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Warfarin Use and Outcomes in Patients With Advanced ChronicSystolic Heart Failure Without Atrial Fibrillation, Prior

Thromboembolic Events, or Prosthetic Valves

Marjan Mujib, MD, MPHa, Abu-Ahmed Z. Rahman, MDb, Ravi V. Desai, MDc,Mustafa I. Ahmed, MDa, Margaret A. Feller, MPHa, Inmaculada Aban, PhDa,

Thomas E. Love, PhDd, Michel White, MDe, Prakash Deedwania, MDf, Wilbert S. Aronow, MDg,Gregg Fonarow, MDh, and Ali Ahmed, MD, MPHa,i,*

Warfarin is often used in patients with systolic heart failure (HF) to prevent adverseoutcomes. However, its long-term effect remains controversial. The objective of this studywas to determine the association of warfarin use and outcomes in patients with advancedchronic systolic HF without atrial fibrillation (AF), previous thromboembolic events, orprosthetic valves. Of the 2,708 BEST patients, 1,642 were free of AF without a history ofthromboembolic events and without prosthetic valves at baseline. Of these, 471 patients(29%) were receiving warfarin. Propensity scores for warfarin use were estimated for eachpatient and were used to assemble a matched cohort of 354 pairs of patients with andwithout warfarin use who were balanced on 62 baseline characteristics. Kaplan-Meier and Coxregression analyses were used to estimate the association between warfarin use and outcomesduring 4.5 years of follow-up. Matched participants had a mean age � SD of 57 � 13 yearswith 24% women and 24% African-Americans. All-cause mortality occurred in 30% ofmatched patients in the 2 groups receiving and not receiving warfarin (hazard ratio 0.86,95% confidence interval 0.62 to 1.19, p � 0.361). Warfarin use was not associated withcardiovascular mortality (hazard ratio 0.97, 95% confidence interval 0.68 to 1.38, p �0.855), or HF hospitalization (hazard ratio 1.09, 95% confidence interval 0.82 to 1.44, p �0.568). In conclusion, in patients with chronic advanced systolic HF without AF or otherrecommended indications for anticoagulation, prevalence of warfarin use was high. How-ever, despite a therapeutic international normalized ratio in those receiving warfarin, itsuse had no significant intrinsic association with mortality and hospitalization. Published

by Elsevier Inc. (Am J Cardiol 2011;107:552–557)

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Heart failure (HF) is a hypercoagulable state, and pa-tients with HF and low left ventricular ejection fraction(LVEF) may be at increased risk of LV thrombus formationand thromboembolic events.1–3 Although use of anticoagu-ants is recommended in patients with HF and atrial fibril-ation (AF) and/or a previous thromboembolic event,4 theres conflicting evidence of the benefit of anticoagulation use

aUniversity of Alabama at Birmingham, Birmingham, Alabama; bCapeear Valley Hospital, Fayetteville, North Carolina; cLehigh Valley Hospi-

tal, Allentown, Pennsylvania; dCase Western Reserve University, Cleve-and, Ohio; eMontreal Heart Institute, Montreal, Quebec, Canada; fUniver-

sity of California at San Francisco, Fresno, California; gNew York Medicalollege, Valhalla, New York; hUniversity of California at Los Angeles,os Angeles, California; iVA Medical Center, Birmingham, Alabama.anuscript received September 21, 2010; revised manuscript received and

ccepted October 5, 2010.Dr. Ahmed is supported by Grants R01-HL085561 and R01-HL097047

rom the National Heart, Lung, and Blood Institute/National Institutes ofealth, Bethesda, Maryland, and a generous gift from Ms. Jean B. Morrisf Birmingham, Alabama. The Beta-Blocker Evaluation of Survival TrialBEST) is conducted and supported by the National Heart, Lung, andlood Institute in collaboration with the BEST study investigators.

*Corresponding author: Tel: 205-934-9632; fax: 205-975-7099.

tE-mail address: aahmed@uab.edu (A. Ahmed).

