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Arrhythmia/Electrophysiology

Cardiac Biomarkers Are Associated With an Increased Riskof Stroke and Death in Patients With Atrial Fibrillation

A Randomized Evaluation of Long-Term Anticoagulation Therapy

(RE-LY) Substudy

Ziad Hijazi, MD; Jonas Oldgren, MD, PhD; Ulrika Andersson, MSc; Stuart J. Connolly, MD;Michael D. Ezekowitz, MB, ChB; Stefan H. Hohnloser, MD; Paul A. Reilly, PhD;

Dragos Vinereanu, MD, PhD; Agneta Siegbahn, MD, PhD;Salim Yusuf, MD, PhD; Lars Wallentin, MD, PhD

BackgroundCardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated

the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association

to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation

Therapy (RE-LY) trial.

Methods and ResultsBiomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Coxproportional hazards models adjusting for established cardiovascular risk factors and the CHADS2 and CHA2DS2-VASc

risk scores. Patients were stratified based on troponin I concentrations: 0.010 g/L, n2663; 0.010 to 0.019 g/L,

n2006; 0.020 to 0.039 g/L, n1023;0.040 g/L, n497; and on NT-proBNP concentration quartiles: 387; 387

to 800; 801 to 1402; 1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year

in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.173.39]; P0.0040),

and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40

[95% CI, 1.414.07]; P0.0014). Vascular mortality was also independently related to biomarker levels with

6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.056.29]; P0.0001),

and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.9511.49];

P0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P0.0001, for a composite of thromboembolic

events.

ConclusionsElevations of troponin I and NT-proBNP are common in patients with AF and independently related to

increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond

currently used clinical variables.

Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

(Circulation. 2012;125:1605-1616.)

Key Words: atrial fibrillation cardiac biomarkers natriuretic peptide risk prediction troponin

The prevalence of atrial fibrillation (AF) is increasing andis projected to reach epidemic proportions in comingdecades.1 AF is associated with a 5-fold increase in the rate of

ischemic stroke and doubled total mortality.2 Strategies for

identifying patients at risk for thromboembolism are com-

monly based on clinical variables, eg, congestive heart

failure, hypertension, age, diabetes mellitus, and prior stroke

or transient ischemic attack (TIA) in the widely used

CHADS2 risk score.3 So far, no biochemical marker has been

shown to provide incremental information. Cardiac troponin,

an intracellular protein involved in heart muscle contraction,

is an established biochemical marker of myocardial cell

Received April 20, 2011; accepted February 16, 2012.From the Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden (Z.H., J.O., L.W.);

Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Population Health Research Institute, Hamilton, Canada (S.J.C., S.Y.);Lankenau Institute for Medical Research and the Heart Center, Wynnewood, PA (M.D.E.); Department of Cardiology, J.W. Goethe University, Frankfurt,Germany (S.H.H.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (P.A.R.); Department of Cardiology, University Hospital of Bucharest,

Bucharest, Romania (D.V.); and Uppsala Clinical Research Center and Department of Medical Sciences, Clinical Chemistry, Uppsala University,Uppsala, Sweden (A.S.).

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.

111.038729/-/DC1.Correspondence to Ziad Hijazi, MD, Uppsala Clinical Research Center, Dag Hammarskjolds vag 14B, 1st floor, SE- 752 37 Uppsala, Sweden. E-mail

[email protected]

2012 American Heart Association, Inc.Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.038729

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http://www.clinicaltrials.gov/http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.111.038729/-/DC1http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.111.038729/-/DC1http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.111.038729/-/DC1http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.111.038729/-/DC1http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.111.038729/-/DC1http://www.clinicaltrials.gov/


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damage. B-type natriuretic peptide (BNP), a neurohormone

secreted from the cardiac ventricles, is a recognized marker of

myocardial wall tension, and its inactive part, N-terminal

fragment (N-terminal pro-B-type natriuretic peptide [NT-

proBNP]]), as well.4 Elevated levels of troponin and NT-

proBNP have repeatedly been demonstrated as important

markers of increased mortality and morbidity in acute coro-

nary syndromes,5,6 stable coronary artery disease,7,8, conges-

tive heart failure,9,10 and even in general community-based

populations.11,12 The prevalence and clinical significance of

elevated cardiac troponin I and NT-proBNP in nonvalvular

AF patients at risk for stroke is unknown.

