Resting Heart Rate and Ischemic Stroke in Patients with Heart Failure.

BACKGROUND: Although high resting heart rate (RHR) is known to be associated with an increased risk of mortality and hospital admission in patients with heart failure, the relationship between RHR and ischemic stroke remains unclear. This study is aimed at investigating the relationship between RHR and ischemic stroke in patients with heart failure in sinus rhythm. METHODS: We examined 2,060 patients with systolic heart failure in sinus rhythm from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. RHR was determined from baseline electrocardiogram, and was examined as both a continuous variable and a categorical variable using quartiles. Ischemic strokes were identified during follow-up and adjudicated by physician review. RESULTS: During 3.5 ± 1.8 years of follow-up, 77 patients (5.3% from Kaplan-Meier [KM] curve) experienced an ischemic stroke. The highest incidence of ischemic stroke (21/503 [KM 6.9%]) was observed in the lowest RHR quartile (RHR <64 beats/min) compared to other groups; 22/573 (KM 5.3%) in 64-70 beats/min, 13/465 (KM 3.5%) in 71-79 beats/min, and 21/519 (KM 5.4%) in RHR >79 beats/min (p = 0.693). Multivariable Cox proportional hazards analysis revealed that RHR was significantly associated with ischemic stroke (hazard ratio per unit decrease: 1.07, 95% CI 1.02-1.13, when RHR <64/beats/min; p = 0.038), along with a history of stroke or transient ischemic attack and left ventricular ejection fraction. CONCLUSIONS: In contrast to its beneficial effect on mortality and hospital re-admissions, lower RHR may increase the risk of ischemic stroke in patients with systolic heart failure in sinus rhythm.

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.

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. METHODS AND RESULTS: 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).

Warfarin and aspirin in patients with heart failure and sinus rhythm.

BACKGROUND: It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS: We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS: The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82). CONCLUSIONS: Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.).

Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.

BACKGROUND AND PURPOSE: WARCEF randomized 2,305 patients in sinus rhythm with ejection fraction (EF) ≤ 35% to warfarin (INR 2.0-3.5) or aspirin 325 mg. Warfarin reduced the incident ischemic stroke (IIS) hazard rate by 48% over aspirin in a secondary analysis. The IIS rate in heart failure (HF) is too low to warrant routine anticoagulation but epidemiologic studies show that prior stroke increases the stroke risk in HF. In this study, we explore IIS rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified. METHODS: We compared potential stroke risk factors between patients with baseline stroke and those without using the exact conditional score test for Poisson variables. We looked for risk factors for IIS, by comparing IIS rates between different risk factors. For EF we tried cut-off points of 10, 15 and 20%. The cut-off point 15% was used as it was the highest EF that was associated with a significant increase in IIS rate. IIS and EF strata were balanced as to warfarin/aspirin assignment by the stratified randomized design. A multiple Poisson regression examined the simultaneous effects of all risk factors on IIS rate. IIS rates per hundred patient years (/100 PY) were calculated in patient groups with significant risk factors. Missing values were assigned the modal value. RESULTS: Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2,048 (3.1%) without had IIS. IIS rate in patients with baseline stroke (2.37/100 PY) was greater than patients without (0.89/100 PY) (rate ratio 2.68, p < 0.001). Fourteen of 219 (6.4%) patients with ejection fraction (EF) <15% and 70 of 2,079 (3.4%) with EF ≥ 15% had IIS. In the multiple regression analysis stroke at baseline (p < 0.001) and EF <15% vs. ≥ 15% (p = 0.005) remained significant predictors of IIS. IIS rate was 2.04/100 PY in patients with EF <15% and 0.95/100 PY in patients with EF ≥ 15% (p = 0.009). IIS rate in patients with baseline stroke and reduced EF was 5.88/100 PY with EF <15% decreasing to 2.62/100 PY with EF <30%. CONCLUSIONS: In a WARCEF exploratory analysis, prior stroke and EF <15% were risk factors for IIS. Further research is needed to determine if a clinically relevant stroke risk reduction is obtainable with warfarin in HF patients with prior stroke and reduced EF.