002-9149/11/$ – see front matter Published by Elsevier Inc.oi:10.1016/j.amjcard.2010.10.012

n patients with HF without AF and/or previous thrombo-mbolic events.5–9 However, because risk of LV thrombusormation increases with decreasing LVEF, clinicians areften concerned about the risk of LV thrombus formation inheir patients with HF and markedly low LVEF. The objec-ive of the present study was to determine the association ofarfarin use and outcomes in patients with advanced

hronic systolic HF without AF and/or previous thrombo-mbolic events.

ethods

We conducted a post hoc analysis of the public-use copyf the Beta-Blocker Evaluation of Survival Trial (BEST)ata for the present study. The BEST was a multicenterandomized placebo-controlled clinical trial of bucindolol, a

� blocker, in HF, the methods and results of which haveeen previously published.10 Briefly, 2,708 patients withdvanced chronic systolic HF were enrolled from 90 differ-nt sites across the United States and Canada from May995 to December 1998. All but 1 patient consented to beart of the public-use copy of the data. At baseline, patientsad a mean duration of 49 months of HF and had a meanVEF of 23%. All patients had New York Heart Associa-

ion (NYHA) class III to IV symptoms and �90% of all

www.ajconline.org

553Warfarin and Outcomes in Chronic Systolic Heart Failure

patients were receiving angiotensin-converting enzyme in-hibitors, diuretics, and digitalis.

Data on use of warfarin at baseline were available in all2,707 participants. For the present analysis, we excluded692 patients with AF, 343 patients with a history of throm-boembolic diseases, and 30 patients with prosthetic valvesat baseline. Thus, our final sample was 1,642, of which 471

Table 1Baseline patient characteristics by use of warfarin before and after propen

Variable Before Prop

No warfarin(n � 1,171)

W(

Age (years) 60 � 12Women 283 (24%) 1African-American 302 (26%) 1Current smoking 213 (18%)Body mass index (kg/m2) 37 � 9New York Heart Association class III 1,086 (93%) 4Medical history

Heart failure duration (months) 46 � 48Coronary artery disease 670 (57%) 2Angina pectoris 624 (53%) 2Hypertension 715 (61%) 2Diabetes mellitus 452 (39%) 1Hyperlipidemia 527 (45%) 2Ventricular fibrillation 79 (7%)Peripheral vascular disease 164 (14%)

MedicationsBucindolol 600 (51%) 2Angiotensin-converting enzyme inhibitors/

angiotensin receptor blocker1,137 (97%) 4

Digitalis 1,056 (90%) 4Diuretics 1,086 (93%) 4Vasodilators 504 (43%) 2Aspirin 738 (63%)Statins 273 (23%) 1

Physical examinationPulse (beats/min) 82 � 13Systolic blood pressure (mm Hg) 119 � 19 1Diastolic blood pressure (mm Hg) 72 � 11Jugular venous distention 399 (42%) 8S3 gallop 477 (41%) 2Pulmonary rales 162 (14%)Hepatomegaly 115 (10%)Edema 288 (25%)

Laboratory dataHemoglobin (g/dl) 13.9 � 1.6 14Serum creatinine (mg/dl) 1.2 � 0.4 1Serum potassium (mEq/L) 4.34 � 0.46 4.Plasma norepinephrine (pg/ml) 484 � 272 5Partial thromboplastin time (seconds) 28 � 8International normalized ratio 1.1 � 0.3 2

Left bundle branch block byelectrocardiogram

303 (26%) 1

Cardiothoracic ratio by chest x-ray 54.8 � 7.2 55Pulmonary edema by chest x-ray 114 (10%) 5Left ventricular ejection fraction by nuclear

scan (%)23.5 � 7.2 21

Right ventricular ejection fraction bynuclear scan (%)

35.5 � 11.7 33

Values presented as number of patients (percentages) or mean � SD.

patients (29%) were receiving warfarin at baseline. Consid-

ering the significant imbalances in baseline characteristicsbetween the 2 groups (Table 1), we used propensity scoresto assemble a matched cohort of 354 pairs of patients whowere well balanced on 62 baseline characteristics.11–17 Pro-pensity scores for warfarin use were estimated for each ofthe 1,642 patients using a nonparsimonious multivariablelogistic regression model.18,19 Absolute standardized differ-

tching

atching After Propensity Matching

n1)

p Value No warfarin(n � 354)

Warfarin(n � 354)

p Value

�0.001 57 � 14 57 � 12 0.353) 0.532 87 (25%) 83 (23%) 0.781) 0.226 84 (24%) 87 (25%) 0.857) 0.406 73 (21%) 68 (19%) 0.709

0.643 37 � 9 37 � 8 0.446) 0.255 322 (91%) 327 (92%) 0.583

0.505 45 � 47 45 � 45 0.939) 0.724 190 (54%) 192 (54%) 0.937) 0.312 172 (49%) 178 (50%) 0.708) �0.001 191 (54%) 191 (54%) 1.000) 0.038 124 (35%) 118 (33%) 0.693) 0.756 145 (41%) 149 (42%) 0.825) 0.002 31 (9%) 33 (9%) 0.896) 0.186 53 (15%) 52 (15%) 1.000

) 0.337 168 (48%) 172 (49%) 0.821) 0.875 340 (96%) 345 (98%) 0.425

) 0.001 333 (94%) 334 (94%) 1.000) 0.573 326 (92%) 327 (92%) 1.000) 0.920 146 (41%) 150 (42%) 0.818) �0.001 91 (26%) 96 (27%) 0.640) 0.511 87 (25%) 83 (23%) 0.794

0.100 83 � 13 83 � 13 0.979�0.001 115 � 16 115 � 16 0.708

0.114 72 � 11 71 � 11 0.738) 0.003 134 (38%) 147 (42%) 0.356) �0.001 165 (47%) 173 (49%) 0.582

) 0.001 36 (10%) 35 (10%) 1.000) 0.973 36 (10%) 39 (11%) 0.807) 0.068 76 (22%) 74 (21%) 0.924

6 0.003 14.0 � 1.6 14.1 � 1.6 0.5224 0.722 1.2 � 0.4 1.2 � 0.4 0.80847 0.046 4.31 � 0.47 4.31 � 0.46 0.8071 0.011 511 � 325 509 � 302 0.917

�0.001 29 � 13 34 � 7 �0.0010 �0.001 1.1 � 0.5 2.2 � 0.9 �0.001) 0.850 98 (28%) 94 (27%) 0.796

9 0.101 55.1 � 7.3 55.4 � 6.9 0.590) 0.505 37 (11%) 36 (10%) 1.0003 �0.001 22.4 � 7.5 22.1 � 7.2 0.520

.5 0.003 33.7 � 11.9 34.1 � 12.4 0.660

sity ma

ensity M

arfarin � 47

56 � 1207 (23%08 (23%94 (20%37 � 829 (91%

44 � 4465 (56%38 (51%39 (51%56 (33%08 (44%54 (12%78 (17%

29 (49%58 (97%

49 (95%33 (92%04 (43%98 (21%17 (25%

83 � 1314 � 1671 � 1136 (48%40 (51%38 (8%46 (10%96 (20%

.2 � 1.

.2 � 0.29 � 0.24 � 3234 � 8.2 � 1.24 (26%

.5 � 6.1 (11%.4 � 7.

.6 � 12

ences were estimated to evaluate the prematch imbalance

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554 The American Journal of Cardiology (www.ajconline.org)

and postmatch balance and presented as a Love plot. Anabsolute standardized difference of 0% indicates no residualbias and differences �10% are considered inconsequential.

BEST participants were followed for a minimum of 18onths and a maximum of 4.5 years.10 Primary outcome for

the present analysis was all-cause mortality during 4.1 yearsof follow-up (mean 2, range 10 days to 4.14 years). Sec-ondary outcomes were cardiovascular and HF mortalitiesand all-cause and HF hospitalizations. Kaplan-Meier andCox regression analyses were used to determine associa-tions between warfarin use and outcomes during 4.1 yearsof follow-up. Log-minus-log scale survival plots were usedto check proportional hazards assumptions. Subgroup anal-yses were conducted to determine the homogeneity of as-sociation between use of warfarin and all-cause mortality.All statistical tests were 2-tailed with a p value �0.05considered statistically significant. All data analyses wereperformed using SPSS 18 for Windows (SPSS, Inc., Chi-cago, Illinois).

Results

Matched patients had a mean age � SD of 57 � 13years, 170 � 24% were women, and 171 � 24% were

frican-Americans. Before matching, patients receivingarfarin were younger, had a lower mean of LVEF and

ight ventricular EF, a lower prevalence of hypertension and

Figure 1. Absolute standardized differences comparing covariate valuesmatching.

iabetes mellitus, but had a greater symptom burden such as i

ugular venous distention and S3 gallop. These and othermbalances in baseline characteristics were well balancedfter matching (Figure 1, Table 1). After matching, absolutetandardized differences for all measured covariates were10% (most were �5%), suggesting substantial covariate

alance across groups (Figure 1). Median international normal-

tients with and without warfarin use before and after propensity score

Figure 2. Kaplan-Meier plots for all-cause mortality by use of warfarin.CI � confidence interval; HR � hazard ratio.

for pa

zed ratios (INRs; interquartile range) were 2.0 (1.1) and 1.0

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555Warfarin and Outcomes in Chronic Systolic Heart Failure

(0.1) for matched patients receiving and not receiving warfarin,respectively.

Overall, 212 matched patients (30%) died from all causesduring a 2.1-year median follow-up. All-cause mortalityoccurred in 30% and 30% of matched patients receiving andnot receiving warfarin, respectively (hazard ratio 0.86, 95%confidence interval 0.62 to 1.19, p � 0.361; Figure 2, Table). The association between warfarin use and all-cause mor-ality was homogenous across a wide spectrum of partici-ants, including those with LVEFs �20% and �20% (Fig-re 3). When we used LVEF as a continuous variable, wetill did not observe any statistically significant interaction

Table 2Effects of warfarin on all-cause mortality in BEST trial

Outcomes Events (%)

No Warfarin Warfarin

efore matchingPatients 1,171 471Unadjusted 321 (27%) 159 (34%)Multivariable-adjusted† — —Propensity-adjusted — —fter matchingPatients 354 354All-cause mortality 106 (30%) 106 (30%)

* Absolute rate increase was calculated by subtracting rates of eventsounded).

† Multivariable model includes all covariates displayed in Figure 1.

Figure 3. Association of use of warfarin and a

etween use of warfarin and LVEF (p for interaction � u

.815). Prematch-unadjusted, multivariable-adjusted, andropensity score–adjusted hazard ratios between warfarinnd no-warfarin use in the 1,642 patients before matchingre listed in Table 2. Warfarin had no association withardiovascular and HF mortalities and all-cause and HFospitalizations after matching (Table 3).

iscussion

Findings from the present study demonstrate that in pa-ients with advanced chronic systolic HF without AF and/orrevious thromboembolic events, prevalence of warfarin

Absolute RiskIncrease*

Hazard Ratio(95% confidence interval)

p Value

�7% 1.20 (0.99–1.45) 0.062— 1.14 (0.91–1.43) 0.253— 1.08 (0.87–1.35) 0.477

0% 0.86 (0.62–1.19) 0.361

group receiving from those not receiving warfarin (before values were

e mortality in subgroups of matched patients.

in the

se was relatively high. Nevertheless, our data suggest that

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556 The American Journal of Cardiology (www.ajconline.org)

despite achieving a mean therapeutic INR, warfarin use didnot provide any intrinsic survival benefit in patients withadvanced chronic systolic HF who had no other establishedindications for anticoagulation. These findings are impor-tant because many practicing physicians perceive advancedchronic systolic HF as a prethrombotic stage and prescribewarfarin, although current American College of Cardiology/American Heart Association guidelines have no clear rec-ommendation on this.4 Thus, warfarin might be prescribed

ithout any proved benefit and with a potential increasedisk of bleeding and other adverse effects.20

The unadjusted association of warfarin use with in-creased risk of cardiovascular mortality is rather surprisingbecause pre-match patients receiving warfarin were youngerand had lower or similar baseline prevalences of cardiovas-cular co-morbidities (Table 1). These suggest strong con-founding by a history of ventricular fibrillation, greatersymptom burden, and lower mean LVEF and right ventric-ular EF, which are known to increase risk of cardiovasculardeath. The near significant unadjusted association betweenwarfarin use and sudden cardiac death is likely due toincreased prevalence of ventricular fibrillation in warfa-rin users. Despite a greater burden of HF symptoms inwarfarin users, lack of significant unadjusted associationsof warfarin use with HF mortality and HF hospitalizationis intriguing but may suggest that LVEF and HF symp-toms were rather weak confounders.

