Susan Graham

Infusible Platelet Membranes Retain Partial Functionality of the Platelet GPIb/IX/V Receptor Complex

Infusible platelet membranes (IPMs) prepared from fresh or outdated human platelets have been shown to correct prolonged bleeding times in thrombocytopenic rabbits. In previous trials, IPMs did not seem to be immunogenic and lacked dose-limiting toxicity. The present study was undertaken to explore whether the platelet glycoprotein (GP) Ib/IX/V complex might retain functionality in the IPM preparation. IPMs did not spontaneously bind von Willebrand factor (vWF), but saturable binding could be induced by ristocetin, with a dissociation constant (Kd) of 0.31 +/- 0.03 microgram/mL at 1.0 mg/mL of ristocetin. Of 4 anti-GPIb-alpha monoclonal antibodies tested, AN-51 inhibited vWF binding 67.8% +/- 5.8%, whereas AS-2, AS-7, and SZ-2 were ineffective. Maximal vWF binding induced by botrocetin was only 10% to 15% of that observed with ristocetin. Retention of partial functionality of the GPIb/IX/V receptor allowing vWF binding in a modulated manner seems to represent a critical mechanism by which IPMs may provide hemostatic efficacy.

Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm A Subgroup Analysis of WARCEF, a Randomized Controlled Trial

Background—The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin. Methods and Results—We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03). Conclusions—In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.Background— The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin. Methods and Results— We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier ( P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P =0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P =0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P =0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P =0.03). Conclusions— In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included. Clinical Trial Registration— URL: . Unique identifier: [NCT00041938][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00041938&atom=%2Fcirchf%2F6%2F5%2F988.atom

Left Ventricular Ejection Fraction and Risk of Stroke and Cardiac Events in Heart Failure: Data From the Warfarin Versus Aspirin in Reduced Ejection Fraction Trial

Background and Purpose— In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments. Methods— In the Warfarin Versus Aspirin in Reduced Ejection Fraction (WARCEF) trial, 2305 patients with systolic HF (LVEF⩽35%) and sinus rhythm were randomized to warfarin or aspirin and followed for 3.5±1.8 years. Although no differences between treatments were observed on primary outcome (death, stroke, or intracerebral hemorrhage), warfarin decreased the stroke risk. The present report compares the incidence of stroke and cardiovascular events across different LVEF and treatment subgroups. Results— Baseline LVEF was inversely and linearly associated with primary outcome, mortality and its components (sudden and cardiovascular death), and HF hospitalization, but not myocardial infarction. A relationship with stroke was only observed for LVEF of <15% (incidence rates: 2.04 versus 0.95/100 patient-years; P=0.009), which more than doubled the adjusted stroke risk (adjusted hazard ratio, 2.125; 95% CI, 1.182–3.818; P=0.012). In warfarin-treated patients, each 5% LVEF decrement significantly increased the stroke risk (adjusted hazard ratio, 1.346; 95% CI, 1.044–1.737; P=0.022; P value for interaction=0.04). Conclusions— In patients with systolic HF and sinus rhythm, LVEF is inversely associated with death and its components, whereas an association with stroke exists for very low LVEF values. An interaction with warfarin treatment on stroke risk may exist. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

CHA2 DS2 -VASc score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm.

The aim of this study was to determine whether the CHA2DS2‐VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm.

Quality of Anticoagulation Control in Preventing Adverse Events in Patients With Heart Failure in Sinus Rhythm Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction Trial Substudy

Background— The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin. Methods and Results— We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P <0.001), death alone (adjusted P =0.001), and improved net clinical benefit (adjusted P <0.001). A similar trend was observed for the other 2 outcomes, but significance was not reached (adjusted P =0.082 for ischemic stroke and adjusted P =0.109 for major hemorrhage). Conclusions— In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration— URL: . Unique identifier: [NCT00041938][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00041938&atom=%2Fcirchf%2F8%2F3%2F504.atomBackground—The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin. Methods and Results—We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P<0.001), death alone (adjusted P=0.001), and improved net clinical benefit (adjusted P<0.001). A similar trend was observed for the other 2 outcomes, but significance was not reached (adjusted P=0.082 for ischemic stroke and adjusted P=0.109 for major hemorrhage). Conclusions—In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

