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BACKGROUND: Each year, millions of patients worldwide have a perioperative myocardial infarction (MI) after noncardiac surgery. OBJECTIVE: To examine the characteristics and short-term outcome of perioperative MI. DESIGN: Cohort study. (ClinicalTrials.gov registration number: NCT00182039) SETTING: 190 centers in 23 countries. PATIENTS: 8351 patients included in the POISE (PeriOperative ISchemic Evaluation) trial. MEASUREMENTS: Four cardiac biomarker or enzyme assays were measured within 3 days of surgery. The definition of perioperative MI included either autopsy findings of acute MI or an elevated level of a cardiac biomarker or enzyme and at least 1 of the following defining features: ischemic symptoms, development of pathologic Q waves, ischemic changes on electrocardiography, coronary artery intervention, or cardiac imaging evidence of MI. RESULTS: Within 30 days of random assignment, 415 patients (5.0%) had a perioperative MI. Most MIs (74.1%) occurred within 48 hours of surgery; 65.3% of patients did not experience ischemic symptoms. The 30-day mortality rate was 11.6% (48 of 415 patients) among patients who had a perioperative MI and 2.2% (178 of 7936 patients) among those who did not (P < 0.001). Among patients with a perioperative MI, mortality rates were elevated and similar between those with (9.7%; adjusted odds ratio, 4.76 [95% CI, 2.68 to 8.43]) and without (12.5%; adjusted odds ratio, 4.00 [CI, 2.65 to 6.06]) ischemic symptoms. LIMITATION: Cardiac markers were measured only until day 3 after surgery, and additional asymptomatic MIs may have been missed. CONCLUSION: Most patients with a perioperative MI will not experience ischemic symptoms. Data suggest that routine monitoring of troponin levels in at-risk patients is needed after surgery to detect most MIs, which have an equally poor prognosis regardless of whether they are symptomatic or asymptomatic. [ABSTRACT FROM AUTHOR]

Context: The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain.Objective: To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux.Design, Setting, and Participants: Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010.Interventions: Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT).Main Outcome Measures: Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30.Results: The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15).Conclusion: Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications.Trial Registration: clinicaltrials.gov Identifier: NCT00790907. [ABSTRACT FROM AUTHOR]

Context: The clinical benefit of glucose-insulin-potassium (GIK) infusion in patients with ST-segment elevation myocardial infarction (STEMI) is unclear. While some smaller trials suggest benefit, in the CREATE-ECLA trial, GIK infusion had no effect on 30-day mortality in 20,201 patients.Objectives: To determine the association between GIK infusion therapy and 30-day and 6-month outcomes in patients with STEMI.Design, Setting, and Participants: Primary analysis of the OASIS-6 GIK randomized controlled trial of 2748 patients with acute STEMI; prespecified analyses of the combined trial data from the OASIS-6 GIK and CREATE-ECLA GIK trial populations of 22,943 patients with acute STEMI; subgroup analysis on the timing of initiation of GIK infusion therapy and outcomes; and post hoc analyses exploring whether GIK infusion may cause early harm by increasing glucose and potassium levels and net fluid gain.Intervention: High-dose GIK solution consisting of 25% glucose, 50 U/L of regular insulin, and 80 mEq/L of potassium infused at 1.5 mL/kg per hour for 24 hours.Main Outcome Measures: Mortality rates at 30 days and 6 months in the OASIS-6 GIK trial and rates of death, heart failure, and the composite of death or heart failure at 3 and 30 days in the combined OASIS-6 GIK and CREATE-ECLA GIK trial populations.Results: At 6 months, 148 (10.8%) GIK infusion patients and 143 (10.4%) control patients died in the OASIS-6 trial (hazard ratio [HR], 1.04; 95% CI, 0.83-1.31; P = .72); 153 (11.1%) GIK patients and 185 (13.5%) control patients had heart failure (HR, 0.83; 95% CI, 0.67-1.02; P = .08); and 240 (17.5%) GIK patients and 264 (19.2%) control patients had a composite of death or heart failure (HR, 0.91; 95% CI, 0.76-1.08; P = .27). In the prespecified analyses of the combined trial data, there were 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group at 3 days (HR, 1.13; 95% CI, 1.02-1.26; P = .03). This difference disappeared by 30 days, with 1108 deaths (9.7%) in the GIK group and 1068 (9.3%) in the control group (HR, 1.04; 95% CI, 0.96-1.13; P = .33). GIK therapy increased levels of glucose, potassium, and net fluid gain postinfusion, all 3 of which predicted death after adjusting for multiple confounders. Adjusting for glucose, potassium, and net fluid gain eliminated the apparent increase in mortality at 3 days observed with GIK infusion, suggesting a direct association with these factors. Administration of GIK infusion within 4 hours of symptom onset yielded no benefit compared with later initiation.Conclusions: Infusion of GIK provided no benefit and may cause early harm following STEMI. Avoidance of infusion-related hyperglycemia, hyperkalemia, and net fluid gain may be advisable in future studies of metabolic modulation in patients with STEMI.Trial Registration: clinicaltrials.gov Identifier: NCT00064428. [ABSTRACT FROM AUTHOR]