Clinical Perspective on p 1616

The Randomized Evaluation of Long-Term Anticoagula-

tion Therapy (RE-LY) trial recently demonstrated the supe-

riority of dabigatran versus warfarin for stroke prevention in

18 113 AF patients.13 In this prospectively designed bio-

marker substudy, we investigated the prevalence of elevated

troponin I and NT-proBNP and their association to cardio-vascular events in a representative subgroup constituting

one-third of the RE-LY cohort.

Methods

Study Population and Trial DesignThe study organization, trial design, patient characteristics andoutcomes of the RE-LY study have been published previously.13 Inbrief, RE-LY was a prospective, multicenter, randomized trialcomparing 2 blinded doses of dabigatran with open-label warfarinfor a minimum of 12 months in 18 113 patients. Inclusion criteriawere documented AF and at least one of the following risk factors forstroke: previous stroke or TIA; congestive heart failure or reducedleft ventricular ejection fraction (40%); at least 75 years of age; or

at least 65 years of age with diabetes mellitus, hypertension, orcoronary artery disease. Exclusion criteria included severe heartvalve disorder, recent stroke, increased risk of hemorrhage, creati-nine clearance 30 mL/min, or active liver disease. The 6189 (of18113) patients in the present study represented 446 of 951 sites in38 of 44 countries in the RE-LY trial. The primary efficacy outcomein the study was fatal and nonfatal stroke (ischemic, hemorrhagic, orunspecified) or systemic embolism, and the secondary outcomeswere total mortality, vascular (including hemorrhagic) mortality,nonvascular mortality, and a composite thromboembolic end pointconsisting of ischemic stroke, systemic embolism, myocardial in-farction, pulmonary embolism, and vascular mortality (excludinghemorrhagic death). The primary safety outcome was major bleed-ing. Median follow-up was 2.0 years for the main trial and 2.2 yearsfor the substudy population. Outcomes were assessed by study visits

scheduled at 3-month intervals during the first year and 4-monthintervals thereafter. Each event was classified by 2 independentadjudicators from an international team, blinded to treatment assign-ments. Definition of the outcomes has been described previously.13

Blood SamplingVenous blood was drawn at randomization, before initiation of studytreatment, with the use of a 21/22 gauge needle into Vacutainer tubescontaining EDTA. The blood was centrifuged within 30 minutes at 2000g

for 10 minutes. The tubes were thereafter immediately frozen at 20 C orcolder. Aliquots were stored at 70C to allow batch analysis.

Laboratory MethodsAll plasma samples were centrally analyzed in Uppsala ClinicalResearch Center laboratory, Sweden. Troponin I was analyzed with

the Access AccuTnI assay (Beckman Coulter, Inc, Fullerton, CA), a2-site immunoenzymatic (sandwich) immunoassay. The lower limit

of detection with this assay is 0.006 g/L with 0.014 g/L as thelowest concentration measurable with a coefficient of variation of10% and 0.02 g/L as the 99th percentile upper reference limit(URL) for subjects aged 60 years14 and 0.04 g/L as the 99thpercentile URL regardless of age.15 With present instrument calibra-tion all troponin I concentrations 0.010 g/L are reported as0.010 g/L and considered undetectable; levels 0.010 are re-garded as detectable and reported with 2 significant figures; levels

0.020 g/L are considered elevated.NT-proBNP was analyzed by using the Sandwich Immunoassay,

Elecsys, Roche Diagnostics. The analytic range extends from 20 to35 000 ng/L according to the manufacturer. The upper referencelevel (97.5th percentile) in men and woman aged 40 to 65 years is184 and 268 ng/L, respectively, and age 66 to 76 years, 269 and 391ng/L, respectively.16 The lowest concentration measurable with acoefficient of variation 10% is 30 ng/L.17

Statistical AnalysisThe sample size for the substudy was prospectively estimated at5744 patients, based on an expected event rate of 1.6%/year(corresponding to a total event rate of 3.2%), and the assumptionsthat the biomarker was related to outcome in the following manner:the total event rate for the lower quartile is 1.6%, for the middle

quartiles 3.2%, and for the upper quartile 6.4%. A 2-sided test of thenull hypothesis of no difference in event rate between the lowerquartile and a middle quartile requires 1436 patients per group whenthe significance level is 5% and the power is 80%. The number ofsamples in total was thus calculated to 414365744, to account formissing information blood samples, was planned from 6200patients of the 18 113 patients in the RE-LY study. The final numberof samples in the present analysis was 6189, composed of 2561patients participating in a comprehensive RE-LY biomarker sub-study program and 3628 randomly selected patients with cardiacbiomarkers (troponin I and NT-proBNP) obtained at randomizationin the main RE-LY study.

