Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Irbesartan in patients with atrial fibrillation.

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.).

Apixaban in patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS: In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS: Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).

Dronedarone in high-risk permanent atrial fibrillation.

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.).

Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.

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.)

Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.

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.

Dabigatran versus warfarin in patients with atrial fibrillation.

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.

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.

Relationship between baseline haemoglobin and major bleeding complications in acute coronary syndromes.

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.

Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment.

BACKGROUND: Many patients with atrial fibrillation (AF) at moderate or high risk for stroke are not treated with a vitamin K antagonist (VKA). Presently, the only alternative to a VKA with a labeled indication for AF is antiplatelet therapy with acetylsalicylic acid (ASA), which is much less effective than a VKA for prevention of stroke. The novel oral factor Xa inhibitor, apixaban, is being developed for prevention of stroke in AF. A noninferiority trial of apixaban versus a VKA (warfarin) is being conducted but does not address the large unmet need of AF patients at risk of stroke who are unsuitable for or unwilling to take a VKA. Apixaban may be an attractive alternative to ASA for prevention of stroke in patients with AF who cannot or will not take a VKA. DESIGN: AVERROES is a double-blind, double-dummy superiority trial of apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) compared with ASA 81 to 324 mg once daily in patients with AF and at least 1 risk factor for stroke who have failed or are unsuitable for VKA therapy. The primary outcome is stroke or systemic embolism, and the primary safety outcome is major bleeding. The trial is event driven and is expected to enroll at least 5,600 patients. CONCLUSIONS: By evaluating the use of apixaban as a replacement for ASA in AF patients who are not treated with a VKA, the AVERROES study is addressing an important unmet clinical need. The results of AVERROES will be complementary to those of a parallel noninferiority trial comparing apixaban with VKA therapy in patients with AF who are able to receive a VKA.

Association of Bicuspid aortic valve morphology and aortic root dimensions: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study.

BACKGROUND: Bicuspid aortic valve (BAV) is the leading cause of aortic stenosis in patients younger than the age of 50. A classification scheme of BAVs is based upon leaflet orientation: Type I (fusion of right and left coronary cusps) and Type II (fusion of right and noncoronary cusps). The correlation between BAV leaflet orientation and aortic root pathology however remains ill defined. OBJECTIVE: The objective was to describe a potential relationship between BAV leaflet morphology and aortic root measurements in the ASTRONOMER study, a multicenter study to assess the effect of rosuvastatin on the progression of AS. METHODS: BAV morphology was classified as Type I or Type II orientation based on the parasternal short-axis view. Echo measurements including left ventricular and aortic root dimensions were obtained. RESULTS: The study population included 89 patients (56 +/- 11 years; 44 males). There were 63 patients with Type I and 26 patients with Type II BAV. Baseline demographics, hemodynamics, and left heart dimensions were similar between both groups. Patients with Type I BAV had larger aortic annulus and ascending root dimensions compared to those patients with Type II BAV (P < 0.05). CONCLUSION: In patients with mild to moderate aortic stenosis due to a BAV, the presence of Type I valve orientation was associated with significantly greater aortic root parameters compared to Type II valve orientation.

Improving clinical outcomes by reducing bleeding in patients with non-ST-elevation acute coronary syndromes.

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.

Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial.

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.

Comparison of fondaparinux and enoxaparin in acute coronary syndromes.

BACKGROUND: The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding. METHODS: We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months. RESULTS: The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combined outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P=0.13) and at the end of the study (1222 vs. 1308, P=0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P=0.02) and at 180 days (574 vs. 638, P=0.05). CONCLUSIONS: Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mortality and morbidity. (ClinicalTrials.gov number, NCT00139815.).

Fondaparinux compared to enoxaparin in patients with acute coronary syndromes without ST-segment elevation: outcomes and treatment effect across different levels of risk.

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.

Association of mitral annular calcification and aortic valve morphology: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study.

AIMS: Mitral annular calcification (MAC) is characterized by calcium and lipid deposition in the annular fibrosa of the mitral valve. Although individuals with MAC are at increased risk of cardiovascular events, little is known about the significance of this finding in patients with concurrent aortic stenosis (AS). The aim of this study was to describe the association of baseline MAC and aortic valve morphology in asymptomatic patients enrolled in the ASTRONOMER study, a multicentre study to assess the effect of Rosuvastatin on the progression of AS. METHODS AND RESULTS: At baseline, transthoracic echocardiography was performed with two-dimensional and Doppler imaging following a standardized protocol. Echo measurements including left ventricular (LV) dimensions and aortic root dimensions were obtained according to the ASE recommendations. MAC was identified by bright echoes at the base of the mitral leaflets or annulus on 2D imaging, and aortic valve calcification by visualization of bright echoes on the aortic valve leaflets. The degree of calcification was semi-quantitated from absent to severe. The study population included 219 patients (57 +/- 14 years; 129 males), divided into two pre-specified categories; bicuspid (n = 133) and tricuspid (n = 86) aortic valves. Baseline LV dimensions, aortic valve haemodynamics, and cholesterol profiles were similar between the two groups at baseline. Individuals with tricuspid aortic valves were older, more hypertensive, with higher degrees of MAC and AV calcification (P < 0.001). The higher degree of MAC persisted in patients with tricuspid AV after adjustment for age and systolic blood pressure (P = 0.004). CONCLUSION: In patients with asymptomatic mild to moderate AS, MAC is more prevalent in those individuals with tricuspid AV, independent of age, and systolic blood pressure. Whether the degree of MAC may be a surrogate for atherosclerosis, and predict the subset of patients who will respond to statin therapy in preventing the progression of AS, remains to be determined.

