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.
Patients with heart failure with reduced ejection fraction (HFrEF) may be at increased risk for ischemic strokes because of left ventricular thrombus formation and subsequent embolism. Randomized clinical trials, such as the Warfarin and Antiplatelet Therapy in Chronic Heart Failure trial and the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, assessed whether warfarin therapy may benefit patients with HFrEF who are in sinus rhythm (SR) and have no other indications for anticoagulation. Although warfarin therapy was found to reduce the risk of ischemic stroke in these trials, it also led to increased rates of major bleeding. A better characterization of bleeding risk in patients with HFrEF who are in SR may therefore identify a subgroup of these patients who could benefit from anticoagulation. One potential approach is to consider 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 and the Outpatient Bleeding Risk Index (OBRI), which has been used to predict risk of bleeding in patients receiving anticoagulation. The HAS-BLED score, in particular, has demonstrated superior performance compared to other bleeding risk scores in patients with atrial fibrillation, whereas the OBRI has been noted to be simple to calculate and has been validated in outpatients receiving warfarin therapy for any indication. However, it is unknown whether these risk scores can also apply to patients with HFrEF who are in SR treated with warfarin or aspirin. We therefore undertook the present analysis of the patients enrolled in the WARCEF trial to determine whether HAS-BLED and OBRI scores predicted bleeding risk in patients with HFrEF who are in SR and to assess whether the effects of warfarin compared with aspirin varied depending on baseline risk of bleeding in this patient population.
Methods
The protocol for the randomized, double-blinded WARCEF trial ( http://www.ClinicalTrials.gov , no. NCT00041938 ) has been described previously. Briefly, patients with left ventricular ejection fraction (LVEF) ≤35% and who were in SR were randomized to receive warfarin (target international normalized ratio [INR] 2.75, with acceptable target range of 2.0 to 3.5) or aspirin (325 mg/day). Additional eligibility criteria included being aged ≥18 years, having no contraindications to warfarin therapy, having a modified Rankin score of ≤4 (on a scale of 0 to 6, with greater scores indicating more severe disability), and treatment with a β blocker, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), or hydralazine and nitrates. Patients were excluded if they had a clear indication for warfarin or aspirin or if they had a condition that conferred a high risk of cardiac embolism, such as atrial fibrillation, a mechanical cardiac valve, endocarditis, or an intracardiac mobile or pedunculated thrombus. Patients were also excluded if they were unable to follow an outpatient study protocol or if they were unable to provide informed consent. Patients in any New York Heart Association (NYHA) functional class were eligible, although patients in NYHA class I could account for no more than 20% of the total sample. A total of 2,305 participants were recruited from 168 centers in 11 countries from October 2002 to January 2010. The investigation conforms with the principles outlined in the Declaration of Helsinki, and the institutional review boards at the coordinating centers for all sites approved the study. All subjects provided informed consent. The maximum follow-up time was 6 years, and the minimum was 1 year.
Major bleeding was defined as intracerebral, epidural, subdural, subarachnoid, spinal intramedullary, or retinal hemorrhage; any other bleeding causing a decrease in the hemoglobin level of >2 g/dl in 48 hours; or bleeding requiring transfusion of ≥2 units of whole blood, hospitalization, or surgical intervention. This definition corresponds closely to the definition for major bleeding recommended by the Internal Society on Thrombosis and Haemostasis. Ischemic stroke was defined as a clinically relevant new lesion detected on computed tomography or magnetic resonance imaging or, in the absence of a new lesion, clinical findings that were consistent with the occurrence of clinical stroke and that lasted for >24 hours. An independent end point adjudication committee, whose members were unaware of the treatment assignments, adjudicated all bleeding and stroke events.