Background: A recent randomized, controlled trial, the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) trial, reported that major bleeding was 2-fold less frequent with fondaparinux than with enoxaparin in acute coronary syndromes (ACS). Renal dysfunction increases the risk for major bleeding.Objective: To compare the efficacy and safety of fondaparinux and enoxaparin over the spectrum of renal dysfunction observed in the OASIS 5 trial.Design: Subgroup analysis of a randomized, controlled trial.Setting: Patients presenting to the hospital with non-ST-segment elevation ACS.Patients: 19,979 of the 20,078 patients in the OASIS 5 trial in whom creatinine was measured at baseline.Measurements: Death, myocardial infarction, refractory ischemia, and major bleeding were evaluated separately and as a composite end point at 9, 30, and 180 days. Glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease formula.Results: The absolute differences in favor of fondaparinux (efficacy and safety) were most marked in patients with a GFR less than 58 mL/min per 1.73 m2; the largest differences occurred in major bleeding events. At 9 days, death, myocardial infarction, or refractory ischemia occurred in 6.7% of patients receiving fondaparinux and 7.4% of those receiving enoxaparin (hazard ratio, 0.90 [95% CI, 0.73 to 1.11]); major bleeding occurred in 2.8% and 6.4%, respectively (hazard ratio, 0.42 [CI, 0.32 to 0.56]). Statistically significant differences in major bleeding persisted at 30 and 180 days. The rates of the composite end point were lower with fondaparinux than with enoxaparin in all quartiles of GFR, but the differences were statistically significant only among patients with a GFR less than 58 mL/min per 1.73 m2.Limitations: Subgroup analyses warrant caution; the study was powered to detect noninferiority at 9 days. Fondaparinux is not approved for use in patients with ACS in the United States.Conclusions: The benefits of fondaparinux over enoxaparin when administered for non-ST-segment elevation ACS are most marked among patients with renal dysfunction and are largely explained by lower rates of major bleeding with fondaparinux. [ABSTRACT FROM AUTHOR]

Background: There is uncertainty regarding the optimal adjunctive unfractionated heparin (UFH) regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with fondaparinux. Objective: The aim of this study is to evaluate the safety of 2 dose regimens of adjunctive intravenous UFH during PCI in high-risk patients with NSTE-ACS initially treated with fondaparinux and referred for early coronary angiography. Design: This is an international prospective cohort study of approximately 4,000 high-risk patients presenting to hospital with unstable angina or non-ST-segment elevation myocardial infarction, treated with fondaparinux as initial medical therapy, and referred for early coronary angiography with a view to revascularization. Within this cohort, 2,000 patients undergoing PCI will be eligible for enrollment into a double-blind international randomized parallel-group trial evaluating standard activated clotting time (ACT)-guided doses of intravenous UFH versus a non-ACT-guided weight-adjusted low dose. The standard regimen uses an 85-U/kg bolus of UFH if there is no platelet glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitor or 60 U/kg if GpIIb-IIIa inhibitor use is planned, with additional bolus guided by blinded ACT measurements. The low-dose regimen uses a 50 U/kg UFH bolus, irrespective of planned GpIIb-IIIa use. The primary outcome is the composite of peri-PCI major bleeding, minor bleeding, or major vascular access site complications. The assessment of net clinical benefit is a key secondary outcome: it addresses the composite of peri-PCI major bleeding with death, myocardial infarction, or target vessel revascularization at day 30. Conclusion: FUTURA/OASIS 8 will help define the optimal UFH regimen as adjunct to PCI in high-risk NSTE-ACS patients treated with fondaparinux. [ABSTRACT FROM AUTHOR]

Background: Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.Methods: Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2.0-3.0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178.Results: The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively).Conclusion: Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy. [ABSTRACT FROM AUTHOR]

Summary Background Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events. Methods Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2·0-3·0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178. Results The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3·93%) and 234 in those on clopidogrel plus aspirin (annual risk 5·60%; relative risk 1·44 (1·18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1·50, 95% CI 1·19-1·89) and a significantly (p=0·03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1·27, 0·85-1·89 and 0·59, 0·32-1·08, respectively). Conclusion Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy. [ABSTRACT FROM AUTHOR]

