the use of heparin is not systematically associated with a GP IIb/IIIa inhibitor. That's why we studied the clinical and economic interest of bivalirudin only versus heparin (UFH) only. Opened pragmatic monocentric study carried out in 2007. We made a chronological matching: for each patient treated with bivalirudin, we included the next patient with the same clinical presentation treated with unfractionated heparin. Ninety-two patients were included (46 in each group). The need for a GP IIb/IIIa inhibitor during the PCI was not significantly different between the two groups (p=0.11). No major hemorrhagic complications were observed in the two groups. Prevalence of ecchymosis was not significantly different: 22 % in the UFH group versus 13 % in the bivalirudin group (p=0.27). The average troponin level the next day was significantly higher in the bivalirudin group (p=0,049), although the change in troponin levels before and after the procedure was similar in the two groups. The average cost by patient of anticoagulation by bivalirudin and HNF is very different, respectively 473+/-150 and 51+/-146 euro (p=0.0001). Bivalirudin can be an interesting alternative for patients with a high risk of having complications. But considering its cost this therapy must be used only for selected patients.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Case-Control Studies; Drug Costs; Ecchymosis; Female; Hemorrhage; Heparin; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Punctures; Recombinant Proteins; Risk Factors; Treatment Outcome; Troponin

In ISAR-REACT 3, 30-day outcomes in 4570 biomarker negative patients undergoing percutaneous coronary intervention (PCI) > or =2 h after pre-treatment with 600 mg of clopidogrel revealed less bleeding with bivalirudin compared with unfractionated heparin, but no difference in 30-day net clinical benefit. The objective of the present analysis was to assess the impact of bivalirudin vs. heparin on 1-year outcomes in ISAR-REACT 3.. The primary outcome for this analysis was the composite of death, myocardial infarction, or target vessel revascularization 1 year after randomization. The composite of death or myocardial infarction was a secondary outcome. At 1 year, the primary outcome occurred in 17.1% of patients assigned to bivalirudin vs. 17.5% assigned to heparin [hazard ratio (HR), 0.98; 95% confidence interval (CI), 0.86-1.13; P = 0.816]. The combined incidence of death or myocardial infarction was 7.7% in the bivalirudin group vs. 6.7% in the heparin group (HR, 1.15; 95% CI, 0.93-1.43; P = 0.200). The mortality rate was 1.9% in the bivalirudin group and 1.7% in the heparin group (HR, 1.10; 95% CI, 0.71-1.70; P = 0.667). At 1 year, no significant differences in the primary outcome were observed with bivalirudin and heparin in any of the subgroups analysed.. Bivalirudin and unfractionated heparin during PCI provide comparable outcomes at 1 year in biomarker negative patients undergoing PCI after pre-treatment with 600 mg of clopidogrel.. URL www.clinicaltrials.gov; Unique identifier NCT00262054.

Topics: Angina Pectoris; Angioplasty; Anticoagulants; Death, Sudden, Cardiac; Double-Blind Method; Female; Heparin; Hirudins; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Peptide Fragments; Recombinant Proteins; Treatment Outcome

Modern antithrombotic strategies for patients undergoing percutaneous coronary interventions (PCIs) must take into account the risk of ischemic and hemorrhagic complications. Bivalirudin decreases the risk of hemorrhagic complications after PCI; however, concerns have been raised about its efficacy in preventing ischemic complications. We evaluated the effectiveness of a prolonged intra- and postprocedural bivalirudin infusion versus a standard regimen in preventing PCI-related myocardial damage. One hundred seventy-eight consecutive patients with stable or unstable angina and complex coronary anatomy were enrolled in this single-center, randomized, single-blinded study. Patients were randomized to bolus plus bivalirudin infusion during PCI (n = 90) or bolus plus bivalirudin infusion during and after PCI (4 hours, n = 88). The primary end point was incidence of periprocedural myocardial damage (creatine kinase-MB increase >or=3 times upper limit of normal). Secondary end points were 30-day and 6-month major adverse cardiovascular events (death, new Q-wave myocardial infarction, target vessel revascularization) and in-hospital bleeding (major/minor). The 2 groups did not differ significantly in baseline and procedural characteristics. The primary end point of the study was significantly less frequent in the prolonged infusion group (6.8% vs 16.7%, p = 0.041). No significant differences for secondary end points were observed. In conclusion, in patients undergoing complex PCI, a prolonged bivalirudin infusion after PCI compared to an intraprocedural-only regimen significantly decreased the incidence of periprocedural myocardial damage.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Delayed-Action Preparations; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Hirudins; Humans; Incidence; Infusions, Intravenous; Italy; Male; Myocardial Infarction; Peptide Fragments; Prospective Studies; Recombinant Proteins; Single-Blind Method; Treatment Outcome

