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Mortality in patients with STEMI-associated cardiogenic shock (CS) is increasing. Whether a comprehensive ST-elevation myocardial infarction (STEMI) protocol (CSP) can improve their care delivery and mortality is unknown. We evaluated the impact of a CSP on incidence and outcomes in patients with STEMI-associated CS. We implemented a 4-step CSP including: (1) Emergency Department catheterization lab activation; (2) STEMI Safe Handoff Checklist; (3) immediate catheterization lab transfer; (4) and radial-first percutaneous coronary intervention (PCI). We studied 1,272 consecutive STEMI patients who underwent PCI and assessed for CS incidence per National Cardiovascular Data Registry definitions within 24-hours of PCI, care delivery, and mortality before (January 1, 2011, to July 14, 2014; n = 723) and after (July 15, 2014, to December 31, 2016; n = 549) CSP implementation. Following CSP implementation, CS incidence was reduced (13.0% vs 7.8%, p = 0.003). Of 137 CS patients, 43 (31.4%) were in the CSP group. CSP patients had greater IABP-Shock II risk scores (1.9 ± 1.8 vs 2.8 ± 2.2, p = 0.014) with otherwise similar hemodynamic and baseline characteristics, cardiac arrest incidence, and mechanical circulatory support use. Administration of guideline-directed medical therapy was similar (89.4% vs 97.7%, p = 0.172) with significant improvements in trans-radial PCI (9.6% vs 44.2%, p < 0.001) and door-to-balloon time (129.0 [89:160] vs 95.0 [81:116] minutes, p = 0.001) in the CSP group, translating to improvements in infarct size (CK-MB 220.9 ± 156.0 vs 151.5 ± 98.5 ng/ml, p = 0.005), ejection fraction (40.8 ± 14.5% vs 46.7 ± 14.6%, p = 0.037), and in-hospital mortality (30.9% vs 14.0%, p = 0.037). In conclusion, CSP implementation was associated with improvements in CS incidence, infarct size, ejection fraction, and in-hospital mortality in patients with STEMI-associated CS. This strategy offers a potential solution to bridging the historically elusive gap in their care., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with chronic kidney disease (CKD) have elevated bleeding and ischemic outcomes. We aim to assess the short- and long-term efficacy and safety of bivalirudin compared to heparin plus glycoprotein IIb/IIIa inhibitors (GPIs) in coronary artery disease (CAD) patients with CKD., Methods: Randomized trials were searched in PubMed, Cochrane, and Embase databases up to January 2017. Among the trials retrieved, efficacy endpoints were defined as mortality, myocardial infarction (MI), repeat revascularization, stent thrombosis, and major adverse cardiac events (MACEs). Safety endpoints were reported as non-coronary artery bypass grafting (CABG) related major bleeding and thrombolysis in myocardial infarction (TIMI) major bleeding. Risk ratio (RR) and 95% confidence interval (CI) were calculated for each outcome using a fixed effect model., Results: Five studies with a total of 3796 patients were included. In short-term follow up (30 days), bivalirudin significantly reduced non-CABG related major bleeding (p=0.0004) and TIMI major bleeding (p=0.007) compared to heparin plus GPIs. No significant differences were observed in rates of mortality, MI, repeat revascularization, stent thrombosis, and MACEs between the two groups in short- and long-term follow up (6 months to 3 years). In patients with ST elevated myocardial infarction (STEMI) with concurrent CKD, the decreased non-CABG related major bleeding (p=0.04) without increasing ischemic events was also observed after short-term follow up., Conclusions: (1) Bivalirudin is safer than and as effective as heparin plus GPIs in CAD patients with CKD. (2) Impaired renal function does not affect the safety benefits of bivalirudin. (3) Similar efficacy profiles were identified between the two groups after both short- and long-term follow up in the CAD patients with CKD., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Aim: To evaluate the impact of antithrombotic regimens during the medical phase of treatment among 13,819 patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) treated with an early invasive strategy in the acute catheterization and urgent intervention triage strategy (ACUITY) trial., Methods and Results: Endpoints included composite major adverse cardiac events (MACE), major bleeding, and net adverse clinical events (NACE; MACE or major bleeding). The median (interquartile range) duration of antithrombin use in the medical only treatment phase was 6.5 (1.8-22.5) hours. MACE, major bleeding, and NACE during the medical only phase occurred in 63 (0.5%), 117 (0.9%), and 178 (1.3%) patients, respectively. MACE rates in the medical-treatment-only phase were not significantly different between the four randomized medical regimens used (heparin alone, bivalirudin alone, heparin plus a glycoprotein IIb/IIIa inhibitor [GPI], and bivalirudin plus GPI) (Ptrend  = 0.65). The lowest rates of major bleeding and NACE during the medical treatment phase occurred in patients treated with bivalirudin alone (Ptrend  = 0.0006 and Ptrend  = 0.0004, respectively)., Conclusions: In patients with NSTE-ACS undergoing an early invasive strategy, treatment with bivalirudin alone significantly reduced major bleeding and improved net clinical outcomes during the upstream medical management phase with comparable rates of MACE. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Background: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding., Methods: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions., Findings: 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002)., Interpretation: The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin., Funding: Regado Biosciences Inc., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Unfractionated heparin is an anticoagulant used in the treatment of myocardial infarction, pulmonary embolism and other thrombotic disorders. However, with anticoagulation comes the risk of bleeding and adverse events. These risks increase with supratherapeutic dosing., Areas Covered: In this review, we discuss the reasons for supratherapeutic dosing, and the incidence of adverse events and clinical consequences of the same, with a focus on heparin use in acute coronary syndromes. We also provide some opportunities for safer use of intravenous heparin. At the end of this article, the reader should have a better understanding of the proper use of heparin as well as the magnitude of bleeding and a respect for its consequences., Expert Opinion: Heparin is an indispensable anticoagulant used in a number of clinical scenarios. Careful attention must be paid to dosing in order to minimize the risk of bleeding and related adverse events including death. The use of weight-based nomograms is paramount. Devices to automate testing and titration are currently under development.