Background: Cardiopulmonary bypass initiates a systemic inflammatory response syndrome that is associated with postoperative morbidity and mortality. Steroids suppress inflammatory responses and might improve outcomes in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. We aimed to assess the effects of steroids in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass., Methods: The Steroids In caRdiac Surgery (SIRS) study is a double-blind, randomised, controlled trial. We used a central computerised phone or interactive web system to randomly assign (1:1) patients at high risk of morbidity and mortality from 80 hospital or cardiac surgery centres in 18 countries undergoing cardiac surgery with the use of cardiopulmonary bypass to receive either methylprednisolone (250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients were assigned with block randomisation with random block sizes of 2, 4, or 6 and stratified by centre. Patients aged 18 years or older were eligible if they had a European System for Cardiac Operative Risk Evaluation of at least 6. Patients were excluded if they were taking or expected to receive systemic steroids in the immediate postoperative period or had a history of bacterial or fungal infection in the preceding 30 days. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcomes were 30-day mortality and a composite of death and major morbidity (ie, myocardial injury, stroke, renal failure, or respiratory failure) within 30 days, both analysed by intention to treat. Safety outcomes were also analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00427388., Findings: Patients were recruited between June 21, 2007, and Dec 19, 2013. Complete 30-day data was available for all 7507 patients randomly assigned to methylprednisolone (n=3755) and to placebo (n=3752). Methylprednisolone, compared with placebo, did not reduce the risk of death at 30 days (154 [4%] vs 177 [5%] patients; relative risk [RR] 0·87, 95% CI 0·70-1·07, p=0·19) or the risk of death or major morbidity (909 [24%] vs 885 [24%]; RR 1·03, 95% CI 0·95-1·11, p=0·52). The most common safety outcomes in the methylprednisolone and placebo group were infection (465 [12%] vs 493 [13%]), surgical site infection (151 [4%] vs 151 [4%]), and delirium (295 [8%] vs 289 [8%])., Interpretation: Methylprednisolone did not have a significant effect on mortality or major morbidity after cardiac surgery with cardiopulmonary bypass. The SIRS trial does not support the routine use of methylprednisolone for patients undergoing cardiopulmonary bypass., Funding: Canadian Institutes of Health Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Nonvalvular atrial fibrillation is a major cause of thromboembolic events. In comparison with atrial fibrillation-related stroke, extracranial systemic embolic events (SEEs) remain poorly defined., Methods and Results: All suspected SEEs reported among 37 973 participants of 4 large contemporary randomized clinical trials of anticoagulation in atrial fibrillation were independently readjudicated for clinical and objective evidence of sudden loss of perfusion of a limb or organ. Over 91 746 patient-years of follow-up, 221 SEEs occurred in 219 subjects. The SEE incidence was 0.24 of 100 and stroke incidence was 1.92 of 100 patient-years. In comparison with patients with stroke, those with SEE were more often female (56% versus 47%; P=0.01) and had comparable mean age (73.1±8.5 versus 73.5±8.8 years; P=0.57) and mean CHADS2 scores (2.4±1.3 versus 2.5±1.2; P=0.33). SEEs more frequently involved the lower extremity (58%) than visceral-mesenteric (31%) or upper extremity (10%). SEE-related care involved clinic assessment alone in 5%, 30% were hospitalized without procedures, 60% underwent endovascular or surgical intervention, and 5% underwent amputation. Within 30 days, 54% of patients recovered fully, 20% survived with deficits, and 25% died. Thirty-day mortality was greater after visceral-mesenteric than lower- or upper-extremity SEE (55%, 17%, and 9%, respectively, P≤0.0001). The relative risk of death throughout follow-up was 4.33 (95% confidence interval, 3.29-5.70) after SEE versus 6.79 (95% confidence interval, 6.22-7.41) after stroke in comparison with patients without either event., Conclusions: SEE constituted 11.5% of clinically recognized thromboembolic events in patients with atrial fibrillation and was associated with high morbidity and mortality. SEE mortality was comparable to that of ischemic stroke and varied by anatomic site., (© 2015 American Heart Association, Inc.)

Background: Defibrillation testing by induction and termination of ventricular fibrillation is widely done at the time of implantation of implantable cardioverter defibrillators (ICDs). We aimed to compare the efficacy and safety of ICD implantation without defibrillation testing versus the standard of ICD implantation with defibrillation testing., Methods: In this single-blind, randomised, multicentre, non-inferiority trial (Shockless IMPLant Evaluation [SIMPLE]), we recruited patients aged older than 18 years receiving their first ICD for standard indications at 85 hospitals in 18 countries worldwide. Exclusion criteria included pregnancy, awaiting transplantation, particpation in another randomised trial, unavailability for follow-up, or if it was expected that the ICD would have to be implanted on the right-hand side of the chest. Patients undergoing initial implantation of a Boston Scientific ICD were randomly assigned (1:1) using a computer-generated sequence to have either defibrillation testing (testing group) or not (no-testing group). We used random block sizes to conceal treatment allocation from the patients, and randomisation was stratified by clinical centre. Our primary efficacy analysis tested the intention-to-treat population for non-inferiority of no-testing versus testing by use of a composite outcome of arrhythmic death or failed appropriate shock (ie, a shock that did not terminate a spontaneous episode of ventricular tachycardia or fibrillation). The non-inferiority margin was a hazard ratio (HR) of 1·5 calculated from a proportional hazards model with no-testing versus testing as the only covariate; if the upper bound of the 95% CI was less than 1·5, we concluded that ICD insertion without testing was non-inferior to ICD with testing. We examined safety with two, 30 day, adverse event outcome clusters. The trial is registered with ClinicalTrials.gov, number NCT00800384., Findings: Between Jan 13, 2009, and April 4, 2011, of 2500 eligible patients, 1253 were randomly assigned to defibrillation testing and 1247 to no-testing, and followed up for a mean of 3·1 years (SD 1·0). The primary outcome of arrhythmic death or failed appropriate shock occurred in fewer patients (90 [7% per year]) in the no-testing group than patients who did receive it (104 [8% per year]; HR 0·86, 95% CI 0·65-1·14; pnon-inferiority <0·0001). The first safety composite outcome occurred in 69 (5·6%) of 1236 patients with no-testing and in 81 (6·5%) of 1242 patients with defibrillation testing, p=0·33. The second, pre-specified safety composite outcome, which included only events most likely to be directly caused by testing, occurred in 3·2% of patients with no-testing and in 4·5% with defibrillation testing, p=0·08. Heart failure needing intravenous treatment with inotropes or diuretics was the most common adverse event (in 20 [2%] of 1236 patients in the no-testing group vs 28 [2%] of 1242 patients in the testing group, p=0·25)., Interpretation: Routine defibrillation testing at the time of ICD implantation is generally well tolerated, but does not improve shock efficacy or reduce arrhythmic death., Funding: Boston Scientific and the Heart and Stroke Foundation (Ontario Provincial office)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: There is substantial variability in the perioperative administration of aspirin in patients undergoing noncardiac surgery, both among patients who are already on an aspirin regimen and among those who are not., Methods: Using a 2-by-2 factorial trial design, we randomly assigned 10,010 patients who were preparing to undergo noncardiac surgery and were at risk for vascular complications to receive aspirin or placebo and clonidine or placebo. The results of the aspirin trial are reported here. The patients were stratified according to whether they had not been taking aspirin before the study (initiation stratum, with 5628 patients) or they were already on an aspirin regimen (continuation stratum, with 4382 patients). Patients started taking aspirin (at a dose of 200 mg) or placebo just before surgery and continued it daily (at a dose of 100 mg) for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed their regular aspirin regimen. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days., Results: The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P=0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P=0.04). The primary and secondary outcome results were similar in the two aspirin strata., Conclusions: Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).