Patients were grouped according to quartiles of NT-proBNP levels,387 ng/L (n1547), 387 to 800 ng/L (n1547), 801 to 1402 ng/L(n1544), and 1402 ng/L (n1551). Troponin I results were, as

expected, extremely skewed, and patients were in the present studygrouped according to cutoff levels based on results from previousstudies, instead of 4 equally sized groups. Troponin I levels wereundetectable (0.010 g/L) in 2663 (43.0%) patients, 2006 (32.4%)patients had detectable troponin I levels0.010 to 0.019 g/L, ie, up tothe 99th percentile for apparently healthy individuals 60 years age.18

One thousand twenty-three (16.5%) patients had slightly elevatedtroponin I levels 0.020 to 0.039 g/L, and 497 (8.0%) had clearlyelevated troponin I levels 0.040 g/L, ie, above the 99th percentileURL for the troponin I assay regardless of age.15

Demographics and baseline characteristics were summarized forthe troponin I and NT-proBNP level groups with the use offrequencies for categorical variables, and median and 25th and 75thquartiles for continuous variables. Because of the low numbers ofpatients in the CHADS2 scores, 0, 4, 5, and 6 patients were groupedin CHADS2 classes of 0 to 1, 2, and 3. For tests of differences

among groups, the 2 test was used for categorical variables, andKruskal-Wallis test was used for continuous variables.

The risk of event is reported as percentage per year, which wascalculated by dividing the total number of patients with events by thetotal number of patient-years of follow-up. Cumulative hazard plotswere used to illustrate the timing of events. The relations betweenlevels of troponin I and NT-proBNP at randomization and eventswere investigated by using Cox proportional hazards regression.Three different models were used. Model A was adjusted for studytreatment, use of (prestudy) anticoagulant treatment at randomizationand established risk factors for cardiovascular disease (age, sex, bodymass index, smoking status, sitting systolic blood pressure, sittingheart rate, AF duration, AF type, creatinine clearance, diabetes,coronary artery disease, previous stroke/systemic embolism/TIA,heart failure, hypertension, treatment at randomization with aspirin,

angiotensin-converting enzyme inhibitors or angiotensin II receptorblockers, and statins). Model B was only adjusted for study treatment

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and the CHADS2 score (1 point for each of congestive heart failure,hypertension, age 75 years, diabetes mellitus, and 2 points forprevious stroke/TIA) by using 6 CHADS2 classes (CHADS2 score of5 and 6 combined). Model C was only adjusted for study treatmentand the CHA2DS2-VASc score (1 point for each of congestive heartfailure, hypertension, age 65 but 75 years, diabetes mellitus,prior stroke or TIA, vascular disease, and sex category; and 2 pointsfor each of age of75 years and prior stroke or TIA) by using 7

classes (scores of 0 and 1 combined, and scores of 7, 8, and 9combined). The 2 cardiac biomarkers were included separately and

jointly, as well, in the models. The results of hazard ratios for modelA are presented in Results and tables. Models B and C yieldedsimilar hazard ratios (see online-only Data Supplement Tables I andII). The effects of randomized treatment on outcome in relation tolevel of biomarker was evaluated with Cox proportional hazardsmodel with treatment group, biomarker, and their interaction asdependent variables. The proportional hazards assumption withrespect to the cardiac biomarkers was assessed by visual inspectionof log-cumulative hazard plots and by extending the Cox model witha time-by-biomarker interaction factor. In addition, sensitivity anal-yses using logistic regression were performed (results not shown).

The increased discriminative values of troponin I and NT-proBNPwere investigated by estimating the difference in C-statistics between

models with and without respective cardiac biomarker19

and also theintegrated discrimination improvement measure (IDI) as describedby Pencina et al.20 In these analyses, the occurrence/nonoccurrenceof stroke or systemic embolism and composite thromboembolicevents, respectively, during the follow-up period was used as abinary response, and the C value will be the same as the area underthe ROC curve. The relative IDI was calculated to facilitate inter-pretation of the IDI.21

A probability value of0.05 from 2-sided tests was considered toindicate statistical significance. The statistical software packageSAS, version 9.2 for Windows (SAS institute, Cary, NC) was usedfor all analyses.