Stroke in heart failure in sinus rhythm: the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial.

BACKGROUND: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses. METHODS: We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions. RESULTS: Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3-5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups. CONCLUSIONS: The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.

Identifying a high stroke risk subgroup in individuals with heart failure.

BACKGROUND: Heart failure (HF) is associated with an overall stroke rate that is too low to justify anticoagulation in all patients. This study was conducted to determine if vascular risk factors can identify a subgroup of individuals with heart failure with a stroke rate high enough to warrant anticoagulation. METHODS: The REGARDS study is a population-based cohort of US adults aged ≥45 years. Participants are contacted every 6 months by telephone for self- or proxy-reported stroke and medical records are retrieved and adjudicated by physicians. Participants were characterized into 3 groups: HF without atrial fibrillation (AF), AF with or without HF, and neither HF nor AF. Cardiovascular risk factors at baseline were compared between participants with and without incident stroke in HF and AF. Stroke incidence was assessed in risk factor subgroups in HF participants. RESULTS: Of the 30,239 participants, those with missing/anomalous data were excluded. Of the remaining 28,832, 1360 (5%) had HF without AF, 2528 (9%) had AF, and 24,944 (86%) had neither. Previous stroke/transient ischemic attack (TIA; P = .0004), diabetes mellitus (DM; P = .03), and higher systolic blood pressure (P = .046) were associated with increased stroke risk in participants with HF without AF. In participants with HF without AF, stroke incidence was highest in those with previous stroke/TIA and DM (2.4 [1.1, 4.0] per 100 person-years). CONCLUSIONS: The combination of previous stroke/TIA and DM increases the incidence of stroke in participants with HF without AF. No analyzed subgroup had a stroke rate high enough to make it likely that the benefits of warfarin would outweigh the risks.

Self-reported atrial fibrillation and risk of stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

BACKGROUND AND PURPOSE: We compared the associations of self-reported atrial fibrillation (AF) and ECG-detected AF with incident stroke in the Risk of Stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. METHODS: In this analysis, 27 109 participants aged 45 years or older without previous stroke were included. Stroke cases were identified and adjudicated during an average of 4.4 years of follow-up. Cox proportional hazards analysis was used to calculate hazard ratios (HR) of self-reported AF, ECG-detected AF, and AF detected by either method with incident stroke. We also examined the predictive ability of the Framingham Stroke Risk Score (FSRS) when the component AF was defined by different methods. RESULTS: After adjustment for components of the FSRS, self-reported AF, ECG-detected AF, and AF by either method were predictive of incident stroke (HR, 1.41; 95% CI, 1.05-1.88; HR, 1.90; 95% CI, 1.10-3.27; HR, 1.53; 95% CI, 1.16-2.01, respectively). When self-report, ECG, or either method, separately, were considered as the method of AF ascertainment in the FSRS, the HR per 1% increase in the FSRS were identical across AF ascertainment methods (HR, 1.04; 95% CI, 1.03-1.04; HR, 1.04; 95% CI, 1.04-1.05; HR, 1.04; 95% CI, 1.03-1.04; respectively). CONCLUSIONS: Self-reported AF is a strong predictor of stroke that can be used interchangeably or in combination with ECG-detected AF in stroke risk prediction models.