Despite the development of newer anticoagulants, unfractionated heparin remains an indispensible agent in the treatment of thrombotic disorders. Heparin exerts its major effect via antithrombin, converting antithrombin to a more efficient inhibitor of circulating thrombin (factor IIa), factor Xa, factor IXa, factor XIIa, and kallikrein. However, due to the multiple anticoagulant mechanisms of heparin, differential molecular weight-based clearance, issues of heparin resistance, and patient-specific characteristics (age, weight, gender, and tobacco), attaining therapeutic anticoagulation is complicated. As a result, a minority of patients in major clinical trials achieve an activated partial thromboplastin time within the target window in an appropriate time-frame despite the use of weight-based titration nomograms. The resultant under- or over-therapeutic anticoagulation is associated with increased risks of ischemic and bleeding complications, suggesting the importance of maintaining heparin anticoagulation within a relatively narrow therapeutic range. In this review we discuss the mechanisms of heparin action, clinical ramifications of incorrect dosing in major trials, and attempts to improve the achievement of therapeutic anticoagulation.

Objectives: This study sought to determine if the efficacy of bivalirudin alone versus heparin plus a glycoprotein (GP) IIb/IIIa inhibitor is dependent upon the duration of clopidogrel pre-treatment in patients undergoing percutaneous coronary intervention (PCI) in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial., Background: The administration of a clopidogrel loading dose several hours before PCI reduces the risk of periprocedural thrombotic events., Methods: Patients with an acute coronary syndrome were randomized to heparin plus a GP IIb/IIIa inhibitor (control), bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Dose and timing of clopidogrel were left to the investigator's discretion., Results: Of 13,819 patients randomized, 7,789 underwent PCI. When clopidogrel was initiated at any time before angiography or within 30 min after PCI, randomization to bivalirudin alone (n = 2,284) or control (n = 2,189) was associated with similar ischemic outcomes (8.2% vs. 8.3%, risk ratio: 0.98, 95% confidence interval: 0.81 to 1.20). Those patients who received clopidogrel >30 min after PCI or not at all experienced an increase in ischemic events when randomized to bivalirudin alone (n = 290) versus control (n = 317) (14.1% vs. 8.5%, risk ratio: 1.66, 95% confidence interval: 1.05 to 2.63). Major bleeding was significantly less frequent in patients treated with bivalirudin alone., Conclusions: This post-hoc analysis suggests that in acute coronary syndrome patients, as long as clopidogrel is administered before or within 30 min of PCI treatment with bivalirudin alone is similarly effective to heparin plus a GP IIb/IIIa inhibitor in suppressing 30-day ischemic events with significantly less bleeding. If it is anticipated that clopidogrel will be given late or not at all after PCI, bivalirudin alone may be associated with worse ischemic outcomes. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes; NCT00093158).

Objectives: The aim of this study was to determine the economic impact of several anticoagulation strategies for moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients managed invasively., Background: The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial demonstrated that bivalirudin monotherapy yields similar rates of ischemic complications and less bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI) for moderate- and high-risk NSTE-ACS., Methods: In ACUITY, 7,851 U.S. patients were randomized to: 1) heparin (unfractionated or enoxaparin) + GPI; 2) bivalirudin + GPI; or 3) bivalirudin monotherapy. Patients assigned to GPI were also randomized to upstream GPI before catheterization or selective GPI only with percutaneous coronary intervention. Resource use data were collected prospectively through 30-day follow-up. Costs were estimated with standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule., Results: At 30 days, ischemic events were similar for all groups. Major bleeding was reduced with bivalirudin monotherapy compared with heparin + GPI or bivalirudin + GPI (p < 0.001). Length of stay was lowest with bivalirudin monotherapy or bivalirudin + catheterization laboratory GPI (p = 0.02). Despite higher drug costs, aggregate hospital stay costs were lowest with bivalirudin monotherapy (mean difference range: $184 to $1,081, p < 0.001 for overall comparison) and at 30 days (mean difference range: $123 to $938, p = 0.005). Regression modeling demonstrated that hospital savings were primarily due to less major and minor bleeding with bivalirudin ($8,658/event and $2,282/event, respectively)., Conclusions: Among U.S. patients in the ACUITY trial, bivalirudin monotherapy compared with heparin + GPI resulted in similar protection from ischemic events, reduced bleeding, and shorter length of stay. Despite higher drug costs, aggregate hospital and 30-day costs were lowest with bivalirudin monotherapy. Thus bivalirudin monotherapy seems to be an economically attractive alternative to heparin + GPI for patients with moderate- and high-risk NSTE-ACS. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Objectives: This study was designed to determine the impact of bivalirudin on 1-year outcomes in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI)., Background: The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated that in moderate- and high-risk ACS patients undergoing PCI, bivalirudin alone compared to unfractionated heparin (UFH) or enoxaparin plus a glycoprotein (GP) IIb/IIIa inhibitor resulted in less major bleeding and similar ischemic outcomes at 30 days. The impact of bivalirudin on 1-year outcomes in ACS patients undergoing PCI is unknown., Methods: In the ACUITY trial, 13,819 patients were enrolled, and 7,789 (56.4%) patients had PCI. Composite ischemia (death, myocardial infarction, or unplanned revascularization) and mortality at 1 year were assessed., Results: Among patients undergoing PCI, 2,561, 2,609, and 2,619 were randomized to UFH or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, and bivalirudin monotherapy, respectively. At 1 year, there were no differences in composite ischemia (17.8% vs. 19.4% vs. 19.2%, p = NS) or mortality (3.2% vs. 3.3% vs. 3.1%, p = NS) among the 3 groups, respectively., Conclusions: Bivalirudin compared with UFH or enoxaparin plus a GP IIb/IIIa inhibitor results in similar rates of composite ischemia and mortality at 1 year in moderate- and high-risk ACS patients undergoing PCI.