Results

Baseline Characteristics in Relation to Levels of

Cardiac BiomarkersPatient characteristics are summarized in Table 1. Troponin I

levels ranged from 0.010 to 7.1 g/L, with a median of

0.011, 25th and 75th percentile values of0.010 and 0.019

g/L. Detectable levels of troponin I (0.010 g/L) were

found in 3526 (57.0%) and elevated levels of troponin I

(0.020 g/L) in 1520 (24.6%) patients (Table 1). Several

patient characteristics, eg, higher age, previous myocardial

infarction, history of congestive heart failure, AF rhythm at

randomization (at the time of blood sampling), and lower

creatinine clearance were significantly associated with higher

troponin I levels, all P0.0001 (Table 1).

NT-proBNP levels ranged from 5 to 44959 ng/L, with a

median of 801, 25th and 75th percentile values of 387 and 1403

ng/L. Several patient characteristics, most prominently age, AF

rhythm at randomization, history of congestive heart failure, and

lower creatinine clearance, were significantly associated with

higher NT-proBNP levels, all P0.0001 (Table 1).

The proportion of patients with CHADS2 risk scores 0 to 1

was highest (37.3% and 38.6%, respectively) in groups with

the lowest levels of cardiac biomarkers (troponin I 0.010

g/L and NT-proBNP 387 ng/L) and lowest (25.4% and

25.6%, respectively) in groups with the highest levels of

cardiac biomarkers (troponin I0.040 g/L and NT-proBNP

1402 ng/L, respectively). The opposite applied to the

proportion of patients with a CHADS2 scores

3, which waslowest (27.8% and 25.5%, respectively) in groups with

undetectable troponin I (0.010 g/L) and low NT-proBNP

387 ng/L, and highest (37.6% and 38.6%, respectively) in

the groups with highest troponin I (0.040) g/L and highest

NT-proBNP (1402 ng/L), respectively (Table 1).

Stroke or Systemic EmbolismDuring the median of 2.2 years follow-up, there were 183 events

of stroke or systemic embolism. The annual rates of stroke or

systemic embolism were lowest, 0.84%, in the group with

undetectable troponin I, in comparison with 2.09% (HR, 1.99;

95% CI, 1.173.39) in the highest troponin I group (P0.0040)

(Figure 1A, Table 2). In relation to NT-proBNP, the annual rates

of stroke or systemic embolism were lowest, 0.92%, in the

quartile group with low NT-proBNP, in comparison with 2.30%

(HR, 2.40; 95% CI, 1.414.07) in the highest NT-proBNP

(P0.0014) (Figure 1B, Table 2). The effects of troponin I

remained significant (P0.0232) after adjustment for NT-

proBNP in the multivariable model, and for NT-proBNP

(P0.0112) adjusted for troponin I, as well.

MortalityDuring the follow up 450 patients died, 297 of which died of

vascular causes. In the group with undetectable troponin I,

annual vascular death rate was 1.04% in comparison with

6.56% (HR, 4.38; 95% CI, 3.05 6.29) in the highest troponin

I group (P0.0001) (Figure 2A, Table 2). In relation to

NT-proBNP, the annual rates of vascular death were 0.61% in

the lowest NT-proBNP group, in comparison with 5.00%

(HR, 6.73; 95% CI, 3.9511.49) in the highest NT-proBNP

group (P0.0001) (Figure 2B, Table 2). The effects of

troponin I remained significant (P0.0001) after adding

NT-proBNP to the multivariable model, and for NT-proBNP

(P0.0001) adjusted for troponin I, as well.One hundred fifty-three patients died of nonvascular

causes. The rate of nonvascular mortality was higher among

patients with elevated troponin I levels, P0.0127, but

without a gradual increase by troponin I levels (Table 2).

There was no significant association between NT-proBNP

levels and nonvascular death.

Myocardial InfarctionThere were 103 myocardial infarctions during follow-up. The

annual rates were 0.49% in the group with undetectable

troponin I and 1.69% (HR 3.04; 95% CI 1.645.64) in the

highest troponin I group (P0.0052) (Table 2). The associ-

ation of troponin I and myocardial infarctions remained

significant after adding NT-proBNP to the model. There was

no significant relation between NT-proBNP levels and myo-

cardial infarctions.