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

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

We assessed the feasibility and safety of a strategy of transfemoral percutaneous coronary intervention (PCI) with bivalirudin anticoagulation, immediate sheath removal, early ambulation, and, where possible, same-day discharge in 100 consecutive patients. Ambulation was achieved by 2 hr 30 min in 85% of patients and same-day discharge in 26%. PCI was angiographically successful in 97%. In hospital, there were no deaths or Q-wave myocardial infarctions. One patient suffered a non-Q-wave infarction, another in-hospital surgical revascularization and one required blood transfusion for rectal bleeding. Femoral access site hematoma > 5 cm diameter occurred in two patients. In addition, by 1 month there had been one death (at 10 days) and one pseudoaneurysm treated nonsurgically. In this preliminary study, the strategy of bivalirudin bolus anticoagulation, immediate sheath removal, and 2-hr ambulation after PCI appeared safe, with same-day discharge possible in 26% of unselected patients with stable or unstable angina.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Surgical Procedures; Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Cardiac Catheterization; Device Removal; Feasibility Studies; Female; Femoral Artery; Hirudins; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Recombinant Proteins; Stents; Time Factors; Treatment Outcome

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

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

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombins; Cost-Benefit Analysis; Drug Costs; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Recurrence; Thrombolytic Therapy

The outcome of coronary angioplasty performed for unstable angina is determined, in part, by the acuteness and severity of the clinical presentation. The risk of abrupt vessel closure is increased in patients with postinfarction angina. The Hirulog Angioplasty Study compared the efficacy and safety of bivalirudin with weight-adjusted heparin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) for unstable or postinfarction angina. We report the results of the intent-to-treat analysis using adjudicated data for the prespecified group of 741 patients who underwent angioplasty within 2 weeks of documented myocardial infarction. Patients received either bivalirudin or heparin immediately before angioplasty. The primary efficacy endpoint was procedural failure defined as abrupt vessel closure, death, myocardial infarction, or revascularization during hospitalization. Bivalirudin significantly (p = 0.004) decreased the incidence of procedural failure compared with heparin (5.1% vs 10.8%, odds ratio 0.45; 95% CI 0.25-0.79). The improved efficacy of bivalirudin was replicated for each individual clinical endpoint. The incidence of major bleeding was significantly (p = 0.001) lower in bivalirudin-treated patients compared with heparin-treated patients (2.4% vs 11.8%, respectively). The benefits observed with bivalirudin are of similar magnitude as those reported for platelet glycoprotein (GP) IIb/IIIa inhibitors, such as abciximab. Bivalirudin may be a more effective foundation anticoagulant than heparin in patients undergoing coronary angioplasty for postinfarction angina.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Drug Monitoring; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Treatment Outcome

The dosing of anticoagulants during coronary angioplasty is commonly guided by measurements of activated clotting time (ACT), but the usefulness of these measurements remains uncertain. The Hirulog Angioplasty Study was a randomized, double-blind comparison of heparin versus bivalirudin in 4,312 patients undergoing angioplasty for unstable or postinfarction angina. In 4,098 of the patients randomized, the balloon was inflated. All patients had ACT measurements 5 minutes after a weight-adjusted bolus of heparin or bivalirudin, and patients undergoing complicated or prolonged angioplasty procedures lasting >45 minutes had additional ACT measurements to guide further anticoagulant therapy. The analysis presented in this article evaluated the relation between the initial or maximum ACT measurements and the risk of abrupt vessel closure during heparin or bivalirudin therapy. Abrupt vessel closure occurred in 189 of 2,039 patients (9.3%) treated with heparin, and in 189 of 2,059 patients (9.2%) treated with bivalirudin (p = not significant). An inverse relation between the risk of abrupt closure and initial ACT measurements was observed in heparin-treated patients: the probability of abrupt vessel closure decreased by 1.3% for every 10-second increase in the initial ACT response to heparin therapy (p = 0.02). Among 903 of 2,039 heparin-treated patients (44%) who received additional heparin for prolonged or complicated procedures, the likelihood of abrupt vessel closure also decreased by 1.1% for every 10-second increase in ACT (p = 0.04). In 2,059 patients treated with bivalirudin, however, no relation between the probability of abrupt vessel closure and the initial ACT measurement was observed (p = 0.88). From the results it was concluded that when heparin is used during coronary angioplasty, the risk of abrupt vessel closure is related to patient responsiveness to anticoagulation therapy. Heparin-resistant patients are more likely to experience abrupt vessel closure than patients who have high ACT values in response to initial therapy. In contrast, when bivalirudin is used during coronary angioplasty, a flat relation between the risk of abrupt vessel closure and ACT values is seen. This suggests that the direct thrombin inhibitor, bivalirudin, provides more even levels of anticoagulation and more predictable levels of risk of abrupt closure than heparin. Measurements of ACT may not be necessary when bivalirudin is used during coronary angioplasty.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Double-Blind Method; Drug Monitoring; Female; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Recombinant Proteins; Recurrence; Risk Factors; Whole Blood Coagulation Time