Background: Marked activation of the sympathetic nervous system occurs during and after noncardiac surgery. Low-dose clonidine, which blunts central sympathetic outflow, may prevent perioperative myocardial infarction and death without inducing hemodynamic instability., Methods: We performed a blinded, randomized trial with a 2-by-2 factorial design to allow separate evaluation of low-dose clonidine versus placebo and low-dose aspirin versus placebo in patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. A total of 10,010 patients at 135 centers in 23 countries were enrolled. For the comparison of clonidine with placebo, patients were randomly assigned to receive clonidine (0.2 mg per day) or placebo just before surgery, with the study drug continued until 72 hours after surgery. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days., Results: Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02)., Conclusions: Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).

Background: Previously, we reported that there was no significant difference at 30 days in the rate of a primary composite outcome of death, myocardial infarction, stroke, or new renal failure requiring dialysis between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report results on quality of life and cognitive function and on clinical outcomes at 1 year., Methods: We enrolled 4752 patients with coronary artery disease who were scheduled to undergo CABG and randomly assigned them to undergo the procedure off-pump or on-pump. Patients were enrolled at 79 centers in 19 countries. We assessed quality of life and cognitive function at discharge, at 30 days, and at 1 year and clinical outcomes at 1 year., Results: At 1 year, there was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (12.1% and 13.3%, respectively; hazard ratio with off-pump CABG, 0.91; 95% confidence interval [CI], 0.77 to 1.07; P=0.24). The rate of the primary outcome was also similar in the two groups in the period between 31 days and 1 year (hazard ratio, 0.79; 95% CI, 0.55 to 1.13; P=0.19). The rate of repeat coronary revascularization at 1 year was 1.4% in the off-pump group and 0.8% in the on-pump group (hazard ratio, 1.66; 95% CI, 0.95 to 2.89; P=0.07). There were no significant differences between the two groups at 1 year in measures of quality of life or neurocognitive function., Conclusions: At 1 year after CABG, there was no significant difference between off-pump and on-pump CABG with respect to the primary composite outcome, the rate of repeat coronary revascularization, quality of life, or neurocognitive function. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Background: The relative benefits and risks of performing coronary-artery bypass grafting (CABG) with a beating-heart technique (off-pump CABG), as compared with cardiopulmonary bypass (on-pump CABG), are not clearly established., Methods: At 79 centers in 19 countries, we randomly assigned 4752 patients in whom CABG was planned to undergo the procedure off-pump or on-pump. The first coprimary outcome was a composite of death, nonfatal stroke, nonfatal myocardial infarction, or new renal failure requiring dialysis at 30 days after randomization., Results: There was no significant difference in the rate of the primary composite outcome between off-pump and on-pump CABG (9.8% vs. 10.3%; hazard ratio for the off-pump group, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P=0.59) or in any of its individual components. The use of off-pump CABG, as compared with on-pump CABG, significantly reduced the rates of blood-product transfusion (50.7% vs. 63.3%; relative risk, 0.80; 95% CI, 0.75 to 0.85; P<0.001), reoperation for perioperative bleeding (1.4% vs. 2.4%; relative risk, 0.61; 95% CI, 0.40 to 0.93; P=0.02), acute kidney injury (28.0% vs. 32.1%; relative risk, 0.87; 95% CI, 0.80 to 0.96; P=0.01), and respiratory complications (5.9% vs. 7.5%; relative risk, 0.79; 95% CI, 0.63 to 0.98; P=0.03) but increased the rate of early repeat revascularizations (0.7% vs. 0.2%; hazard ratio, 4.01; 95% CI, 1.34 to 12.0; P=0.01)., Conclusions: There was no significant difference between off-pump and on-pump CABG with respect to the 30-day rate of death, myocardial infarction, stroke, or renal failure requiring dialysis. The use of off-pump CABG resulted in reduced rates of transfusion, reoperation for perioperative bleeding, respiratory complications, and acute kidney injury but also resulted in an increased risk of early revascularization. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294.).