Quality of Anticoagulation Control in Preventing Adverse Events in Heart Failure Patients in Sinus Rhythm: A Warfarin Aspirin Reduced Cardiac Ejection Fraction Trial (WARCEF) Substudy

Background— The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin. Methods and Results— We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P <0.001), death alone (adjusted P =0.001), and improved net clinical benefit (adjusted P <0.001). A similar trend was observed for the other 2 outcomes, but significance was not reached (adjusted P =0.082 for ischemic stroke and adjusted P =0.109 for major hemorrhage). Conclusions— In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration— URL: . Unique identifier: [NCT00041938][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00041938&atom=%2Fcirchf%2F8%2F3%2F504.atomBackground—The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin. Methods and Results—We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P<0.001), death alone (adjusted P=0.001), and improved net clinical benefit (adjusted P<0.001). A similar trend was observed for the other 2 outcomes, but significance was not reached (adjusted P=0.082 for ischemic stroke and adjusted P=0.109 for major hemorrhage). Conclusions—In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

COGNITIVE FUNCTION IN AMBULATORY PATIENTS WITH SYSTOLIC HEART FAILURE: INSIGHTS FROM THE WARFARIN VERSUS ASPIRIN IN REDUCED CARDIAC EJECTION FRACTION (WARCEF) TRIAL

We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.

Clinical and Echocardiographic Factors Associated With New-Onset Atrial Fibrillation in Heart Failure – Subanalysis of the WARCEF Trial –

BACKGROUND Heart failure (HF) patients have a high incidence of new-onset AF. Given the adverse prognostic influence of AF in HF, identifying patients at high risk of developing AF is important. METHODSANDRESULTS The incidence and factors associated with new-onset AF were investigated in patients in sinus rhythm with reduced LVEF enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. Analyses involved clinical factors alone (n=2,219), and clinical plus echocardiographic findings (n=1,125). During 3.5±1.8 years of follow-up, 212 patients (9.6% of total cohort) developed AF. In both samples, new-onset AF was associated with age, male sex, White race, and IHD. Among echocardiographic variables, only LAD predicted AF. On multivariate Cox modeling, age (HR, 1.02; 95% CI: 1.00-1.03, P=0.008), IHD (HR, 1.37; 95% CI: 1.02-1.84, P=0.036) and LAD (HR, 1.48; 95% CI: 1.15-1.91, P=0.003) remained associated with AF onset. Patients with IHD, LAD>4.5 cm and age>50 years had a 2.5-fold higher risk of AF than patients without any of these characteristics (HR, 2.52; 95% CI: 1.72-3.69, P<0.0001). CONCLUSIONS Age, IHD and LAD independently predict new-onset AF in HF patients in sinus rhythm, at younger age and smaller LAD than generally believed. This information may be useful to risk-stratify HF patients for AF development, allowing close monitoring and possibly early detection. (Circ J 2016; 80: 619-626).

Benefit of Warfarin Compared with Aspirin in Heart Failure Patients in Sinus Rhythm: A Subgroup Analysis of WARCEF, a Randomized Controlled Trial

Background—The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin. Methods and Results—We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03). Conclusions—In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.Background— The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin. Methods and Results— We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier ( P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P =0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P =0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P =0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P =0.03). Conclusions— In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included. Clinical Trial Registration— URL: . Unique identifier: [NCT00041938][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00041938&atom=%2Fcirchf%2F6%2F5%2F988.atom

Left atrial volume and cardiovascular outcomes in systolic heart failure: effect of antithrombotic treatment: Left atrial volume and outcome in heart failure

Left atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement.