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

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

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

Abstract 192: Stroke in the WARCEF Trial

Background The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference between warfarin and aspirin in heart failure patients in sinus rhythm for the outcome of first to occur of 84 ischemic strokes (IS), 7 intracerebral hemorrhages or 531 deaths. Pre-specified secondary analysis showed a 48% HR reduction (p=0.005) in IS risk for warfarin vs. aspirin. We examined this IS benefit for warfarin in post-hoc analyses. Methods We used the Wilcoxon rank sum test, stratified by prior IS or TIA, to compare the distributions of mRS among warfarin and aspirin IS patients in WARCEF. Median (md) scores and interquartile ranges (IQR) are shown for warfarin and aspirin arms, respectively. We used Fisher’s exact test to compare the effect of warfarin vs. aspirin on fatal IS; a stratified exact test to compare proportions of severe (mRS 3-5) IS; and stratified Poisson regression to compare IS subtypes. Results Twenty-nine (2.5%) of 1142 patients on warfarin and 55 (4.7%) of 1163 on aspirin had IS. The warfarin IS rate (0.72 per 100 patient years [/100PY]) was lower than for aspirin (1.36/100PY). There were no differences between warfarin and aspirin IS patients in baseline mRS (md 1, IQR, 2, N=29 vs. md 1, IQR 2, N=55); fatal IS (3/29, 10.3% vs. 6/55, 10.9%, p=1.0), or post-IS (after 90+30 days) mRS (md 2, IQR 3, n=23 vs. md 2, IQR 3, n=48, p=0.437). There were also no differences between warfarin and aspirin in change from baseline to post-IS mRS (md 1, IQR 3, n=23 vs. md 1, IQR 3, n=48, p=0.884). Cardioembolic IS was significantly less frequent on warfarin than on aspirin (9 [0.22/100PY] vs. 22 [0.55/100PY], p=0.012). The warfarin arm showed trends to fewer severe (mRS 3-5) IS (3/23 [13.0%] vs. 16/48 [33.3%], p=0.086) and a lower rate of IS of potential cardioembolic etiology (15 [0.37/100PY] vs. 27 [0.67/100PY] p=0.063). There was no difference between warfarin and aspirin in rate of non-cardioembolic IS (5 [0.12/100PY] vs. 6 [0.15/100PY], p=0.768). Conclusions Warfarin appears superior to aspirin in reducing the frequency of cardioembolic IS in heart failure patients in sinus rhythm. This is supported by trends to lower frequencies of severe IS and potentially cardioembolic IS in patients on warfarin compared to aspirin

Abstract 53: Recurrent Stroke in the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) Trial

Background: WARCEF randomized 2305 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. We here explore IIS rates in WARCEF patients with and without baseline stroke to determine if a subgroup with an IIS rate high enough (3-5 per 100 patient-years [PY]) to give a clinically relevant warfarin effect can be identified. Methods: We compared the IIS rate 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 levels of each potential risk factor. For EF we tried cut-off points of 10%, 15% and 20%. 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. Missing values were assigned the modal value. Results: Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2048 (3.1%) without had IIS. IIS rates in patients with baseline stroke were significantly greater compared to patients without (rate ratio 2.67; 2.37 per 100PY and 0.89 per 100PY, respectively, p=0.0004). Fourteen of 219 (6.4%) patients with EF<15% and 70 of 2079 (3.4%) with EF ≥15% had IIS. IIS rates in patients with EF<15% and patients with EF ≥15% were 2.04 per 100PY and 0.95 per 100PY, respectively (p=0.012). IIS rate in patients with baseline stroke and EF<15% was 5.88 per 100PY. In the multiple Poisson regression analysis only stroke at baseline (p=0.0001) and EF<15% vs. ≥15% (p=.005) remained significant predictors of IIS. Conclusions: In a WARCEF exploratory analysis, prior stroke and EF<15% were risk factors for IIS. A clinically relevant stroke risk reduction might be obtainable with warfarin in HF patients with prior stroke and EF<15%