Composite Thromboembolic End PointThere were 482 composite thromboembolic events (ischemic

stroke, systemic embolism, pulmonary embolism, myocardial

infarction, and vascular death excluding hemorrhagic death).

In the group with undetectable troponin, the annual rates of

the composite thromboembolic end point were 2.00% in

comparison with 8.85% (HR, 3.43; 95% CI, 2.574.56) in the

highest troponin I group (P0.0001) (Table 2). ConcerningNT-proBNP, the annual rates of the composite thromboem-

Hijazi et al Cardiac Biomarkers in Atrial Fibrillation 1607


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bolic end point were 1.78% in the lowest quartile group ofNT-proBNP, in comparison with 6.76% (HR, 3.55; 95% CI,

2.515.02) in the highest NT-proBNP group (P0.0001)

(Table 2). The effects of troponin I remained significant

(P0.0001) after adding NT-proBNP to the multivariable

model, and for NT-proBNP (P0.0001) adjusted for effects

of troponin I, as well.

Major BleedingThere were 334 major bleeds. In the group with undetectable

troponin I, the annual rate of major bleed was 1.72% in

comparison with 4.38% (HR, 2.01; 95% CI, 1.39 2.90) in the

highest troponin I group (P0.0009) (Table 2). There was no

significant association between NT-proBNP levels and majorbleeding.

Cardiac Biomarkers Levels in Relation toCHADS

2Score

Figure 3A illustrates the annual rates of the composite

thromboembolic end point according to troponin I levels and

CHADS2 score. The pattern of gradually higher rates of the

composite thromboembolic end point concomitant with

higher troponin I levels was consistent in all CHADS2 scores,

including the group with CHADS2 scores 0 to 1. The highest

annual rates of the composite end point, 11.4%, were found in

the group with CHADS2 3 and highest troponin I (0.040

g/L) compared with the lowest annual risk of 1.48%, in the

group with CHADS2 0 to 1 and undetectable troponin I

(0.010 g/L).

Annual rates of the composite thromboembolic end pointaccording to NT-proBNP levels and CHADS2 score are

Table 1. Baseline Characteristics According to Troponin I and NT-proBNP group

Groups All

Troponin I

0.010 g/L 0.010 0.019 g/L 0.0200.039 g/L 0.040 g/L P Value*

No. in substudy 6189 2663 2006 1023 497

Follow-up time, median (25th, 75th pct), y 2.20 (1.78, 2.52) 2.22 (1.88, 2.54) 2.25 (1.74, 2.56) 2.08 (1.67, 2.40) 2.10 (1.71, 2.46)

Region West EuropeNorth America 3512 (56.7) 1553 (58.3) 1175 (58.6) 529 (51.7) 255 (51.3)

Age, median (25th, 75th pct), y 72.0 (67.0, 77.0) 71.0 (66.0, 76.0) 73.0 (67.0, 78.0) 73.0 (67.0, 78.0) 72.0 (65.0, 78.0) 0.0001

Body mass index, median (25th, 75th pct), kg/m2 28.1 (25.3, 31.6) 28.2 (25.6, 31.8) 28.1 (25.2, 31.5) 28.0 (25.1, 31.9) 27.6 (24.8, 31.2) 0.0190

Male sex, n (%) 3944 (63.7) 1631 (61.2) 1288 (64.2) 685 (67.0) 340 (68.4) 0.0008

Current smoker, n (%) 483 (7.8) 202 (7.6) 157 (7.8) 79 (7.7) 45 (9.1) 0.7369

Systolic blood pressure, median (25th, 75th

pct), mm Hg

130.0 (120.0, 144.0) 130.0 (120.0, 142.0) 133.0 (120.0, 145.0) 130.0 (120.0, 145.0) 130.0 (120.0, 140.0) 0.0027

Heart rate median (25th, 75th pct) 72.0 (62.0, 82.0) 72.0 (63.0, 82.0) 72.0 (62.0, 82.0) 72.0 (63.0, 82.0) 72.0 (62.5, 81.0) 0.9794

AF rhythm at baseline (%) 4519 (73.2) 1867 (70.3) 1490 (74.5) 783 (76.8) 379 (76.4) 0.0001

Type of AF, n (%)