Demographic characteristics including age, gender, race or ethnicity, and body mass index (BMI) were determined at the initial study visit. Health behaviors were assessed by self-report at time of enrollment, including smoking status and alcohol consumption. Clinical characteristics that were collected include medical co-morbidities (atrial fibrillation, hypertension, diabetes mellitus, history of myocardial infarction, and history of ischemic heart disease), history of stroke or transient ischemic attacks (TIAs), presence of liver impairment (defined as having an aspartate aminotransferase [AST] level of 114 IU/l, which represents 3 times the upper limit of normal), renal impairment (defined as having a creatinine clearance level of <30 ml/min, estimated through the Cockcroft–Gault equation), anemia (defined as having a hematocrit of <30%), left ventricular ejection fraction (measured by quantitative echocardiography or radionuclide or contrast ventriculography), NYHA functional class, and time-in-therapeutic range (calculated as the percentage of days when the INR is from 2.0 to 3.5). Additional details for these measurements are as described previously.
For each patient, the HAS-BLED risk score was calculated on the basis of the approach described by Lip et al, with modifications as described in the following. Because the HAS-BLED risk score was derived in patients on anticoagulation therapy and because all patients in the WARCEF trial received either aspirin or warfarin but not both concurrently, the item for aspirin use in the HAS-BLED score was coded as 0 for all patients. Furthermore, for patients assigned to aspirin, the item for labile INR in the HAS-BLED score was coded as 0. For liver impairment, on the basis of available data in WARCEF, we used a cutoff for AST level of >114 IU/l. The OBRI score was similarly calculated for each patient using the approach described by Beyth et al. A brief summary of how HAS-BLED and OBRI risk scores were calculated is provided in Table 1 .
| HAS-BLED Risk Score | OBRI Risk Score |
|---|---|
| Hypertension (SBP >160 mm Hg) | Age >65 years |
| Abnormal renal/ liver function (1 point for each) | History of stroke |
| Stroke | History of GIB |
| Bleeding | Recent MI, HCT <30%, Cr >1.5 mg/dL, or diabetes mellitus |
| Labile INRs (TTR <60%) | |
| Elderly (age >65 years) | |
| Drugs (antiplatelet agents / NSAIDs) or excess alcohol (1 point for each) |
Because bleeding risk is expected to differ for patients receiving warfarin and aspirin, we performed all analyses separately for the warfarin and aspirin arms of the WARCEF trial on an intent-to-treat basis. For each arm, baseline demographic and clinical characteristics were compared between patients who had a major bleeding event during follow-up and those who did not, using the chi-square tests for categorical variables and the Student t tests for continuous variables. We further tabulated the proportion of participants with and without a major bleeding event by HAS-BLED and OBRI scores.
To assess whether HAS-BLED and OBRI scores were predictive of major bleeding, we constructed separate Cox proportional hazards models with the time to the first major bleeding as the outcome and HAS-BLED or OBRI scores as ordinal predictor variables. We performed statistical testing for trend of increased risk of major bleeding associated with increased HAS-BLED or OBRI scores. We then calculated the C -statistics and the associated 95% confidence intervals (CI) for each proportional hazards model using the R software package “survcomp.” We also compared ability of HAS-BLED and OBRI scores to classify bleeding risk for each arm by calculating the net reclassification improvement (NRI) index and its associated 95% CIs, using the R software package “nricens” as per the methods described by Pencina et al. Because the NRI is sensitive to the selection of cutoffs for defining risk categories, we used a 2-category (i.e., high risk of bleeding vs low risk of bleeding) approach to calculate the NRI, based on the empirically observed rates of major bleeding across HAS-BLED and OBRI scores in the WARCEF trial.
We further constructed Cox proportional hazards models to assess the effect of warfarin versus aspirin on clinical outcomes, including death or ischemic stroke, ischemic stroke, and major bleeding, for subgroups of WARCEF participants defined by high versus low bleeding risk through HAS-BLED and OBRI scores. We also tested for interactions between treatment groups and bleeding risk for the previously mentioned outcomes. p Values of <0.05 were considered statistically significant for all testing. All statistical analyses were conducted using SAS version 9.3 (SAS Institute, Cary, North Carolina) or R version 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
The baseline characteristics of WARCEF participants by treatment group and bleeding risk are presented in Table 2 . Of the 1,142 patients randomized to warfarin therapy, 66 (5.8%) experienced at least 1 major bleeding event. Those who experienced major bleeding were more likely to be aged ≥65 years, to be female, and to have renal impairment. For those randomized to aspirin, 31 (2.7%) of 1,163 patients had at least 1 major bleeding event, with those with major bleeding more likely to have less BMI, to have had a previous stroke or TIA, to have renal impairment, and to have a previous history of alcohol use.