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

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

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

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

Enhanced thrombin activity has been associated with acute and long-term complications following balloon angioplasty (percutaneous transluminal coronary angioplasty (PTCA). We evaluated, in a 2-to-1 randomized, double-blind trial, the effects of recombinant hirudin, CGP 39 393, relative to unfractionated sodium heparin on periprocedural events, bleeding, early angiographic outcome, and coagulation in 113 patients with stable angina undergoing PTCA.. Prior to PTCA, 20 mg CGP 39 393 was administered as a bolus, followed by continuous infusion at a rate of 0.16 mg.kg-1 x h-1, or 10,000 IU sodium heparin was administered as a bolus and continued at a rate of 12 IU.kg-1 x h-1 for 24 hours. Infusion was adjusted to activated partial thromboplastin time (APTT) levels. ST segment was monitored for 24 hours, and angiograms were analyzed with quantitative technique (QCA). In 74 CGP 39 393- and 39 heparin-treated patients, 132 lesions were dilated. Myocardial infarction and/or emergency coronary bypass surgery occurred in 1 (1.4%) CGP 39 393 patient compared with 4 (10.3%) heparin patients (relative risk, 7.6; 95% confidence interval, 0.9, 65.6). At 24 hours, complete perfusion was present in 91% heparin and 100% CGP 39 393 patients. Significant ST segment displacement was found in 11% of heparin versus 4% of CGP 39 393 subjects. Bleeding occurred only at the puncture site in 4 CGP 39 393-treated patients. QCA did not reveal significant differences between the groups. APTT values were more often in the target range and more stable in CGP 39 393 patients. Levels of thrombin-antithrombin III complexes, prothrombin fragment F1+2, and fibrinopeptide A indicated that CGP 39 393 was an effective inhibitor of thrombin activity.. CGP 39 393 can safely be administered to patients undergoing elective PTCA for stable anginal symptoms and may have a more favorable anticoagulant profile than heparin.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Blood Coagulation; Coronary Angiography; Densitometry; Double-Blind Method; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Randomized controlled trials have shown improved short-term bleeding outcomes for bivalirudin compared to unfractionated heparin (UFH) in patients undergoing percutaneous coronary intervention (PCI) for stable angina and acute coronary syndrome. This study analyzed the impact of bivalirudin-based anticoagulation strategy versus UFH-based anticoagulation strategy on long-term bleeding complications and major adverse cardiac events in patients undergoing PCI in routine clinical practice. From September 2005 to April 2009, 3,367 consecutive patients who underwent PCI for stable angina or non-ST-segment elevation acute coronary syndrome at Brigham and Women's Hospital were studied. Of these patients, 2,228 patients (66%) received UFH and 1,139 (34%) received bivalirudin. Bleeding complication and major adverse cardiac event rates were compared at discharge, 30 days, and 1 year. In a propensity-score matched analysis, bivalirudin-based anticoagulation strategy was associated with lower bleeding complications at 30 days (7.0% vs 13.7%, p = 0.001) and 1 year (12.7% vs 18.9%, p = 0.013). Major adverse cardiac event rates were not significantly different between groups at discharge, 30 days, and 1 year (6.4% vs 8.3%, p = 0.103; 9.4% vs 10.9%, p = 0.449; 12.1% vs 14.8%, p = 0.235, respectively). There was no difference in all-cause mortality rates between the 2 groups (0.9% vs 0.8%, p = 0.808, at discharge; 1.9% vs 3.6%, p = 0.112, at 30 days; 3.6% vs 5.5%, p = 0.195, at 1 year). In conclusion, in a real-world cohort of patients undergoing PCI, bivalirudin-based anticoagulation strategy is associated with a significant decrease in risk of bleeding complications after 30 days and 1 year compared to a UFH-based anticoagulation strategy with no increase in risk for major adverse cardiac events.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Anticoagulants; Chi-Square Distribution; Combined Modality Therapy; Female; Hemorrhage; Heparin; Hirudins; Humans; Incidence; Logistic Models; Male; Myocardial Infarction; Peptide Fragments; Propensity Score; Prospective Studies; Recombinant Proteins; Risk Factors

To determine whether a regimen of aspirin pretreatment, bivalirudin during the procedure and clopidogrel (600 mg) immediately after percutaneous coronary intervention (PCI) was associated with platelet activation during and shortly after (1 and 2 h) PCI, we characterized platelet function in 10 patients with the use of flow cytometry in the absence of agonist and in response to thrombin (10 nM), ADP (1 microM), the collagen-mimetic convulxin (5 ng/ml), and platelet activating factor (10 nM). Activation of platelets in peripheral blood was rare (<0.5% of platelets) before, during and after PCI. Platelet reactivity in response to each of the agonists was lower after the PCI compared with that in blood taken before the PCI. Accordingly, platelet activation and platelet reactivity were not increased after elective PCI when patients were treated during the procedure with aspirin and bivalirudin and immediately after the procedure with a 600 mg loading dose of clopidogrel.

Topics: Adenosine Diphosphate; Angina Pectoris; Anticoagulants; Aspirin; Cardiac Catheterization; Clopidogrel; Elective Surgical Procedures; Hemostatics; Hirudins; Humans; Peptide Fragments; Platelet Activation; Platelet Aggregation Inhibitors; Postoperative Period; Recombinant Proteins; Thrombin; Ticlopidine; Time Factors

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

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

In acute myocardial infarction (AMI), proinflammatory plasma C-reactive protein values are strongly associated with postinfarction morbidity and mortality. So far, the cause of these inflammatory changes is not well understood. Therefore, we sought to investigate the relationship between the activation of coagulation and subsequent systemic inflammatory changes in AMI.. Factor Xa (FXa) bound to tissue factor pathway inhibitor and prothrombin fragments F1+2 (F1+2) were used as a measure for activated coagulation. To assess systemic inflammatory changes, plasma interleukin (IL)-6 and IL-8 concentrations were analyzed by immunoassay. Blood samples were taken from 21 patients with AMI and 20 patients with stable angina pectoris. In AMI, tissue factor pathway inhibitor FXa but not F1+2 plasma levels were associated with circulating IL-8 (P=0.01). In vitro experiments revealed that FXa stimulated IL-8 and monocyte chemoattractant protein-1 release and RNA expression in endothelial cells and mononuclear leukocytes by activation of protease-activated receptor-1.. Our data suggest that coagulation FXa may contribute to proinflammatory changes in AMI by stimulation of IL-8 release. Therapeutic inhibition of the proinflammatory effects of FXa may improve the clinical course in AMI. This study investigates the relationship between the activation of coagulation and systemic inflammatory changes in acute myocardial infarction. Tissue factor pathway inhibitor factor Xa but not F1+2 plasma levels were associated with circulating interleukin-8. In vitro factor Xa stimulated interleukin-8 and monocyte chemoattractant protein-1 release and RNA expression by activation of protease-activated receptor 1 as an underlying mechanism.

Topics: Adult; Aged; Angina Pectoris; Cells, Cultured; Chemokine CCL2; Endothelial Cells; Endothelium, Vascular; Factor Xa; Factor Xa Inhibitors; Female; Hirudins; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipoproteins; Male; Middle Aged; Myocardial Infarction; Oligopeptides; Peptide Fragments; Prothrombin; Recombinant Proteins; Umbilical Veins