Paroxysmal 1848 (29.9) 871 (32.7) 580 (28.9) 259 (25.3) 138 (27.8) 0.0001

Persistent 1609 (26.0) 726 (27.3) 474 (23.6) 285 (27.9) 124 (24.9)

Permanent 2731 (44.1) 1066 (40.0) 951 (47.4) 479 (46.8) 235 (47.3)

AF duration, n (%)

3 mo 1794 (29.0) 756 (28.4) 562 (28.0) 316 (30.9) 160 (32.2) 0.2226

3 mo2 y 1441 (23.3) 646 (24.3) 461 (23.0) 220 (21.5) 114 (22.9)

2 y 2954 (47.7) 1261 (47.4) 983 (49.0) 487 (47.6) 223 (44.9)

Heart failure, n (%) 1859 (30.0) 618 (23.2) 588 (29.3) 436 (42.6) 217 (43.7) 0.0001

Hypertension, n (%) 4852 (78.4) 2112 (79.3) 1575 (78.5) 791 (77.3) 374 (75.3) 0.1773

Age 75 y, n (%) 2356 (38.1) 883 (33.2) 838 (41.8) 426 (41.6) 209 (42.1) 0.0001

Diabetes mellitus, n (%) 1322 (21.4) 519 (19.5) 447 (22.3) 239 (23.4) 117 (23.5) 0.0153

Previous stroke/TIA, n (%) 1216 (19.6) 538 (20.2) 387 (19.3) 183 (17.9) 108 (21.7) 0.2560

CHADS2 score, n (%)

01 2025 (32.7) 992 (37.3) 636 (31.7) 271 (26.5) 126 (25.4) 0.0001

2 2197 (35.5) 932 (35.0) 710 (35.4) 371 (36.3) 184 (37.0)

3 1967 (31.8) 739 (27.8) 660 (32.9) 381(37.2) 187 (37.6)

Prior myocardial infarction, n (%) 1078 (17.4) 330 (12.4) 375 (18.7) 241 (23.6) 132 (26.6) 0.0001

Coronary artery disease, n (%) 1540 (24.9) 578 (21.7) 516 (25.7) 293 (28.6) 153 (30.8) 0.0001

CrCL at baseline, mL/min (25th-75th pct) 69.0 (54.2, 87.1) 73.4 (58.1, 90.3) 68.1 (53.6, 85.4) 64.3 (50.1, 82.0) 63.1 (49.3, 81.1) 0.0001

Medications at baseline, n (%)

Aspirin 2214 (35.8) 900 (33.8) 722 (36.0) 394 (38.5) 198 (39.8) 0.0093

-blocker 4102 (66.3) 1762 (66.2) 1352 (67.4) 656 (64.1) 332 (66.8) 0.3445

ACE inhibitor and/or ARB 4313 (69.7) 1761 (66.1) 1447 (72.1) 737 (72.0) 368 (74.0) 0.0001

Statin 2670 (43.1) 1198 (45.0) 851(42.4) 409 (40.0) 212 (42.7) 0.0396

Amiodarone 700 (11.3) 296 (11.1) 214 (10.7) 118 (11.5) 72 (14.5) 0.1127

NT-proBNP indicates N-terminal pro-B-type natriuretic peptide; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CrCL, creatine clearance;

AF, atrial fibrillation; pct, percentile; and TIA, transient ischemic attack.

*The P value is based on Kruskal-Wallis test for continuous variables and the 2 test for categorical variables.



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illustrated in Figure 3B. The general trend of increasing ratesof the composite thromboembolic end point with increasing

NT-proBNP levels was consistent in all CHADS2 scores,

including the group with CHADS2 scores 0 to 1. The

highest annual rate of the composite end point, 8.99%, was

found in the group with CHADS2 3 and highest NT-

proBNP (1402 ng/L) compared with the lowest yearly

risk of 1.55%, in the group with CHADS2 0 to 1 and lowest

NT-proBNP (387 ng/L).

Figure 3C illustrates the annual rates of the composite

thromboembolic end point in relation to cardiac biomarkers

only. The pattern of gradually higher rates of the composite

thromboembolic end point is apparent in all biomarkergroups, with the highest annual rate of the composite end

point, 12.0%, found in patients with highest levels of troponinI (0.040 g/L) in combination with highest levels of

NT-proBNP (1402 ng/L).