Lack of significant associations of warfarin use withmortality and hospitalization in matched patients suggestslack of an intrinsic effect of warfarin on outcomes in pa-tients with advanced systolic HF without AF and/or throm-boembolic disorders. Although a low LVEF is often con-sidered an indication for warfarin use in these patients,findings from our subgroup analysis suggest that the asso-ciation between warfarin use and all-cause mortality wassimilar regardless of LVEF categories. Lack of an intrinsiceffect of warfarin in patients with advanced systolic HFwithout AF and/or thromboembolic events, despite a ther-apeutic INR, suggests that thromboembolic events may not

Table 3Effects of warfarin on other outcomes in BEST trial

Outcomes Events (%)

No Warfarin Warfarin

efore matchingPatients 1,171 471Cardiovascular mortality 268 (23%) 143 (30%)Sudden cardiac death 151 (13%) 81 (17%)Heart failure mortality 91 (8%) 45 (10%)All-cause hospitalization 702 (60%) 291 (62%)Heart failure hospitalization 412 (35%) 186 (40%)fter matchingPatients 354 354Cardiovascular mortality 84 (24%) 95 (27%)Heart failure mortality 27 (8%) 31 (9%)All-cause hospitalization 217 (61%) 225 (64%)Heart failure hospitalization 131 (37%) 141 (40%)

* Absolute rate increase was calculated by subtracting rates of eventsounded).

underlie mechanisms of death or hospitalization in these c

patients. Findings from our study provide further evidencesupporting current guideline recommendations that use ofwarfarin in patients with HF should be restricted to thosewith AF and/or previous thromboembolic events.4

There is conflicting evidence in the literature regardingthe role of warfarin in patients with advanced systolic HFwithout AF or other indications for anticoagulation.5,21 In 1study warfarin use was associated with lower mortality andmorbidity in patients with mild to moderate (2/3 had NYHAclass I to II symptoms) chronic systolic HF.6 Our study isistinguished by patients with more advanced HF (all withYHA class III to IV symptoms) and use of a propensity-atched design that allowed the assembly of a balanced

ohort. Findings from our study are consistent with thoserom the largest randomized clinical trial of anticoagulationn patients with HF and normal sinus rhythm to date inhich there was no difference in outcomes between patients

eceiving warfarin (open label), aspirin, or clopidogrel.8

However, this study was not considered definitive because itwas terminated prematurely because of slow enrollmentresulting in an estimated power of only 40% to detect a 20%difference. In the absence of another large clinical trial withadequate power, observational studies such as ours addfurther evidence of lack of benefit for therapeutic anticoag-ulation in these patients.

As in all observational studies, a key limitation of ourstudy is potential confounding by an unmeasured covariate.Sensitivity analysis would normally help quantify the de-gree of a hidden bias that would need to be present toinvalidate conclusions based on significant associations inan observational study. However, sensitivity analyses canbe performed only if the observed association is statisticallysignificant.22 Another limitation is lack of data on otherardiovascular events including stroke and adversevents such as bleeding. In conclusion, in patients withdvanced chronic systolic HF without AF and/or otherndications for anticoagulation, despite a mean INR thatas therapeutic, use of warfarin was not associated with

Absolute RiskIncrease*

Hazard Ratio(95% confidence interval)

p Value

�7% 1.29 (1.06–1.58) 0.013�4% 1.31 (1.00–1.71) 0.052�2% 1.19 (0.83–1.70) 0.336�2% 0.99 (0.86–1.14) 0.883�5% 1.13 (0.95–1.34) 0.174

�3% 0.97 (0.68–1.38) 0.855�1% 0.73 (0.38–1.39) 0.332�3% 0.96 (0.76–1.22) 0.763�3% 1.09 (0.82–1.44) 0.568

group receiving from those not receiving warfarin (before values were

in the

linical outcomes.

1

1

557Warfarin and Outcomes in Chronic Systolic Heart Failure

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