| Variable | Warfarin | Aspirin | ||||
|---|---|---|---|---|---|---|
| Major bleeding (n=66) | No major bleeding (n=1076) | p -value | Major bleeding (n=31) | No major bleeding (n=1132) | p -value | |
| Age >65 yrs old | 36 (55%) | 358 (33%) | < 0.001 | 13 (42%) | 389 (34%) | 0.420 |
| Women | 21 (32%) | 215 (20%) | 0.021 | 8 (26%) | 216 (19%) | 0.349 |
| Non-Hispanic white | 45 (68%) | 814 (76%) | 0.182 | 24 (77%) | 855 (76%) | 0.866 |
| Non-Hispanic black | 9 (14%) | 157 (15%) | 5 (16%) | 161 (14%) | ||
| Hispanic | 9 (14%) | 76 (7%) | 1 (3%) | 80 (7%) | ||
| Other | 3 (6%) | 29 (3%) | 1 (3%) | 36 (3%) | ||
| Body mass index (kg/m 2 ) | 0.228 | <0.001 | ||||
| < 25 | 22 (33%) | 279 (26%) | 16 (52%) | 263 (23%) | ||
| 25-30 | 26 (39%) | 400 (37%) | 4 (13%) | 452 (40%) | ||
| > 30 | 18 (27%) | 397 (37%) | 11 (35%) | 417 (37%) | ||
| Hypertension | 37 (59%) | 634 (61%) | 0.732 | 18 (62%) | 678 (62%) | 0.967 |
| Diabetes mellitus | 23 (35%) | 348 (32%) | 0.673 | 7 (23%) | 344 (30%) | 0.350 |
| Atrial fibrillation | 2 (3%) | 42 (4%) | 0.721 | 0 (0%) | 42 (4%) | 0.275 |
| Myocardial infarction | 33 (50%) | 516 (48%) | 0.747 | 12 (39%) | 551 (49%) | 0.273 |
| Ischemic heart disease | 33 (50%) | 455 (42%) | 0.219 | 9 (29%) | 494 (44%) | 0.105 |
| Prior stroke or TIA | 14 (21%) | 141 (13%) | 0.062 | 8 (26%) | 131 (12%) | 0.016 |
| Renal impairment | 4 (6%) | 22 (2%) | 0.033 | 2 (6%) | 16 (1%) | 0.026 |
| Liver impairment | 2 (3%) | 39 (4%) | 0.321 | 2 (6%) | 36 (3%) | 0.646 |
| Anemia, defined as hematocrit < 30% | 1 (2%) | 3 (0.3%) | 0.106 | 0 (0%) | 3 (0.3%) | 0.777 |
| Smoking status | 0.549 | 0.347 | ||||
| Current | 10 (15%) | 203 (19%) | 6 (19%) | 189 (17%) | ||
| Former | 38 (58%) | 547 (51%) | 19 (61%) | 585 (52%) | ||
| Never | 18 (27%) | 326 (30%) | 6 (19%) | 358 (32%) | ||
| Alcohol consumption | 0.240 | 0.025 | ||||
| Current, > 2oz/day | 17 (26%) | 262 (24%) | 6 (19%) | 287 (25%) | ||
| Previous, >2oz/day | 9 (14%) | 241 (22%) | 13 (42%) | 243 (21%) | ||
| Never | 40 (60%) | 573 (53%) | 12 (39%) | 602 (53%) | ||
| NYHA classification | 0.898 | 0.916 | ||||
| I | 8 (12%) | 146 (14%) | 5 (16%) | 163 (14%) | ||
| II | 35 (53%) | 596 (55%) | 18 (58%) | 643 (57%) | ||
| III | 22 (33%) | 324 (30%) | 8 (26%) | 311 (27%) | ||
| IV | 1 (2%) | 10 (1%) | 0 (0%) | 15 (1%) | ||
| LV ejection fraction (%) | 25.3±7.3 | 24.5±7.5 | 0.426 | 24.7±6.1 | 24.8±7.6 | 0.932 |
| TTR <60% | 33 (52%) | 465 (46%) | 0.349 | NA | NA | NA |
The distribution of HAS-BLED and OBRI scores for patients with and without major bleeding was calculated for each arm of the WARCEF trial ( Table 3 and Figure 1 ). The proportion of patients who had any major bleeding on warfarin therapy was 5.3% for those with a HAS-BLED score of 0, increasing to 12.0% for those with a HAS-BLED score of ≥4 (p = 0.015 for trend). For those randomized to aspirin, the proportion of patients who had any major bleeding was 2.0% for those with a HAS-BLED score of 0, increasing to 6.3% for those with a HAS-BLED score of ≥4 (p = 0.04 for trend; Figure 1 ). Similarly, the proportion of patients who had any major bleeding on warfarin therapy was 4.0% for those with an OBRI score of 0 but was over 10% for those with an OBRI score of 2 or 3 (p = 0.01 for trend; Figure 1 ). For patients randomized to aspirin, the proportion of those who had any major bleeding ranged from 2.6% for those with an OBRI score of 0% to 6.1% for those with an OBRI score of 3, but the increase was not statistically significant (p = 0.38 for trend). On the basis of these results, for subsequent analyses, we defined a patient as having high risk of bleeding as having a score of ≥2 for OBRI and a score of ≥3 for HAS-BLED.
| Risk scores | Warfarin | Aspirin | ||||
|---|---|---|---|---|---|---|
| All patients (n=1142) | Major bleeding (n=66) | % with major bleeding | All patients (n=1163) | Major bleeding (n=31) | % with major bleeding | |
| HAS-BLED | ||||||
| 0 | 76 (7%) | 4 (6%) | 5.3% | 150 (13%) | 3 (10%) | 2.0% |
| 1 | 314 (28%) | 14 (21%) | 4.5% | 416 (36%) | 8 (26%) | 1.9% |
| 2 | 390 (34%) | 19 (29%) | 4.9% | 427 (37%) | 12 (39%) | 2.8% |
| 3 | 287 (25%) | 20 (30%) | 7.0% | 154 (13%) | 7 (23%) | 4.5% |
| 4 | 68 (6%) | 8 (12%) | 11.8% | 16 (1%) | 1 (3%) | 6.3% |
| 5 | 7 (1%) | 1 (2%) | 14.3% | 0 (0%) | 0 (0%) | NA |
| Risk category | ||||||
| 0 to 2 | 780 (68%) | 37 (56%) | 4.7% | 993 (86%) | 23 (74%) | 2.3% |
| ≥ 3 | 362 (32%) | 29 (44%) | 8.0% | 170 (14%) | 8 (26%) | 4.7% |
| OBRI | ||||||
| 0 | 253 (22%) | 10 (15%) | 4.0% | 271 (23%) | 7 (23%) | 2.6% |
| 1 | 479 (42%) | 13 (20%) | 2.7% | 491 (42%) | 12 (39%) | 2.4% |
| 2 | 371 (32%) | 39 (59%) | 10.5% | 368 (32%) | 10 (32%) | 2.7% |
| 3 | 39 (3%) | 4 (6%) | 10.3% | 33 (3%) | 2 (6%) | 6.1% |
| Risk category | ||||||
| 0 to 1 | 732 (64%) | 23 (35%) | 3.1% | 762 (23%) | 19 (61%) | 2.5% |
| ≥ 2 | 410 (36%) | 43 (65%) | 10.5% | 403 (32%) | 12 (39%) | 3.0% |
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