Study Treatment and SubgroupsFor all the above outcomes there were no significant interac-

tions between troponin I or NT-proBNP groups and effects of

study treatment with warfarin or dabigatran 110 mg or 150

mg. Exploratory analyses of relations between troponin or

NT-proBNP levels and outcomes within subgroups defined

by age (75; 75 years), sex, regions (North America and

Western Europe versus others, Asian versus non-Asian coun-

tries), CHADS2 score (01; 2; 36), prevalent coronaryartery disease versus no coronary artery disease, or prevalent

Table 1. Continued

NT-proBNP

387 ng/L 387 800 ng/L 8011402 ng/L 1402 ng/L P Value*

1547 1547 1544 1551

2.17 (1.78, 2.42) 2.23 (1.79, 2.54) 2.23 (1.84, 2.57) 2.19 (1.71, 2.50)

872 (56.4) 895 (57.9) 887 (57.4) 858 (55.3)

70.0 (65.0, 75.0) 71.0 (66.0, 76.0) 73.0 (67.0, 78.0) 74.0 (68.0, 79.0) 0.0001

28.6 (25.6, 32.0) 28.4 (25.7, 32.0) 27.9 (25.2, 31.6) 27.5 (24.7, 30.8) 0.0001

965 (62.4) 1056 (68.3) 977 (63.3) 946 (61.0) 0.0002

121 (7.8) 132 (8.5) 119 (7.7) 111 (7.2) 0.5589

134.0 (122.0, 145.0) 130.0 (120.0, 144.0) 131.0 (120.0, 144.0) 130.0 (120.0, 140.0) 0.0001

65.0 (60.0, 76.0) 73.0 (64.0, 82.0) 75.0 (65.0, 84.0) 75.0 (66.0, 86.0) 0.0001

502 (32.6) 1233 (80.0) 1379 (89.4) 1405 (90.8) 0.0001

955 (61.7) 373 (24.1) 257 (16.7) 263 (17.0) 0.0001

325 (21.0) 401 (25.9) 447 (29.0) 436 (28.1)

267 (17.3) 773 (50.0) 839 (54.4) 852 (54.9)

529 (34.2) 396 (25.6) 392 (25.4) 477 (30.8) 0.0001

393 (25.4) 331 (21.4) 349 (22.6) 368 (23.7)

625 (40.4) 820 (53.0) 803 (52.0) 706 (45.5)

292 (18.9) 422 (27.3) 473 (30.6) 672 (43.3) 0.0001

1273 (82.3) 1207 (78.0) 1193 (77.3) 1179 (76.0) 0.0001

422 (27.3) 538 (34.8) 660 (42.7) 736 (47.5) 0.0001

359 (23.2) 335 (21.7) 332 (21.5) 296 (19.1) 0.0456

296 (19.1) 299 (19.3) 293 (19.0) 328 (21.1) 0.3901

597 (38.6) 546 (35.3) 485 (31.4) 397 (25.6) 0.0001

556 (35.9) 548 (35.4) 537 (34.8) 556 (35.8)

394 (25.5) 453 (29.3) 522 (33.8) 598 (38.6)

190 (12.3) 214 (13.8) 296 (19.2) 378 (24.4) 0.0001

315 (20.4) 354 (22.9) 414 (26.8) 457 (29.5) 0.0001

76.4 (61.1, 93.9) 73.2 (57.8, 91.1) 68.3 (54.6, 85.2) 59.0 (46.1, 74.8) 0.0001

587 (37.9) 519 (33.5) 531 (34.4) 577 (37.2) 0.0272

922 (59.6) 968 (62.6) 1070 (69.3) 1142 (73.6) 0.0001

1053 (68.1) 1067 (69.0) 1059 (68.6) 1134 (73.1) 0.0081

704 (45.5) 667 (43.1) 668 (43.3) 631 (40.7) 0.0613

278 (18.0) 173 (11.2) 122 (7.9) 127 (8.2) 0.0001



6/12

cardiovascular disease (prior stroke, prevalent congestive

heart failure, and/or coronary artery disease) versus no

cardiovascular disease, yielded similar results as in the total

material with no significant interactions (data not shown).

Predictive Ability of Cardiac Biomarkers in AFfor Thromboembolic EventsIn this cohort the C-statistic for stroke and systemic embolism

was 0.605 for troponin I, 0.598 for NT-proBNP, and 0.631

when combining the cardiac biomarkers (Table 3). A model

based on the CHADS2 score (model B) yielded a C-statistic

of 0.614. The separate addition of each cardiac biomarker

improved the predictive model significantly, and even further

when adding both cardiac biomarkers to a model simulta-

neously (Table 3). The IDI was significant for all models

when adding cardiac biomarkers, separately or combined,

with relative IDI ranging from 24% to 124% depending on

the model.