The purpose of this research was to examine the prognostic value of ST-segment changes (concordant ST-segment elevation and/or precordial V1 to V3 ST-segment depression) during presumed-new left bundle branch block (LBBB) in patients receiving fibrinolytic therapy.. These patients are often considered high-risk, but their outcome is not well-defined.. The Hirulog and Early Reperfusion or Occlusion (HERO)-2 trial compared bivalirudin with heparin in patients receiving streptokinase for ST-segment elevation or presumed-new LBBB. Each patient with LBBB was matched with a control (with normal intraventricular conduction) for age, gender, pulse rate, systolic blood pressure, Killip class, and region.. A total of 300 patients had LBBB (92 with and 208 without ST-segment changes) and 15,340 had normal conduction. Acute myocardial infarction (AMI) occurred in 80.7% of LBBB patients and 88.7% of controls (p = 0.006). ST-segment changes were specific (96.6%) but not sensitive (37.8%) for enzymatic diagnosis of AMI. Mortality at 30 days was similar in LBBB patients with ST-segment changes (21.7%) and controls (25.0%, p = 0.563), but lower in LBBB patients without ST-segment changes than in controls (13.5% vs. 21.6%, p = 0.022). In the whole HERO-2 cohort, the LBBB patients with ST-segment changes had higher mortality than patients with normal conduction (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.78 to 2.42). The LBBB patients without ST-segment changes had lower mortality than patients with normal conduction (OR 0.52, 95% CI 0.33 to 0.80).. ST-segment changes during LBBB are specific for the diagnosis of AMI and predict 30-day mortality; LBBB patients without ST-segment changes have lower adjusted 30-day mortality than those with normal conduction. Trials are required to determine the best treatment for high-risk and low-risk patients with LBBB.

Topics: Aged; Angina Pectoris; Anticoagulants; Bundle-Branch Block; Electrocardiography; Female; Fibrinolytic Agents; Heparin; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Predictive Value of Tests; Recombinant Proteins; Streptokinase; Survival Rate; Time Factors

We report herein a patient with coronary artery disease that developed heparin-induced thrombocytopenia after coronary artery bypass graft with resulting thrombosis of multiple saphenous vein grafts and myocardial infarction after heparin exposure. The patient required lepirudin and a cardiac catheterization with placement of stents.

Topics: Angina Pectoris; Angioplasty, Balloon; Anticoagulants; Autoantibodies; Autoantigens; Autoimmune Diseases; Cardiac Catheterization; Coronary Artery Bypass; Coronary Restenosis; Drug Therapy, Combination; Eptifibatide; Heparin, Low-Molecular-Weight; Hirudins; Humans; Internal Mammary-Coronary Artery Anastomosis; Male; Middle Aged; Myocardial Infarction; Peptides; Platelet Factor 4; Postoperative Complications; Recombinant Proteins; Recurrence; Saphenous Vein; Stents; Thrombocytopenia; Thrombosis

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

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

Desirudin, a recombinant hirudin used in the prevention and management of thromboembolic disease, is a thrombin inhibitor which binds directly and with high affinity to clot-bound and fluid phase thrombin. As a prophylaxis in patients undergoing hip replacement surgery, desirudin was significantly more effective in reducing the incidence of deep vein thrombosis (DVT) than either unfractionated or low molecular weight heparin. However, results in patients with acute coronary syndromes are less conclusive. A significant reduction with desirudin compared with heparin in the incidence of death or non-fatal (re)infarction at 24 hours in patients with acute myocardial infarction (MI) was reported in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial but not in the TIMI (Thrombolysis and Thrombin Inhibition in Myocardial Infarction) 9B trial. Despite the early reduction shown in GUSTO IIb, desirudin was not associated with an improved long term clinical benefit at 30 days compared with heparin. Similar results were seen in patients with unstable angina/non-Q-wave MI enrolled in the GUSTO IIb trial. In addition, desirudin and heparin showed similar efficacy in preventing restenosis 30 weeks after coronary angioplasty for unstable angina, despite desirudin being associated with a significant reduction in the rate of cardiac events within the first 96 hours. Desirudin is as well tolerated as heparin with a similar incidence of moderate and severe bleeding, intracranial haemorrhage or stroke reported when trialled in the prevention of DVT associated with hip replacement surgery or the treatment of acute coronary syndromes. However, in the GUSTO IIb trial a significantly higher incidence of transfusions was observed in patients with unstable angina/non-Q-wave MI.. Desirudin is clearly more effective than heparin in the prevention of DVT in patients undergoing elective hip replacement, although cost factors may influence its ultimate place in therapy. In the treatment of acute coronary syndromes the role of desirudin is less certain; however, it may be useful for patients in whom heparin therapy is not a viable option.

Topics: Angina Pectoris; Anticoagulants; Arthroplasty, Replacement, Hip; Drug Administration Schedule; Hirudins; Humans; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Thromboembolism

Topics: Angina Pectoris; Coronary Thrombosis; Fibrinolytic Agents; Heparin; Hirudins; Humans; Myocardial Infarction; Practice Patterns, Physicians'; Thrombin

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