Objectives: The aim of this study was to compare outcomes in patients receiving consistent unfractionated heparin (UFH)/enoxaparin (ENOX) therapy and in those switched at randomization to bivalirudin monotherapy., Background: Crossover between UFH and ENOX has been associated with increased adverse outcomes in patients with acute coronary syndromes. The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated superior net clinical outcomes with similar rates of ischemia and significantly less major bleeding with bivalirudin monotherapy compared with UFH/ENOX plus a glycoprotein (GP) IIb/IIIa inhibitor. It is unknown if these results would be preserved in patients switched from UFH/ENOX to bivalirudin monotherapy., Methods: We compared composite ischemia, major bleeding, and net clinical outcomes at 30 days in patients receiving consistent UFH/ENOX therapy and in those switched at randomization from pre-treatment with UFH/ENOX to bivalirudin monotherapy. We also compared outcomes in patients naive to antithrombin therapy who were randomized to UFH/ENOX or bivalirudin monotherapy., Results: Two thousand one hundred thirty-seven patients received consistent UFH/ENOX (UFH n = 1,294, ENOX n = 843), and 2,078 patients pre-treated with UFH/ENOX were switched to bivalirudin. Patients switching to bivalirudin had similar rates of ischemia (6.9% vs. 7.4%, p = 0.52), less major bleeding (2.8% vs. 5.8%, p < 0.01), and improved net clinical outcomes (9.2% vs. 11.9%, p < 0.01) than those on consistent UFH/ENOX plus a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy who were administered bivalirudin (n = 1,427) had similar rates of ischemia (6.2% vs. 5.5%, p = 0.47), less major bleeding (2.5% vs. 4.9%, p < 0.001), and similar net clinical outcomes (8.0% vs. 9.4%, p = 0.17) compared with naive patients administered UFH/ENOX plus a GP IIb/IIIa inhibitor (n = 1,462)., Conclusions: Switching from UFH/ENOX to bivalirudin monotherapy results in comparable ischemic outcomes and an approximately 50% reduction in major bleeding compared with consistent UFH/ENOX plus a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy administered bivalirudin monotherapy had a significant reduction in bleeding and similar rates of ischemia compared with naive patients initiated with UFH or ENOX plus a GP IIb/IIIa inhibitor.

Context: At 30-day follow-up, patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing early invasive treatment in the ACUITY trial with bivalirudin monotherapy vs heparin plus glycoprotein (GP) IIb/IIIa inhibitors had noninferior rates of adverse ischemic events with reduced rates of major bleeding. Deferred upstream use of GP IIb/IIIa inhibitors for selective administration to patients undergoing percutaneous coronary intervention (PCI) resulted in a significant reduction in major bleeding, although a small increase in composite ischemia could not be excluded., Objective: To determine 1-year ischemic outcomes for patients in the ACUITY trial., Design, Setting, and Patients: A prospective, randomized, open-label trial with 1-year clinical follow-up at 450 academic and community-based institutions in 17 countries. A total of 13,819 patients with moderate- and high-risk ACS undergoing invasive treatment were enrolled between August 23, 2003, and December 5, 2005., Interventions: Patients were assigned to heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream GP IIb/IIIa administration and 4602 were deferred to selective GP IIb/IIIa inhibitor administration., Main Outcome Measure: Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year., Results: Composite ischemia at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95-1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95-1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80-1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77-1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97-1.20; P = .15)., Conclusions: At 1 year, no statistically significant difference in rates of composite ischemia or mortality among patients with moderate- and high-risk ACS undergoing invasive treatment with the 3 therapies was found. There was no statistically significant difference in the rates of composite ischemia between patients receiving routine upstream administration of GP IIb/IIIa inhibitors vs deferring their use for patients undergoing PCI., Trial Registration: clinicaltrials.gov Identifier: NCT00093158.

Background: This study assessed the use of bivalirudin as an alternative anticoagulant in patients with heparin-induced thrombocytopenia-thrombotic syndrome (HIT/TS) or antiplatelet factor four-heparin (anti-PF4/H) antibodies undergoing off-pump coronary artery bypass (OPCAB)., Methods: In a prospective, open-label, multicenter study, fifty-one patients with documented anti-PF4/H antibodies and (or) HIT/TS underwent OPCAB with bivalirudin anticoagulation (0.75 mg/kg i.v. bolus, 1.75 mg/kg/hour infusion). Procedural success (absence of death, Q-wave myocardial infarction, repeat revascularization, and stroke), bleeding, and transfusion at day seven/discharge, thirty days, and twelve weeks were assessed., Results: Thirty-five patients (67%) were included with positive anti-PF4/H antibodies and no thrombocytopenia or thrombosis, eleven patients (22%) had thrombocytopenia, and five patients had clinical HIT/TS (10%). Procedural success at seven days/discharge was achieved in forty-seven patients (92%), while procedural success at thirty days and twelve weeks was 88%. There were no deaths. Chest tube output over the first twenty-four hours was 936 +/- 525 mL and twenty-five patients received a red blood cell transfusion during their hospitalization. Two patients required reexploration for persistent postoperative hemorrhage., Conclusions: Bivalirudin was an effective alternative anticoagulant for patients with HIT/TS or circulating anti-PF4/H antibodies undergoing OPCAB, with high rates of procedural success and an acceptable incidence of bleeding or transfusions.

The REPLACE-2 trial of patients who underwent urgent or elective percutaneous coronary intervention (PCI) demonstrated a significantly lower bleeding risk with bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor compared with unfractionated heparin with planned glycoprotein IIb/IIIa inhibitor. The goal of this analysis was to evaluate whether a hazard existed when unfractionated heparin or low-molecular-weight heparin was administered before study medication in the REPLACE-2 trial. The REPLACE-2 trial randomized 6,010 patients undergoing PCI to receive bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor or unfractionated heparin plus planned glycoprotein IIb/IIIa inhibitor. The present study compared bleeding among patients treated with or without antithrombin therapy in the 48 hours before study treatment. Among patients treated with bivalirudin, there was no difference in protocol-defined major or minor bleeding, bleeding according to Thrombolysis In Myocardial Infarction criteria, or noncoronary artery bypass graft blood transfusions between the patients treated with versus without antithrombin therapy (p=NS). However, in patients treated with unfractionated heparin plus planned glycoprotein IIb/IIIa inhibitor, there was a significant increase in the composite of protocol-defined major or minor bleeding and in noncoronary artery bypass graft blood transfusions (p<0.05 for 3-way comparison vs no unfractionated heparin and for 2-way comparisons of no unfractionated heparin vs unfractionated heparin or low-molecular-weight heparin). In conclusion, in patients treated with bivalirudin, pretreatment with antithrombin therapy was not associated with increased bleeding. In contrast, among patients randomized to receive unfractionated heparin and planned glycoprotein IIb/IIIa, pretreatment with antithrombin therapy was associated with increased protocol-defined composite major or minor bleeding and increased need for transfusion.

Background: The aim of this study was to assess anticoagulation with the direct thrombin inhibitor bivalirudin during percutaneous coronary intervention in individuals with moderate and high-risk acute coronary syndromes., Methods: 13,819 individuals in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial were prospectively randomly assigned to receive heparin (unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibitors, bivalirudin plus glycoprotein IIb/IIIa inhibitors, or bivalirudin alone. Of these individuals, 7789 underwent percutaneous coronary intervention after angiography. The effect of the three regimens on the primary 30-day endpoints of composite ischaemia (death, myocardial infarction, or unplanned revascularisation for ischaemia), major bleeding, and net clinical outcomes (composite ischaemia or major bleeding) was assessed in this subgroup. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00093158., Findings: Of the individuals who underwent percutaneous coronary intervention, 2561 received heparin plus glycoprotein IIb/IIIa inhibitors, 2609 received bivalirudin plus glycoprotein IIb/IIIa inhibitors, and 2619 received bivalirudin alone. 26 (0.3%) individuals dropped out or were lost to follow-up. There was no significant difference in the proportion of individuals with composite ischaemia, major bleeding, or net clinical outcomes at 30 days between those who received bivalirudin plus glycoprotein IIb/IIIa inhibitors and those who received heparin plus glycoprotein IIb/IIIa inhibitors (composite ischaemia: 243 [9%] patients vs 210 [8%] patients, p=0.16; major bleeding: 196 [8%] patients vs 174 [7%] patients, p=0.32; net clinical outcomes: 389 [15%] patients vs 341 [13%] patients, p=0.1). Rates of composite ischaemia were much the same in those who received bivalirudin alone and those who received heparin plus glycoprotein IIb/IIIa inhibitors (230 [9%] patients vs 210 [8%] patients, p=0.45); however, there were significantly fewer individuals who experienced major bleeding among those who received bivalirudin alone than among those who received heparin plus glycoprotein IIb/IIIa inhibitors (92 [4%] patients vs 174 [7%] patients, p<0.0001, relative risk 0.52, 95% CI 0.40-0.66), resulting in a trend towards better 30-day net clinical outcomes (303 [12%] patients vs 341 [13%] patients, p=0.057; 0.87, 0.75-1.00)., Interpretation: Substitution of unfractionated heparin or enoxaparin with bivalirudin results in comparable clinical outcomes in patients with moderate and high-risk acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors in whom percutaneous coronary intervention is done. Anticoagulation with bivalirudin alone suppresses adverse ischaemic events to a similar extent as does heparin plus glycoprotein IIb/IIIa inhibitors, while significantly lowering the risk of major haemorrhagic complications.

Background: The coronary artery bypass grafting (CABG) heparin-induced thrombocytopenia thrombosis syndrome (HITTS) on- and off-pump safety and efficacy (CHOOSE-ON) trial was designed as a safety and efficacy trial of bivalirudin for use in anticoagulation during cardiopulmonary bypass (CPB) in patients with confirmed or suspected HIT and (or) antiplatelet factor 4/heparin (anti-PF4/H) antibodies., Methods: In an open-label, multicenter trial, 50 patients were enrolled prospectively. The primary study endpoint was in-hospital acute procedural success, defined as the absence of death, Q-wave myocardial infarction (MI), repeat operation for coronary revascularization, and stroke at day seven after surgery or hospital discharge, whichever occurred first. The secondary study endpoints were procedural success, defined as the absence of death, Q-wave MI, repeat operation for coronary revascularization, and stroke, at 30 days and 12 weeks after surgery. Perioperative blood loss, transfusions, and the incidence of major bleeding events were also captured., Results: There were 49 patients treated with bivalirudin of which 43 had acute HIT and thrombosis syndrome (HITTS) with antibodies at time of surgery. Procedural success in-hospital or at 7 days was achieved in 46 (94%) patients. At day 30 procedural success was achieved in 42 (86%) patients, and after 12 weeks in 40 (82%) patients. Mean intraoperative blood loss was 575 +/- 524 mL, and mean 24-hour postoperative blood loss was 998 +/- 595 mL. Forty-one (84%) patients received transfusions before day 7 or discharge with a mean of 5.6 +/- 3.8 units of red blood cells, 8.6 +/- 7.2 units of platelets, and 6.0 +/- 4.7 units of fresh frozen plasma. No differences in outcome among bivalirudin-treated patients were observed between those in the overall group and those with moderately impaired renal function (n = 10)., Conclusions: The current investigation expands the experience of safe and effective anticoagulation with bivalirudin during CPB to patients with confirmed or suspected HIT and anti-PF4/H antibodies, including in the setting of impaired renal function.

Background: Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients., Methods: We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding., Results: Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97)., Conclusions: In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].)., (Copyright 2006 Massachusetts Medical Society.)