Blood pressure and stroke in heart failure in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

BACKGROUND AND PURPOSE: The prevalence of stroke is increased in individuals with heart failure (HF). The stroke mechanism in HF may be cardiogenic embolism or cerebral hypoperfusion. Stroke risk increases with decreasing ejection fraction and low cardiac output is associated with hypotension and poor survival. We examine the relationship among blood pressure level, history of stroke/transient ischemic attack (TIA), and HF. METHODS: We compared the prevalence of self-reported history of stroke or TIA in the REasons for Geographic And Racial Differences in Stroke (REGARDS) participants with HF (as defined by current digoxin use) and without HF. We excluded participants with atrial fibrillation or missing data. We examined the relationship between HF and history of stroke/TIA within tertiles of systolic blood pressure (SBP) adjusting for patient demographic and health characteristics. RESULTS: Prevalent stroke/TIA were reported by 66 (26.3%) of 251 participants with and 1805 (8.5%) of 21 202 participants without HF (P<0.0001). Within each tertile of SBP, the unadjusted OR (95% CI) for prior stroke/TIA among those with HF compared with those without HF (the reference group) was, 4.0 (2.8 to 5.8) for SBP <119.5 mm Hg, 2.7 (1.8 to 3.9) for SBP >or=119.5 but <131.5 mm Hg, and 2.3 (1.6 to 3.2) for SBP >or=131.5 mm Hg. After adjustment, the relationship between prior stroke/TIA and HF remained significant only within the lowest tertile of SBP (<119.5 mm Hg; 3.0; 1.5 to 6.1). CONCLUSIONS: The odds of prevalent self-reported stroke/TIA are increased in participants with HF and most markedly increased in participants with low SBP. Longitudinal data are needed to determine whether this reflects stroke/TIA secondary to thromboembolism from poor cardiac function or secondary to cerebral hypoperfusion.

Cognitive Decline Over Time in Patients With Systolic Heart Failure: Insights From WARCEF.

OBJECTIVES: This study sought to characterize cognitive decline (CD) over time and its predictors in patients with systolic heart failure (HF). BACKGROUND: Despite the high prevalence of CD and its impact on mortality, predictors of CD in HF have not been established. METHODS: This study investigated CD in the WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) trial, which performed yearly Mini-Mental State Examinations (MMSE) (higher scores indicate better cognitive function; e.g., normal score: 24 or higher). A longitudinal time-varying analysis was performed among pertinent covariates, including baseline MMSE and MMSE scores during follow-up, analyzed both as a continuous variable and a 2-point decrease. To account for a loss to follow-up, data at the baseline and at the 12-month visit were analyzed separately (sensitivity analysis). RESULTS: A total of 1,846 patients were included. In linear regression, MMSE decrease was independently associated with higher baseline MMSE score (p < 0.0001), older age (p < 0.0001), nonwhite race/ethnicity (p < 0.0001), and lower education (p < 0.0001). In logistic regression, CD was independently associated with higher baseline MMSE scores (odds ratio [OR]: 1.13; 95% confidence interval [CI]: 1.07 to 1.20]; p < 0.001), older age (OR: 1.37; 95% CI: 1.24 to 1.50; p < 0.001), nonwhite race/ethnicity (OR: 2.32; 95% CI: 1.72 to 3.13 for black; OR: 1.94; 95% CI: 1.40 to 2.69 for Hispanic vs. white; p < 0.001), lower education (p < 0.001), and New York Heart Association functional class II or higher (p = 0.03). Warfarin and other medications were not associated with CD. Similar trends were seen in the sensitivity analysis (n = 1,439). CONCLUSIONS: CD in HF is predicted by baseline cognitive status, demographic variables, and NYHA functional class. The possibility of intervening on some of its predictors suggests the need for the frequent assessment of cognitive function in patients with HF. (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF]; NCT00041938).

Association between mortality and implantable cardioverter-defibrillators by aetiology of heart failure: a propensity-matched analysis of the WARCEF trial.