Background: The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events-Aspirin (ACTIVE-A) demonstrated that in patients with atrial fibrillation unsuitable for vitamin K antagonist (VKA) therapy, a combination of clopidogrel and aspirin reduced stroke risk by 28% but increased major hemorrhage risk by 57%. This analysis examined cost implications of adding clopidogrel to aspirin (C+A) for ACTIVE-A patients., Methods: Health care use was extracted for each patient. We considered only direct costs and included only hospitalization events. We used Canadian unit costs for the health care resources consumed and Canadian list price of brand clopidogrel. Costs, in 2008 Canadian dollars, were discounted at 3% per year., Results: C+A reduced costs of health care use components except for the study medication. Stroke prevention resulted in important cost savings that offset the cost of clopidogrel. Total costs per patient for C+A were $14,132 (95% confidence interval [CI], $13,445-$14,842), compared with $13,756 (95% CI, $13,032-$14,544) for aspirin alone, resulting in incremental cost of $376 (95% CI, -$645 to $1397) for C+A, confirmed through bootstrap simulation. Estimates were sensitive to the price of clopidogrel, varying from cost savings to a significant increase., Conclusion: C+A in patients unsuitable for VKA therapy is cost neutral (following our predefined conditions) as cost of clopidogrel is offset by prevention of costly strokes. These findings support the use of C+A in ACTIVE-A patients for whom VKA therapy is unsuitable., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to compare benefits and risks of a routine invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes., Methods and Results: We randomly assigned 184 women, either to a routine or to a selective invasive strategy as a substudy to the OASIS 5 trial, who were followed for 2 years. Meta-analysis of data from previous randomized trials was also done. There were no significant differences between the two treatment strategies in the primary outcome death/myocardial infarction (MI)/stroke [21.0 vs. 15.4%, HR = 1.46, 95% CI (0.73-2.94)], in the secondary outcome death/MI [18.8 vs. 14.3%, HR = 1.39, 95% CI (0.67-2.88)], or separately analysed outcomes MI [12.9 vs. 13.3%, HR = 0.95, 95% CI (0.42-2.19)] or stroke [2.3 vs. 4.4%, HR = 0.67, 95% CI (0.12-3.70)]. However, there were significantly more deaths after 1 year (8.8 vs. 1.1%, HR = 9.01, 95% CI (1.11-72.90) and a higher rate of major bleeding at 30 days [8.8 vs. 1.1%, HR = 11.45, 95% CI (1.43-91.96)] in the routine invasive strategy group. A meta-analysis including 2692 women in previous randomized trials, with a gender perspective, showed no significant difference in the composite outcome death/MI, OR = 1.18, 95% CI (0.92-1.53) but a higher mortality with a routine invasive strategy for women, OR = 1.51, 95% CI (1.00-2.29)., Conclusion: The rate of death, MI, or stroke in women was not different in patients treated with a routine invasive strategy compared with a selective invasive strategy, but there was a concerning trend towards higher mortality. When combined with data from previous trials, there does not appear to be a benefit of an early invasive strategy in women with ACS, which differs from the results in men. These data emphasize the lack of clear evidence in favour of an invasive strategy in women and suggest caution in extrapolating the results from men to women.

Background: Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation., Methods: We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death., Results: After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02)., Conclusions: Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).

Background: Small trials have suggested that radial access for percutaneous coronary intervention (PCI) reduces vascular complications and bleeding compared with femoral access. We aimed to assess whether radial access was superior to femoral access in patients with acute coronary syndromes (ACS) who were undergoing coronary angiography with possible intervention., Methods: The RadIal Vs femorAL access for coronary intervention (RIVAL) trial was a randomised, parallel group, multicentre trial. Patients with ACS were randomly assigned (1:1) by a 24 h computerised central automated voice response system to radial or femoral artery access. The primary outcome was a composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft (non-CABG)-related major bleeding at 30 days. Key secondary outcomes were death, myocardial infarction, or stroke; and non-CABG-related major bleeding at 30 days. A masked central committee adjudicated the primary outcome, components of the primary outcome, and stent thrombosis. All other outcomes were as reported by the investigators. Patients and investigators were not masked to treatment allocation. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT01014273., Findings: Between June 6, 2006, and Nov 3, 2010, 7021 patients were enrolled from 158 hospitals in 32 countries. 3507 patients were randomly assigned to radial access and 3514 to femoral access. The primary outcome occurred in 128 (3·7%) of 3507 patients in the radial access group compared with 139 (4·0%) of 3514 in the femoral access group (hazard ratio [HR] 0·92, 95% CI 0·72-1·17; p=0·50). Of the six prespecified subgroups, there was a significant interaction for the primary outcome with benefit for radial access in highest tertile volume radial centres (HR 0·49, 95% CI 0·28-0·87; p=0·015) and in patients with ST-segment elevation myocardial infarction (0·60, 0·38-0·94; p=0·026). The rate of death, myocardial infarction, or stroke at 30 days was 112 (3·2%) of 3507 patients in the radial group compared with 114 (3·2%) of 3514 in the femoral group (HR 0·98, 95% CI 0·76-1·28; p=0·90). The rate of non-CABG-related major bleeding at 30 days was 24 (0·7%) of 3507 patients in the radial group compared with 33 (0·9%) of 3514 patients in the femoral group (HR 0·73, 95% CI 0·43-1·23; p=0·23). At 30 days, 42 of 3507 patients in the radial group had large haematoma compared with 106 of 3514 in the femoral group (HR 0·40, 95% CI 0·28-0·57; p<0·0001). Pseudoaneurysm needing closure occurred in seven of 3507 patients in the radial group compared with 23 of 3514 in the femoral group (HR 0·30, 95% CI 0·13-0·71; p=0·006)., Interpretation: Radial and femoral approaches are both safe and effective for PCI. However, the lower rate of local vascular complications may be a reason to use the radial approach., Funding: Sanofi-Aventis, Population Health Research Institute, and Canadian Network for Trials Internationally (CANNeCTIN), an initiative of the Canadian Institutes of Health Research., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The risk of cardiovascular events among patients with atrial fibrillation is high. We evaluated whether irbesartan, an angiotensin-receptor blocker, would reduce this risk., Methods: We randomly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo. These patients were already enrolled in one of two trials (of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants). The first coprimary outcome was stroke, myocardial infarction, or death from vascular causes; the second was this composite outcome plus hospitalization for heart failure., Results: A total of 9016 patients were enrolled and followed for a mean of 4.1 years. The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group, and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater. The first coprimary outcome occurred at a rate of 5.4% per 100 person-years in both groups (hazard ratio with irbesartan, 0.99; 95% confidence interval [CI], 0.91 to 1.08; P=0.85). The second coprimary outcome occurred at a rate of 7.3% per 100 person-years among patients receiving irbesartan and 7.7% per 100 person-years among patients receiving placebo (hazard ratio, 0.94; 95% CI, 0.87 to 1.02; P=0.12). The rates of first hospitalization for heart failure (a prespecified secondary outcome) were 2.7% per 100 person-years among patients receiving irbesartan and 3.2% per 100 person-years among patients receiving placebo (hazard ratio, 0.86; 95% CI, 0.76 to 0.98). Among patients who were in sinus rhythm at baseline, there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography, nor was there a benefit in a subgroup that underwent transtelephonic monitoring. More patients in the irbesartan group than in the placebo group had symptomatic hypotension (127 vs. 64) and renal dysfunction (43 vs. 24)., Conclusions: Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation. (Funded by Bristol-Myers Squibb and Sanofi-Aventis; ClinicalTrials.gov number, NCT00249795.).

Background: Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes., Objectives: The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy., Design: This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non-coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites., Conclusions: The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI., Methods: The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25,086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17,263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452., Findings: 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74-0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39-0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84-1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09-1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92-1·53, p=0·20)., Interpretation: In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI., Funding: Sanofi-Aventis and Bristol-Myers Squibb., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent., Methods: We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days., Results: The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90)., Conclusions: In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)

Aims: To assess the risk of death after the occurrence of different types of non-fatal events in patients with atrial fibrillation (AF). Antithrombotic therapies in AF have primarily focused on stroke prevention and bleeding. However, strokes and bleeds differ in severity, and the level of severity may differently impact mortality., Methods and Results: We analysed the risk of subsequent mortality after the occurrence of non-fatal vascular and bleeding events in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-W trial. In the 3371 patients randomized to vitamin K antagonists and the 3335 patients randomized to clopidogrel plus aspirin in ACTIVE-W, the hazard ratio (HR) and 95% confidence intervals (95% CIs) for subsequent death associated with the occurrence of non-fatal stroke was 5.58 (95% CI 3.84-8.10, P < 0.0001). Both ischaemic (HR 5.29, 95% CI 3.53-7.93, P < 0.0001) and haemorrhagic strokes (HR 7.38, 95% CI 2.74-19.9, P < 0.0001) increased mortality, but transient ischaemic attacks did not. Disabling strokes (Rankin's score > or =3) increased mortality (HR 9.54; 95% CI 6.42-14.2, P< 0.0001), but non-disabling strokes did not. Severe bleeding increased mortality (HR 3.35, 95% CI 2.12-5.27, P < 0.0001), but major bleeding that was not severe according to the study definitions did not., Conclusion: Non-fatal strokes increased mortality in ACTIVE-W, but non-disabling strokes did not. Among major bleeding events, only those also classified as severe increased mortality. Future research should emphasize the prevention of disabling strokes and severe bleeds and place less emphasis on non-disabling stroke or major bleeds that are not severe.