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

Background: Outcomes in women undergoing percutaneous coronary intervention (PCI) in the contemporary era are poorly defined. The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GpIIb-IIIa) blockade is noninferior to heparin with planned GpIIb-IIIa blockade during PCI, with regard to ischemic and bleeding end points., Objectives: The aim of this study was to define sex-based clinical ischemic and bleeding outcomes from the REPLACE-2 trial., Methods: A retrospective sex-based subgroup analysis of the REPLACE-2 trial comparing clinical ischemic and inhospital bleeding end points was conducted., Results: Compared with men in REPLACE-2, women were older, had more diabetes, congestive heart failure and hypertension, and less prior revascularization and myocardial infarction. Female sex was a univariate predictor of death and bleeding complications. Among women treated with either bivalirudin or heparin, there was no significant difference in the individual or composite ischemic end points of death, myocardial infarction, or urgent revascularization at 30 days or 6 months. Protocol-defined major bleeding, minor bleeding, and access site bleeding were less frequent with bivalirudin compared with heparin. Multivariable modeling found no significant interactions between sexes, with the composite ischemic end point, major bleeding, or 1-year mortality., Conclusions: Women remain at higher risk for poorer outcomes with contemporary PCI, likely because of comorbidities. Bivalirudin with provisional GpIIb-IIIa confers similar protection against ischemic end points compared with heparin and planned GpIIb-IIIa blockade and significantly reduces the inherent bleeding risk of women undergoing contemporary PCI.

Objectives: Unfractionated heparin and its antidote, protamine sulfate, allow for rapid and reversible anticoagulation during cardiac surgery with cardiopulmonary bypass, yet limitations exist, including a variable dose-response, dependence on a cofactor for anticoagulant effect, and antigenic potential. This trial was performed to evaluate the safety and efficacy of bivalirudin as an alternative to heparin with protamine reversal in on-pump cardiac surgery., Methods: We conducted a randomized, open-label, multicenter trial comparing heparin with protamine reversal to bivalirudin in patients undergoing cardiac surgery with cardiopulmonary bypass. The primary objective was to demonstrate comparable rates of in-hospital procedural success defined as freedom from death, Q-wave myocardial infarction, stroke, or repeat revascularization. Twenty-one institutions enrolled 101 patients randomized to bivalirudin and 49 patients to heparin treatment., Results: The primary end point of procedural success was not significantly different between the bivalirudin arm and the heparin/protamine arms at 7 days, 30 days, or 12 weeks' follow-up. Adequate anticoagulation was achieved in all patients. Secondary end points including mortality, 24-hour blood loss, overall incidence of transfusions, and duration of surgery were similar between the two arms., Conclusions: Bivalirudin is a safe and effective anticoagulant for patients undergoing a wide range of cardiac surgical procedures with cardiopulmonary bypass. Procedural success rates with bivalirudin were similar to rates in patients receiving heparin anticoagulation, with no difference in mortality. Avoidance of blood stasis and attention to the intraoperative medical management of patients is critical for successful use of bivalirudin during cardiopulmonary bypass.

Objectives: Unfractionated heparin has many shortcomings, including indirect and partial inhibition of thrombin, antibody formation, and platelet activation. Bivalirudin, a short-acting direct thrombin inhibitor, avoids these limitations and has superior outcomes during percutaneous revascularization. This trial was performed to evaluate the safety and efficacy of bivalirudin in off-pump coronary artery bypass grafting., Methods: An open-label, multicenter randomized trial compared heparin with protamine reversal to bivalirudin in patients undergoing off-pump coronary artery bypass. The primary objective was safety as demonstrated by similar rates of procedural success defined as freedom from a composite of death, myocardial infarction, stroke, and repeat revascularization. Twenty-one institutions randomized 105 patients to receive bivalirudin and 52 patients to receive heparin., Results: The mean age was 65 years for both groups. The bivalirudin group had more grafts: 3.0 +/- 1 versus 2.5 +/- 1. Procedural success rates at 30 days were identical in bivalirudin- and heparin-treated patients (93%). Operative times, total blood loss, reoperations for bleeding, and major adverse events were not significantly different. Strokes were more frequent in the heparin group: 5.5% versus 0; P = .05. Mortality was 2% in each group. Repeat revascularization was required in 3% of bivalirudin- and 2% of the heparin-treated patients., Conclusions: For patients undergoing off-pump coronary artery bypass grafting, bivalirudin was an effective anticoagulant, without excessive bleeding and with a safety profile similar to that of heparin. Further trials are warranted to assess whether anticoagulation with bivalirudin improves clinical outcomes.

Objective: This study evaluates outcomes with bivalirudin vs heparin in various patient subgroups and the overall population during percutaneous coronary interventions (PCI)., Background: Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, provides ischemic protection superior to heparin and comparable to heparin plus glycoprotein (GP) IIb/IIIa inhibitors but with significantly fewer bleeding complications. Whether this advantage persists in different subgroups has not been fully defined. To our knowledge, this is the largest pooled analysis of bivalirudin to date., Methods: Four randomized controlled trials were identified that compared bivalirudin to heparin (with or without GP IIb/IIIa inhibitors) in PCI. The incidence of death, myocardial infarction (MI), revascularization, and major bleeding at 48 hours was compared between these two agents overall and in patients with and without diabetes mellitus, hypertension, renal insufficiency, and advanced age., Results: The trials consisted of 11,638 patients (bivalirudin, 5,861; heparin, 5,777). There were no significant differences in patient characteristics between the two groups. At 48 hours, the incidence of death, MI, revascularization, and major bleeding was significantly reduced in the bivalirudin group (7.8% vs 1.08%, P < .001); individual ischemic end points were significantly reduced for death (0.01% vs 0.02%, P = .049) and revascularization (2.0% vs 2.7%, P = .02), with similar reductions for major bleeding (2.7% vs 5.8%, P < .001). Subgroup analysis was generally consistent with the overall findings., Conclusion: This analysis further supports the superiority of bivalirudin compared with heparin. Bivalirudin provides excellent ischemic protection with a significant reduction of bleeding complications, even in high-risk subgroups.

Aims: To evaluate the relationship between activated partial thromboplastin time (aPTT) and clinical outcomes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-V) trial comparing standard-dose reteplase to half-dose reteplase and abciximab., Methods and Results: We analysed data on 11,420 patients receiving unfractionated heparin. Peak aPTT levels recorded during the hospitalization were correlated with clinical outcomes. Multivariable logistic regression models examined the relationship between peak aPTT levels and (i) moderate-to-severe bleeding, (ii) intracerebral haemorrhage, (iii) reinfarction, and (iv) 30-day mortality. Non-linear relationships were explored in the models using cubic spline functions. Higher rates of significant complications were seen in both groups when aPTT levels were <50 s or when levels were >70 s. In the combination therapy group, the relationship between aPTT levels and bleeding appeared accentuated. Reinfarction rates increased gradually as aPTT levels were >70 s in both groups, but the relationships were not statistically significant. Peak aPTT levels <50 s were associated with increased 30-day mortality even after multivariable adjustment., Conclusion: Peak aPTT levels <50 s and >70 s are associated with worse clinical outcomes in the modern era of fibrinolytic therapy; these relationships are different in patients receiving standard reteplase vs. combination therapy.

Objectives: The objective of this study was to confirm that the efficacy and safety of percutaneous coronary intervention (PCI) in diabetic patients are not compromised by a bivalirudin-based antithrombotic strategy., Background: Previous studies have shown a survival benefit with use of platelet glycoprotein (GP) IIb/IIIa inhibitors in diabetic patients undergoing PCI. The Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial showed the non-inferiority of a strategy of bivalirudin with provisional GP IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. The relative efficacy of these two strategies in diabetic patients has not been studied., Methods: We evaluated the diabetic patients enrolled in the REPLACE-2 trial to assess the impact of these antithrombotic strategies on the short- and long-term outcome after PCI., Results: The REPLACE-2 trial enrolled 1,624 diabetic patients and 4,368 non-diabetic patients. Compared with non-diabetic patients, diabetic patients had similar short-term outcome but higher mortality at 1 year (3.06% vs. 1.85%, p = 0.004). There was no difference in short-term or long-term ischemic events among the diabetic patients randomized to the two arms. Specifically, the 1-year mortality rate was non-significantly lower in the bivalirudin arm, suggesting no differential survival impact of the two strategies (2.3% vs. 3.9%). There was less minor bleeding in the bivalirudin arm in diabetic patients (12.6% vs. 24.4%, p < 0.001), whereas no difference was seen in the incidence of major bleeding (3.0% vs. 3.3%, p = 0.69)., Conclusions: Compared with routine GP IIb/IIIa inhibition, the use of bivalirudin with provisional GP IIb/IIIa inhibitors in diabetic patients is associated with no differences in clinical outcomes at 30 days, a trend toward lesser mortality at 1 year, and a reduction in minor bleeding.

Objective: Bivalirudin has been successfully used as a replacement for heparin during on-pump coronary artery bypass grafting. This study was conducted to assess the effects of the currently suggested protocol for bivalirudin on hemostatic activation during cardiopulmonary bypass with and without cardiotomy suction., Methods: Ten patients scheduled for coronary artery bypass grafting were enrolled. Bivalirudin was given with a bolus of 50 mg in the priming solution and 1.0 mg/kg for the patient, followed by an infusion of 2.5 mg . kg(-1) . h(-1) until 15 minutes before the conclusion of cardiopulmonary bypass. Cardiopulmonary bypass was performed with a closed system in 5 patients with and in 5 patients without the use of cardiotomy suction. Blood samples were obtained before and after cardiopulmonary bypass. D-dimers, fibrinopeptide A, prothrombin 1 and 2 fragments, thrombin-antithrombin, and factor XIIa were determined., Results: Values for factor XIIa remained almost unchanged in both groups, indicating a minor effect of contact activation. In patients without cardiotomy suction, post-cardiopulmonary bypass values for D-dimers, fibrinopeptide A, prothrombin 1 and 2 fragments, and thrombin-antithrombin were not significantly increased compared with pre-cardiopulmonary bypass values. In patients with cardiotomy suction, values obtained for these parameters had significantly increased compared with pre-cardiopulmonary bypass values and the values obtained in the group without cardiotomy suction after cardiopulmonary bypass., Conclusions: With this protocol, hemostatic activation during cardiopulmonary bypass was almost completely attenuated when cardiotomy suction was avoided. Cardiotomy suction results in considerable activation of the coagulation system and should therefore be restricted and replaced by cell saving whenever possible.

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.

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

Background: Patients with acute coronary syndromes (ACS; unstable angina and non-ST-segment elevation myocardial infarction) are at significant risk for death and myocardial infarction. Early angiography followed by revascularization is considered the treatment of choice for moderate- to high-risk patients with ACS. However, despite the integration of newer therapies including stents, glycoprotein IIb/IIIa inhibitors, and thienopyridines, the rate of adverse ischemic events still remains unacceptably high, and the intensive pharmacologic regimens used to stabilize the disrupted atherosclerotic plaque and support angioplasty and surgical revascularization procedures elicit a high rate of bleeding complications. Pilot trials suggest that the thrombin-specific anticoagulant bivalirudin may improve clinical outcomes in ACS., Study Design: In the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial, 13,800 patients with moderate- to high-risk ACS are being prospectively randomly assigned at up to 600 centers to unfractionated heparin or enoxaparin + IIb/IIIa inhibition, versus bivalirudin + IIb/IIIa inhibition, versus bivalirudin + provisional IIb/IIIa inhibition. All patients undergo cardiac catheterization within 72 hours, followed by percutaneous or surgical revascularization when appropriate. In a second random assignment, patients assigned to receive IIb/IIIa inhibitors are subrandomized to upstream drug initiation, versus IIb/IIIa inhibitor administration during angioplasty only. The primary study end point is the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. Clinical follow-up will continue for 1 year., Conclusions: The ACUITY trial is the largest study yet performed in patients with ACS undergoing an invasive strategy. In addition to evaluating the utility of bivalirudin in ACS, this study will also provide important guidance regarding the necessity for and timing of IIb/IIIa inhibitor administration.

Background: Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications., Methods and Results: We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001)., Conclusions: In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.

Context: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI)., Objective: To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year., Design, Setting, and Participants: Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002., Interventions: Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI., Main Outcome Measures: Incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment., Results: At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P =.15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P =.24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P =.45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P =.16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients., Conclusion: Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI.

Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.