AIMS: There is debate on whether the beneficial effect of implantable cardioverter-defibrillators (ICDs) is attenuated in patients with non-ischaemic cardiomyopathy (NICM). We assess whether any ICD benefit differs between patients with NICM and those with ischaemic cardiomyopathy (ICM), using data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. METHODS AND RESULTS: We performed a post hoc analysis using WARCEF (N = 2293; ICM, n = 991 vs. NICM, n = 1302), where participants received optimal medical treatment. We developed stratified propensity scores for having an ICD at baseline using 41 demographic and clinical variables and created 1:2 propensity-matched cohorts separately for ICM patients with ICD (N = 223 with ICD; N = 446 matched) and NICM patients (N = 195 with ICD; N = 390 matched). We constructed a Cox proportional hazards model to assess the effect of ICD status on mortality for patients with ICM and those with NICM and tested the interaction between ICD status and aetiology of heart failure. During mean follow-up of 3.5 ± 1.8 years, 527 patients died. The presence of ICD was associated with a lower risk of all-cause death among those with ICM (hazard ratio: 0.640; 95% confidence interval: 0.448 to 0.915; P = 0.015) but not among those with NICM (hazard ratio: 0.984; 95% confidence interval: 0.641 to 1.509; P = 0.941). There was weak evidence of interaction between ICD status and the aetiology of heart failure (P = 0.131). CONCLUSIONS: The presence of ICD is associated with a survival benefit in patients with ICM but not in those with NICM.

A propensity-matched study of hypertension and increased stroke-related hospitalization in chronic heart failure.

Hypertension is a risk factor for heart failure and stroke. However, the effect of hypertension on stroke in patients with heart failure has not been well studied. In the Digitalis Investigation Group trial, 3,674 (47%) of the 7,788 patients had a history of hypertension. Probability or propensity scores for a history of hypertension were calculated for each patient through use of a multivariable logistic regression model and were then used to match 2,386 pairs of patients with and without a history of hypertension. Kaplan-Meier and matched Cox regression analyses were used to estimate associations of a history of hypertension hospitalization for stroke during 37 months of median follow-up. After matching, patients without and with a history of hypertension had a mean systolic blood pressure of 127 mm Hg. Hospitalization for stroke occurred in 90 patients (rate, 129/10,000 person-years of follow-up) without a history of hypertension and 121 patients (rate, 178/10,000 person-years of follow-up) with a history of hypertension (hazard ratio when hypertension was compared with no hypertension=1.52; 95% confidence interval=1.11 to 2.08; p=0.010). This association was also observed among patients with baseline systolic blood pressure <140 mm Hg (hazard ratio=1.35; 95% confidence interval=1.01 to 1.81; p=0.044). In conclusion, a history of hypertension was associated with increased risk of hospitalization for stroke among patients with heart failure who were balanced in all measured baseline covariates, including blood pressure.

Factors contributing to global cognitive impairment in heart failure: results from a population-based cohort.

BACKGROUND: Heart failure (HF) and cognitive impairment are both common in older adults. However, the association between the two has not been well studied. METHODS AND RESULTS: We explored the relationship between very probable HF, determined by self-reported symptoms, and cognitive impairment, defined as four or fewer correct on the Six-item Screener, in 14,089 participants of the Reasons for Geographic and Racial Differences in Stroke cohort. We determined the effect of adding demographic, socioeconomic status (SES), health behavior, and comorbidity covariates. In the univariate model, participants with very probable HF were 1.51 (95% confidence interval: 1.15-1.96) times more likely to have cognitive impairment than those without HF. As covariates were added to the model, the relationship between HF and cognitive impairment was attenuated and lost statistical significance after adjustment for depression. Demographic variables, Stroke Belt location (1.28 [1.11-1.48]), SES factors, prior stroke (1.43 [1.18-1.73]), and depression (1.66 [1.38-2.01]) remained significant in the multivariable model. Higher hemoglobin was associated (0.95 [0.9-1.00]) with modestly reduced odds of cognitive impairment. CONCLUSIONS: The relationship between cognitive impairment and HF can be accounted for by multiple demographic and SES factors, and by comorbidities, some of which are modifiable. Persons with HF and cognitive impairment should be screened for anemia and depression.

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

AIMS: 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. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments. METHODS AND RESULTS: Two-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034). CONCLUSIONS: In patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial).

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

Echocardiography in patients with symptomatic intracranial stenosis.

BACKGROUND: Echocardiography is often performed in patients with stroke, even when alternative stroke causes are identified. We evaluated the use of echocardiography in patients with transient ischemic attack (TIA) or stroke caused by stenosis of a major intracranial artery. METHODS: The Warfarin Versus Aspirin for Symptomatic Intracranial Disease (WASID) trial was a National Institutes of Health-funded, randomized, double-blind, multicenter clinical trial in which 569 patients with TIA or ischemic stroke attributed to angiographically proven 50% to 99% stenosis of a major intracranial artery were randomly assigned to warfarin or aspirin. Patients with unequivocal cardiac sources of embolism were excluded. The risk of ischemic stroke, myocardial infarction, and vascular death was compared among patients who had or did not have echocardiography performed before enrollment, and Cox proportional hazards models were used to determine whether echocardiographic abnormalities present in greater than 5% of patients were associated with these outcomes. RESULTS: In all, 264 of 569 patients in WASID had echocardiograms; 37% were transesophageal. Of these 264 patients, 69 had subsequent ischemic stroke, myocardial infarction, or vascular death. Patients who underwent echocardiography had similar event rates to those who did not (P = .18). Common abnormalities identified on echocardiography were not associated with subsequent risk in this population. CONCLUSIONS: Among patients with TIA or stroke caused by intracranial arterial stenosis, echocardiography appears to offer limited diagnostic and prognostic value.

Pharmacological prevention of thromboembolism in patients with left ventricular dysfunction.

Chronic left ventricular systolic dysfunction is a well recognized problem with an increasingly significant impact on healthcare in the form of congestive heart failure (CHF). Advances in medicine have led to improved survival after myocardial infarction (MI) and as a result, an increased prevalence of left ventricular systolic dysfunction. An increased incidence of thromboembolism, especially stroke, in patients with left ventricular systolic dysfunction is also well recognized. Pharmacological strategies to prevent stroke have been proposed in numerous studies. For example, anticoagulation in patients with atrial fibrillation and heart failure has been shown to reduce mortality rates and the incidence of stroke; however, its role in patients with left ventricular dysfunction and normal sinus rhythm is unclear and utilization of anticoagulation in these patients varies widely. The role of aspirin to prevent thromboembolism in patients with CHF is controversial. The relatively new pharmacological agent ximelagatran, which has an advantage of unmonitored oral administration has the potential to change the anticoagulation strategy in patients with heart failure. Important trials to define optimal therapy for reducing the risk of thromboembolism and death in patients with left ventricular systolic dysfunction and sinus rhythm include the recently reported WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure) trial and the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial, which is currently underway. The WATCH trial failed to outline significant differences between aspirin (acetylsalicylic acid), warfarin, and clopidogrel in the primary composite endpoint of all-cause mortality, nonfatal MI, and nonfatal stroke. Combined data from WATCH and WARCEF may provide sufficient statistical power to clarify outcomes such as stroke and death in patients with reduced cardiac ejection fraction. The pooled data may also help define optimal preventative measures for thromboembolism in patients with left ventricular systolic dysfunction and sinus rhythm.

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

AIMS: The aim of this study was to determine whether the CHA2 DS2 -VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure in sinus rhythm. METHODS AND RESULTS: CHA2 DS2 -VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage. Using proportional hazards models, we found that each 1-point increase in the CHA2 DS2 -VASc score was associated with increased hazard of death or ischaemic stroke events [hazard ratio (HR) for the warfarin arm = 1.21, 95% confidence interval (CI) 1.13-1.30, P < 0.001; for aspirin, HR = 1.20, 95% CI 1.11-1.29, P < 0.001]. Similar increased hazards for higher CHA2 DS2 -VASc scores were observed for death alone, ischaemic stroke alone, and major haemorrhage. Overall performance of the CHA2 DS2 -VASc score was assessed using c-statistics for full models containing the risk score, treatment assignment, and score-treatment interaction, with the c-statistics for the full models ranging from 0.57 for death to 0.68 for major haemorrhage. CONCLUSIONS: The CHA2 DS2 -VASc score predicted adverse outcomes in patients with systolic heart failure in sinus rhythm, with modest prediction accuracy.