Aims: In patients with acute coronary syndromes (ACS), the negative impact of baseline haemoglobin levels on ischaemic events, particularly death, is well established, but the association with bleeding risk is less well studied. The aim of this study was to assess the impact of baseline haemoglobin levels on major bleeding complications., Methods and Results: Pooled analysis of OASIS 5 and 6 data involving 32 170 patients with ACS with and without ST-segment elevation was performed. The association between baseline haemoglobin and major bleeding or ischaemic events was examined using multiple regression model., Main Outcome Measures: were 30-day rates of major bleeding, death, and death/myocardial infarction (MI) analysed according to baseline haemoglobin levels. Baseline haemoglobin level independently predicted the risk of overall, procedure-related, and non-procedure-related major bleedings at 30 days [odds ratio (OR) 0.94, 95% CI 0.90-0.98; OR 0.94, 95% CI 0.90-0.99; and OR 0.89, 95% CI 0.83-0.95, respectively, per 1 g/dL haemoglobin increment above 10 g/dL]. In addition, a curvilinear relationship between baseline haemoglobin levels and death at 30 days was observed with a 6% decrease in the risk for every 1 g/dL haemoglobin increment above 10 g/dL up to 15.9 g/dL (OR 0.94, 95% CI 0.90-0.98) and a 19% increase above this value (OR 1.19, 95% CI, 0.98-1.43). A similar relationship for the composite outcome of death/MI was observed., Conclusion: A low baseline haemoglobin level is an independent predictor of the risk of major bleeding in ACS as well as of the risk of death and death and MI. Among other predictors of bleeding risk, baseline haemoglobin should be taken into account in patients presenting with ACS., Clinical Trial Registration: ClinicalTrials.gov number, NCT00139815. http://clinicaltrials.gov/ct2/show/NCT00139815?term=NCT00139815&rank=1.

Background: Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain., Methods: We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography < or = 24 hours after randomization) or delayed intervention (coronary angiography > or = 36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, or refractory ischemia at 6 months., Results: Coronary angiography was performed in 97.6% of patients in the early-intervention group (median time, 14 hours) and in 95.7% of patients in the delayed-intervention group (median time, 50 hours). At 6 months, the primary outcome occurred in 9.6% of patients in the early-intervention group, as compared with 11.3% in the delayed-intervention group (hazard ratio in the early-intervention group, 0.85; 95% confidence interval [CI], 0.68 to 1.06; P=0.15). There was a relative reduction of 28% in the secondary outcome of death, myocardial infarction, or refractory ischemia in the early-intervention group (9.5%), as compared with the delayed-intervention group (12.9%) (hazard ratio, 0.72; 95% CI, 0.58 to 0.89; P=0.003). Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89) but not in the two thirds at low-to-intermediate risk (hazard ratio, 1.12; 95% CI, 0.81 to 1.56; P=0.01 for heterogeneity)., Conclusions: Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients. (ClinicalTrials.gov number, NCT00552513.), (2009 Massachusetts Medical Society)

Background: Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation., Methods: A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes., Results: At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001)., Conclusions: In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage. (ClinicalTrials.gov number, NCT00249873.), (2009 Massachusetts Medical Society)

Background: The OASIS-5 (Organization to Assess Strategies in Ischemic Syndromes-5) trial demonstrated that fondaparinux was noninferior to enoxaparin while reducing the risk of bleeding by 50%. The objectives of our study were to assess the effects of fondaparinux compared to enoxaparin in patients stratified by their Global Registry of Acute Coronary Events (GRACE) score and to examine the ability of the GRACE score to predict bleeding in patients with acute coronary syndromes (ACS)., Methods: We analyzed efficacy and safety according to the GRACE admission risk score., Results: The impact of fondaparinux versus enoxaparin on the primary outcome of death, myocardial infarction, and refractory ischemia at 180 days was similar in the low-, intermediate-, and high-risk groups: 7.0% versus 7.7% (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.75-1.08), 10.2% versus 11.3% (HR 0.89, 95% CI 0.77-1.03), and 20.1% versus 21.1% (HR 0.95, 95% CI 0.85-1.06). Major bleeding rates were higher with increasing GRACE risk scores: 2.2%, 3.2%, and 4.1% in the low, intermediate, and high-risk groups. Six-month mortality was 2.2%, 4.2%, and 12.3% in the 3 groups. The risk of major bleeding was substantially lower with fondaparinux in all groups: 1.6% versus 2.9% (HR 0.55, 95% CI 0.39-0.77), 2.2% versus 4.1% (HR 0.53, 95% CI 0.40-0.70), 2.8% versus 5.5% (HR 0.50, 95% CI 0.38-0.64)., Conclusion: The GRACE score predicted both bleeding and mortality in patients with ACS. The efficacy and safety of fondaparinux were consistent in all risk groups supporting its use in a broad range of ACS patients.