The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial is one of the largest acute randomized controlled trials evaluating the efficacy of two anticoagulant strategies during contemporary urgent or elective percutaneous coronary intervention (PCI). The direct thrombin inhibitor, bivalirudin, with provisional use of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor was compared to low-dose unfractionated heparin (UFH) plus planned GP IIb/IIIa inhibitor. At 30-day follow-up, the primary quadruple composite endpoint (death, myocardial infarction (MI), urgent repeat revascularization, or in-hospital major bleeding) occurred in 9.2% of patients in the bivalirudin group versus 10.0% of patients in the UFH plus GP IIb/IIIa inhibitor group. The secondary triple composite endpoint (death, MI, urgent repeat revascularization) occurred in 7.6% of patients in the bivalirudin group compared with 7.1% of patients in the UFH plus GP IIb/IIIa inhibitor group. Both endpoints met formal statistical criteria for noninferiority to UFH plus GP IIb/IIIa inhibitor. By imputed comparison from historic GP IIb/IIIa trials between bivalirudin versus UFH alone, REPLACE-2 demonstrated that bivalirudin was superior to UFH alone with respect to the quadruple and triple composite endpoints. Furthermore, bivalirudin plus provisional GP IIb/IIIa blockade was associated with a significant reduction in in-hospital bleeding (2.4% vs. 4.1%; p < 0.001). At 6 months' follow-up, there was no significant difference in rates of death, MI, or revascularization between the two groups. Furthermore, there was no evidence that the early, nonsignificant 0.5% excess non-Q-wave MI in the bivalirudin group translated into later mortality. There was a trend toward decreased mortality at 6 months in the bivalirudin arm (0.95% vs. 1.35%; p = 0.148). The relative efficacy of bivalirudin versus UFH plus GP IIb/IIIa inhibitor was similar in several high-risk subgroups, including patients with diabetes mellitus or prior MI, women, the elderly (age > 65 years), and patients undergoing PCI of bypass grafts. Bivalirudin represents an exciting alternative to UFH plus GP IIb/IIIa inhibitor in patients undergoing urgent and elective PCI with similar suppression of ischemic events, fewer bleeding complications, and the potential for greater cost savings and ease of administration.

To assess the efficacy of the direct thrombin inhibitor bivalirudin relative to heparin during contemporary coronary intervention, 1,056 patients who underwent elective or urgent revascularization were randomized in a large-scale pilot study to receive heparin (70 U/kg initial bolus) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). All patients received aspirin; pretreatment with clopidogrel was encouraged, and glycoprotein (GP) IIb/IIIa blockade was at the physician's discretion. Stents were placed in 85% of patients; 72% received a GP IIb/IIIa inhibitor, and 56% were pretreated with clopidogrel. Activated clotting times were higher among patients randomized to bivalirudin than among those given heparin before device activation (median 359 vs 293 seconds, p <0.001). The composite efficacy end point of death, myocardial infarction, or repeat revascularization before hospital discharge or within 48 hours occurred in 5.6% and 6.9% of patients in the bivalirudin and heparin groups, respectively (p = 0.40). Major bleeding occurred in 2.1% versus 2.7% of patients randomized to bivalirudin or heparin, respectively (p = 0.52). This trial represents the largest prospective dataset of bivalirudin administered concomitantly with planned GP IIb/IIIa blockade and provides evidence of the safety and efficacy of this combined antithrombotic approach.

Because of its potential for antigenicity, theoretical concerns related to readministration of abciximab have been raised. We conducted the ReoPro Readministration Registry to assess the efficacy and safety of abciximab readministration. A total of 1,342 patients who underwent percutaneous coronary intervention and who received abciximab for at least a second time were recruited. Safety end points were hypersensitivity reactions, major bleeding, and thrombocytopenia (TCP). Human antichimeric antibody (HACA) titers were determined before and after readministration. Procedural success was 98% and was not influenced by the number of courses of abciximab or the presence of HACA. There were no cases of anaphylaxis. There were 5 minor allergic reactions, none of which required termination of the infusion. Clinically significant bleeding occurred in 31 patients (2.3%), including 1 (0.07%) with intracranial hemorrhage. TCP (<100 x 10(9)/L) developed in 5% of patients; profound TCP (<20 x 10(9)/L) occurred in 2%. In patients who received abciximab within 1 month of a previous treatment (n = 115), the risk of developing TCP and profound TCP was 16.5% and 12.2%, respectively. Having a positive HACA before readministration was not correlated with adverse clinical outcomes or bleeding, but was associated with TCP (14.1% vs 4.4%, p = 0.002) and profound TCP (5.6% vs 1.6%, p = 0.036). Readministration of abciximab can be accomplished without severe allergic responses and with a bleeding and efficacy profile similar to first-time administration. However, the rate of severe and profound TCP is increased relative to first-time administration, particularly when the time between treatments is <30 days or when HACA is present.

Background: Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI)., Objectives: To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI., Patients and Methods: Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I-III were designed to achieve concentrations of > 100 ng mL-1, > 75 ng mL-1, and > 150 ng mL-1. Stage IV used the stage III regimen but included patients recently given heparin., Results: At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL-1 in stages I-IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL-1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose., Conclusions: Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study.

Context: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI)., Objective: To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications., Design, Setting, and Participants: The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002., Interventions: Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI., Main Outcome Measures: The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization., Results: Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; P =.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; P =.40). Prespecified statistical criteria for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs 4.1%; P<.001)., Conclusions: Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.

Objectives: This study was designed to assess whether use of enoxaparin during percutaneous coronary intervention (PCI) increased bleeding compared with unfractionated heparin, in addition to background therapy with eptifibatide., Background: Data supporting the benefits of enoxaparin and the glycoprotein IIb/IIIa inhibitor eptifibatide evolved in parallel. Information on combining these two classes of medications is limited., Methods: A total of 261 patients undergoing elective or urgent PCI were randomized to either eptifibatide plus enoxaparin or eptifibatide plus unfractionated heparin., Results: The primary end point of the study, the bleeding index (change in hemoglobin corrected for blood transfusions), was 0.8 in the patients randomized to enoxaparin and 1.1 in patients randomized to unfractionated heparin (p = 0.15). The rate of vascular access site complications was 9.3% in the enoxaparin arm versus 9.8% in the unfractionated heparin arm (p = NS). The rate of bleeding complications was not significantly different between the two arms of the study, including in those patients who received vascular closure devices. The rate of angiographic complications was 6.3% in the enoxaparin group and 6.2% in the unfractionated heparin group (p = NS). Similarly, there were no significant differences in the composite of death, myocardial infarction, or urgent target vessel revascularization at 48 h or 30 days., Conclusions: Compared with unfractionated heparin plus eptifibatide, the combination of enoxaparin plus eptifibatide is not associated with an excess of bleeding or vascular complications, including in those receiving closure devices. Despite no monitoring of anticoagulation activity with enoxaparin, there was no apparent increase in angiographic or clinical complications.