The first prognostic model for stroke and death in patients with systolic heart failure.

BACKGROUND: Patients with systolic heart failure (HF) are at increased risk of both ischemic stroke and death. Currently, no risk scores are available to identify HF patients at high risk of stroke or death. The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial studied 2305 HF patients, in sinus rhythm, followed for up to 6 years (3.5±1.5 years). This trial showed no overall difference in those treated with warfarin vs aspirin with regard to death or stroke. The present study develops the first prognostic model to identify patients at higher risk of stroke or death based on their overall risk profile. METHODS AND RESULTS: A scoring algorithm using 8 readily obtainable clinical characteristics as predictors, age, gender, hemoglobin, blood urea nitrogen, ejection fraction, diastolic blood pressure, diabetes status, and prior stroke or transient ischemic attack (C-index=0.65, 95% CI: 0.613-0.681), was developed. It was validated internally using a bootstrap method. In predicting 1-year survival for death alone, our 8-predictor model had an AUC of 0.63 (95% CI: 0.579-0.678) while the 14-predictor Seattle model had an AUC of 0.72. The Seattle model did not report stroke. CONCLUSIONS: This novel prognostic model predicts the overall risk of ischemic stroke or death for HF patients. This model compares favorably for death with the Seattle model and has the added utility of including stroke as an endpoint. Use of this model will help identify those patients in need of more intensive monitoring and therapy and may help identify appropriate populations for trials of new therapies. CLINICAL TRIAL REGISTRATION: http://www.Clinicatrials.govNCT00041938.

Bleeding Risk and Antithrombotic Strategy in Patients With Sinus Rhythm and Heart Failure With Reduced Ejection Fraction Treated With Warfarin or Aspirin.

We sought to assess the performance of existing bleeding risk scores, such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score or the Outpatient Bleeding Risk Index (OBRI), in patients with heart failure with reduced ejection fraction (HFrEF) in sinus rhythm (SR) treated with warfarin or aspirin. We calculated HAS-BLED and OBRI risk scores for 2,305 patients with HFrEF in SR enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. Proportional hazards models were used to test whether each score predicted major bleeding, and comparison of different risk scores was performed using Harell C-statistic and net reclassification improvement index. For the warfarin arm, both scores predicted bleeding risk, with OBRI having significantly greater C-statistic (0.72 vs 0.61; p = 0.03) compared to HAS-BLED, although the net reclassification improvement for comparing OBRI to HAS-BLED was not significant (0.32, 95% confidence interval [CI] -0.18 to 0.37). Performance of the OBRI and HAS-BLED risk scores was similar for the aspirin arm. For participants with OBRI scores of 0 to 1, warfarin compared with aspirin reduced ischemic stroke (hazard ratio [HR] 0.51, 95% CI 0.26 to 0.98, p = 0.042) without significantly increasing major bleeding (HR 1.24, 95% CI 0.66 to 2.30, p = 0.51). For those with OBRI score of ≥2, there was a trend for reduced ischemic stroke with warfarin compared to aspirin (HR 0.56, 95% CI 0.27 to 1.15, p = 0.12), but major bleeding was increased (HR 4.04, 95% CI 1.99 to 8.22, p <0.001). In conclusion, existing bleeding risk scores can identify bleeding risk in patients with HFrEF in SR and could be tested for potentially identifying patients with a favorable risk/benefit profile for antithrombotic therapy with warfarin.