The importance of echocardiography in physicians' support of endocarditis prophylaxis.

BACKGROUND: Guidelines advocate for antimicrobial prophylaxis for prevention of bacterial endocarditis. Our objective was to explore physicians' perspectives regarding the importance of echocardiography in the evaluation and management of endocarditis prophylaxis. METHODS: A total of 260 cardiologists and 300 family physicians practicing in Ontario, Canada, were surveyed. Our main outcome measures were physician ratings of the importance of a murmur, echocardiogram findings, echocardiogram comments, comorbid conditions, guidelines, patient insistence, and medicolegal concerns on the decision to recommend prophylaxis, as well as the degree of echocardiographically detected mitral valve abnormality required prior to recommending prophylaxis. RESULTS: The survey response rate was 62%. Echocardiographic findings were rated by 81% of physicians as the most important factor influencing the decision to provide prophylaxis. Conversely, only 27% of physicians placed similar importance on clinical findings. Family physicians relied more heavily on echocardiographic than on clinical findings when supporting endocarditis prophylaxis recommendations. On average, prophylaxis was recommended for moderate to severe regurgitation in a normal valve and mild regurgitation in a mildly abnormal structural mitral valve. Physicians who reported greater reliance on echocardiographic findings advocated for prophylaxis at lower echocardiographic thresholds than did those who reported greater reliance on murmur detection for endocarditis prophylaxis decisions. CONCLUSIONS: Physicians strongly support the use of echocardiography in endocarditis prophylaxis decision making. However, the importance of echocardiography relative to other factors varies across physician specialties. Further studies must evaluate the role of echocardiography in the assessment and management of antimicrobial endocarditis prophylaxis to assist in the development of clear clinical guidelines.

Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial.

CONTEXT: Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. OBJECTIVE: To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS: Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12,092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. MAIN OUTCOME MEASURES: Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months). RESULTS: Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. CONCLUSION: In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00064428.

Design and rationale of the MICHELANGELO Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial program evaluating fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST-segment elevation acute coronary syndromes.

BACKGROUND: Factor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial thrombosis. Fondaparinux, a synthetic pentasaccharide, is a factor Xa inhibitor, which has been shown to be superior to enoxaparin for the prevention of venous thrombosis. We designed a large, phase III, randomized trial to evaluate the efficacy and safety of fondaparinux compared with enoxaparin in acute coronary syndromes. STUDY DESIGN: The OASIS-5 trial is a randomized, double-blind trial of fondaparinux versus enoxaparin in 20,000 patients with unstable angina or non-ST-segment elevation myocardial infarction. The primary objective is to determine whether fondaparinux is noninferior to enoxaparin in preventing the composite of death, new myocardial infarction, and refractory ischemia at 9 days (primary outcome) and at 30 days (secondary outcome) after randomization. There will be additional follow-up of all patients for 3 to 6 months after randomization. If noninferiority is established at 9 days, superiority will be tested. The primary safety outcome is to evaluate the rates of major bleeds in the 2 groups with the balance of benefit and risk assessed by comparing the impact on the composite of the primary and safety outcomes. Secondary outcomes are each component of the composite primary outcome separately at days 9, 30, and up to 6 months. The TIMACS, a major substudy using a partial 2x2 factorial design evaluating whether early angiography and intervention (within 24 hours) are superior to a more delayed approach (after 36 hours) in reducing major ischemic events at 6 months after randomization. CONCLUSIONS: The MICHELANGELO OASIS 5 program will provide a comprehensive and reliable evaluation of fondaparinux in a broad spectrum of patients with ACS.

Patient prosthesis mismatch is rare after aortic valve replacement: valve size may be irrelevant.

BACKGROUND: Although small valve size and patient-prosthesis mismatch are both considered to decrease long-term survival, little direct evidence exists to support this hypothesis. METHODS: To assess the prevalence of patient-prosthesis mismatch and the influence of small valve size on survival, we prospectively studied 1,129 consecutive patients undergoing aortic valve replacement between 1990 and 2000. Mean and peak gradients and indexed effective orifice area were measured by transthoracic echocardiography postoperatively (3 months to 10 years). Abnormal postoperative gradients were defined as those patients with mean or peak gradient above the 90th percentile (mean gradient > or = 21 or peak gradient > or = 38 mm Hg). Patient-prosthesis mismatch was defined as those patients with indexed effective orifice area below the 10th percentile (< 0.60 cm2/m2). RESULTS: A multivariable analysis identified internal diameter of the implanted valve as the only independent predictor of abnormal gradients postoperatively. However, there was no significant difference in actuarial survival between normal and abnormal gradient groups (7 years: 91.2% +/- 1.5% versus 95.0% +/- 2.2%; p = 0.48). Freedom from New York Heart Association class III or IV (7 years: 74.5% +/- 3.1% versus 74.6% +/- 6.2%; p = 0.66) and left ventricular mass index were not different between normal and abnormal gradient groups. Patients with and without patient-prosthesis mismatch were similar with respect to postoperative left ventricular mass index, 7-year survival (95.1% +/- 1.3% versus 94.7% +/- 3.0%; p = 0.54), and 7-year freedom from New York Heart Association class III or IV (79.3% +/- 6.6% versus 74.5% +/- 2.5%; p = 0.40). In patients with patient-prosthesis mismatch and abnormal gradients, the majority had prosthesis dysfunction owing to degeneration. CONCLUSIONS: Severe patient-prosthesis mismatch is rare after aortic valve replacement. Patient-prosthesis mismatch, abnormal gradient, and the size of valve implanted do not influence left ventricular mass index or intermediate-term survival.