We analyzed vascular access site bleeding from the EPIC, EPILOG, and EPISTENT trials to quantify the decrease in vascular bleeding complications in these three trials, especially those attributable to abciximab. The incidence of combined major and minor vascular access site bleeding in nonabciximab (heparin plus placebo) patients progressively decreased from EPIC (8.2%) to EPILOG (2.9%) to EPISTENT (1.7%; P < 0.001). Combined major and minor vascular access site bleeding in abciximab (heparin plus abciximab) patients decreased from EPIC (20%) to EPILOG (5.8%) to EPISTENT (2.2%; P < 0.001). There were more major vascular access site bleeds with abciximab compared to placebo in EPIC (odds ration 3.2; P < 0.001) but not in EPILOG or EPISTENT. Modified abciximab and heparin dosing and improved vascular access site management strategies have decreased the risk of vascular access bleeding during coronary intervention and have essentially eliminated the excess access site bleeding associated with abciximab., (Copyright 2002 Wiley-Liss, Inc.)

Background: Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa., Methods and Results: In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001)., Conclusions: This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

Background: The direct thrombin inhibitor bivalirudin has previously been associated with better efficacy and lower hemorrhage risk than heparin during balloon angioplasty. This agent has not yet been tested with stenting or in combination with platelet glycoprotein IIb/IIIa antagonists., Methods and Results: In a pilot trial, 268 patients who underwent coronary intervention were randomized in 3 sequential phases to treatment with bivalirudin (with or without abciximab) or the control regimen of low-dose weight-adjusted heparin with abciximab. Patients in the bivalirudin arms received bivalirudin (1.0 mg/kg bolus, infusion of 2.5 mg/kg/h for 4 hours) plus abciximab in phase A, bivalirudin (0.5 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional ("rescue") abciximab in phase B, or bivalirudin (0.75 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional abciximab in phase C. Abciximab was necessitated on a provisional basis in 24% of the patients in the bivalirudin arms of phases B and C. A composite clinical endpoint of death, myocardial infarction, repeat revascularization, or major bleeding by 7 days occurred in 3.3%, 5.9%, 0, and 10.6% of the patients in the bivalirudin phase A, bivalirudin phase B, bivalirudin phase C, and heparin plus planned abciximab arms, respectively (P =.018 for the pooled bivalirudin groups versus the heparin group)., Conclusion: Bivalirudin with planned or provisional abciximab may be at least as safe and effective as low-dose heparin plus abciximab during percutaneous coronary intervention.

Objectives: We examined the utility of early percutaneous coronary intervention (PCI) in a trial that encouraged its use after thrombolysis and glycoprotein IIb/IIIa inhibition for acute myocardial infarction (MI)., Background: Early PCI has shown no benefit when performed early after thrombolysis alone., Methods: We studied 323 patients (61%) who underwent PCI with planned initial angiography, at a median 63 min after reperfusion therapy began. A blinded core laboratory reviewed cineangiograms. Ischemic events, bleeding, angiographic results, and clinical outcomes were compared between early PCI and no-PCI patients (n = 162), between patients with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1 before PCI versus flow grade 2 or 3, and among three treatment regimens., Results: Early PCI patients showed a procedural success (<50% residual stenosis and TIMI flow grade 3) rate of 88% and a 30-day composite incidence of death, reinfarction, or urgent revascularization of 5.6%. These patients had fewer ischemic events and bleeding complications (15%) than did patients not undergoing early PCI (30%, p = 0.001). Early PCI was used more often in patients with initial TIMI flow grade 0 or 1 versus flow grade 2 or 3 (83% vs. 60%, p < 0.0001). Patients receiving abciximab with reduced-dose reteplase (5 U double bolus) showed an 86% incidence of TIMI grade 3 flow at approximately 90 min and a trend toward improved outcomes., Conclusions: In this analysis, early PCI facilitated by a combination of abciximab and reduced-dose reteplase was safe and effective. This approach has several advantages for acute MI patients, which should be confirmed in a dedicated, randomized trial.

New strategies for profound inhibition of platelet activity at the injured coronary plaque focus on blockade of the platelet surface membrane glycoprotein IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor and crosslinks platelets as the final common pathway to platelet aggregation. Intravenous agents directed against this receptor include the chimeric monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and nonpeptide mimetics tirofiban and lamifiban. Over 33,000 patients have been evaluated in 11 large-scale, placebo-controlled trials of these agents. During percutaneous coronary intervention, an absolute reduction of 1.5% to 6.5% in the 30-day risk of death, myocardial infarction or repeat urgent revascularization has been observed, with some variability in treatment effect among the agents tested (abciximab, eptifibatide and tirofiban). Treatment effect is achieved early with every modality of revascularization and is maintained over the long-term (up to three years). Increased bleeding risk may be minimized by reduction and weight-adjustment of concomitant heparin dosing. In the acute coronary syndromes without ST segment elevation, absolute 1.5% to 3.2% reductions in 30-day rates of death or myocardial (re-) infarction have been achieved with two to four day courses of eptifibatide or tirofiban. Clinical benefit accrues during the period of drug infusion and is durable. Treatment effect may be enhanced among patients undergoing early coronary revascularization, with evidence of stabilization before intervention and suppression of postprocedural ischemic events. Thus, blockade of the platelet glycoprotein IIb/IIIa receptor reduces ischemic complications when used as an adjunct to percutaneous coronary intervention or the management of acute ischemic syndromes.