Aims: Bleeding in patients with coronary artery disease has been linked with adverse outcomes. We examined the incidence and outcomes after bleeding in 20 078 patients with acute coronary syndromes (ACS) enrolled in the OASIS-5 trial who were treated with fondaparinux or the low-molecular weight heparin, enoxaparin., Methods and Results: Nine hundred and ninety (4.9%) patients developed major bleeding and 423 (2.1%) developed minor bleeding. Fondaparinux compared with enoxaparin reduced fatal bleeding [0.07 vs. 0.22%, relative risk (RR) 0.30, 95% CI: 0.13-0.71], non-fatal major bleeding (2.2 vs. 4.2%, RR 0.52, 95% CI: 0.44-0.61), minor bleeding (1.1 vs. 3.2%, RR 0.34, 95% CI: 0.27-0.42), and need for transfusion (1.8 vs. 3.1%, RR 0.56, 95% CI: 0.47-0.61) during the first 9 days. One of every six deaths during the first 30 days occurred in patients who experienced bleeding. Cox proportional hazards model revealed that major bleeding was associated with about a four-fold increased hazard of death, myocardial infarction, or stroke during the first 30 days and about a three-fold increased hazard during 180 days of follow up., Conclusion: Bleeding in patients with ACS is a powerful determinant of fatal and non-fatal outcomes. Reducing the risk of bleeding using a safer anticoagulant strategy during the first 9 days is associated with substantial reductions in morbidity and mortality.

Background: Antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) reduces major cardiovascular events in patients with ST and non-ST-segment-elevation acute coronary syndromes (ACS). Recent mechanistic and clinical data suggest that higher loading and maintenance doses of clopidogrel may achieve a more rapid and greater degree of platelet inhibition that translates into improved clinical outcomes, but this is yet to be formally evaluated in an adequately powered randomized trial., Objectives: To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy., Design: Multicenter, international, randomized, 2 x 2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA (300-325 mg daily) versus low-dose ASA (75-100 mg daily) in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients., Conclusions: The CURRENT-OASIS 7 trial will help to define optimal dosing regimens for clopidogrel and ASA in patients with ST and non-ST-segment-elevation ACS treated with an early invasive strategy.

Aims: No antithrombotic therapy has been shown to reduce mortality when used with thrombolytics in acute myocardial infarction (AMI). In the OASIS-6 trial, fondaparinux significantly reduced mortality and reinfarction without increasing bleeding in 12 092 patients with acute ST elevation MI., Methods and Results: We report the results of a subgroup analysis in the 5436 patients (45%) receiving thrombolytics. According to local practice, 4415 patients did not have an indication for unfractionated heparin (stratum 1) and 1021 did (stratum 2). Fondaparinux reduced the primary study outcome of death or MI at 30 days [Hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.68-0.92] with consistent reductions in both mortality (HR and CI) and reinfarction (HR and CI). There was a non-significantly lower rate of stroke (HR 0.77, CI 0.48-1.25). The risk of severe bleeding was significantly reduced (HR 0.62, CI 0.40-0.94), and thus the balance of benefit and risk (death, MI and severe haemorrhage) was clearly reduced by fondaparinux (HR 0.77, 95% CI 0.67-0.90). Results were consistent in the two strata, by the different types of thrombolytics and across various time intervals from symptom onset to treatment., Conclusion: In STEMI patients treated with thrombolytic agents (predominantly streptokinase), fondaparinux significantly reduced the risk of death, re-MI and severe bleeds.

Aims: At least one quarter of ST-segment elevation myocardial infarction (STEMI) patients do not receive reperfusion therapy, and these patients are at high risk for new ischaemic events. We evaluated fondaparinux treatment vs. usual care, i.e. placebo or unfractionated (UF) heparin, in a pre-specified subgroup of 2867 (out of 12 092) patients not receiving reperfusion treatment in the OASIS-6 trial., Methods: In all, 1458 patients were randomized to fondaparinux 2.5 mg once daily subcutaneously up to 8 days and 1409 patients to usual care (control). Randomization was stratified by indication for UF heparin (stratum II, n = 1226) or not (stratum I, n = 1641) based on the investigator's judgment., Results: The proportion of patients who suffered death or myocardial re-infarction at 30 days (primary outcome) was 12.2% in the fondaparinux vs. 15.1% in the control group, hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.65-0.98. There was no increase in severe bleedings, HR 0.82; CI 0.44-1.55, or strokes, HR 0.62; CI 0.29-1.33. Consequently, the composite of death, myocardial re-infarction, or severe bleeding were significantly reduced at 30 days, HR 0.81; CI 0.67-0.99. Reductions in death or myocardial re-infarction at 30 days were consistent in stratum I with fondaparinux vs. placebo, HR 0.88; 95% CI 0.65-1.19, and in stratum II with fondaparinux vs. UF heparin infusion for 24-48 h (n = 806), HR 0.74; CI 95% 0.57-0.97, P = 0.41 for heterogeneity., Conclusion: In STEMI patients not receiving reperfusion treatment, fondaparinux reduces the composite of death or myocardial re-infarction without an increase in severe bleedings or strokes as compared to placebo or UF heparin.