For the composite thromboembolic end point, theC-statistic was 0.639 for troponin I, 0.636 for NT-proBNP,

and 0.676 when combining troponin I and NT-proBNP (Table

3). A model based on the CHADS2 score yielded a C-statistic

of 0.590. The separate addition of a cardiac biomarker

improved the predictive model significantly, and even further

when adding both cardiac biomarkers simultaneously to the

model (Table 3). The IDI was significant for all models whenadding cardiac biomarkers, separately or combined, with

relative IDI ranging from 41% to 425% depending on the

model.

The improvements in C-statistic and IDI in relation to the

CHA2DS2-VASc score (model C) were similar to the im-

provements with the CHADS2 score (model B) (Table 3).

DiscussionThe present RE-LY substudy demonstrated a high prevalence

of detectable and elevated troponin I and considerably ele-

vated NT-proBNP in patients with nonvalvular AF and a

raised risk of stroke. The degree of troponin I and NT-proBNP elevations were both independently related to a

CumulativeHazardRate

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Months

0 6 12 18 24 30

Numbers at Risk

266320061023497

26391969989476

25981925958459

23821711835411

17151269593286

701543212117

0.040 g/L

0.020-0.039 g/L

0.010-0.019 g/L


7/12

Table 2. Cox Proportional Hazards Model With Troponin I and NT-proBNP at Randomization in Relation to Outcomes

Outcome Biomarkers Group

Total Number of

Events, n (%/y) HR (95% CI)

P Value Effect of

Biomarker Level

Addition of Cardiac

Biomarker* HR (95% CI)

P Value Effect of

Biomarker Level

Stroke and systemic

embolism

Troponin I group

(g/L)

0.010 48 (0.84) 0.0040 0.0232

0.0100.019 73 (1.72) 1.79 (1.232.59) 1.71 (1.182.48)

0.0200.039 41 (1.99) 1.97 (1.283.04) 1.76 (1.132.73)

0.040 21 (2.09) 1.99 (1.173.39) 1.68 (0.972.89)

NT-proBNP quartile

group (ng/L)

387 30 (0.92) 0.0014 0.0112

387800 40 (1.22) 1.35 (0.802.27) 1.29 (0.762.17)

8011402 40 (1.22) 1.31 (0.762.27) 1.21 (0.702.09)

1402 73 (2.30) 2.40 (1.414.07) 2.09 (1.223.58)

Vascular death Troponin I group

(g/L)

0.010 59 (1.04) 0.0001 0.0001

0.0100.019 102 (2.40) 1.94 (1.402.69) 1.75 (1.262.42)

0.0200.039 70 (3.39) 2.31 (1.613.30) 1.88 (1.312.70)

0.040 66 (6.56) 4.38 (3.056.29) 3.20 (2.204.65)

NT-proBNP quartile

group (ng/L)

387 20 (0.61) 0.0001 0.0001

387800 46 (1.40) 2.44 (1.404.27) 2.23 (1.273.89)

8011402 72 (2.19) 3.71 (2.156.41) 3.19 (1.855.52)

1402 159 (5.00) 6.73 (3.9511.49) 5.07 (2.958.71)

Nonvascular death Troponin I group(g/L)

0.010 49 (0.86) 0.0127 0.01500.0100.019 52 (1.22) 1.19 (0.801.77) 1.18 (0.791.75)

0.0200.039 42 (2.04) 1.92 (1.252.93) 1.87 (1.212.88)

0.040 10 (0.99) 0.89 (0.451.77) 0.83 (0.411.67)

NT-proBNP quartile

group (ng/L)

387 27 (0.83) 0.0767 0.0862

387800 42 (1.28) 1.31 (0.762.24) 1.25 (0.732.14)

8011402 27 (0.82) 0.79 (0.431.45) 0.73 (0.401.34)

1402 57 (1.79) 1.42 (0.802.50) 1.30 (0.732.30)

Myocardial infarction Troponin I group

(g/L)

0.010 28 (0.49) 0.0052 0.0122

0.0100.019 37 (0.87) 1.59 (0.972.62) 1.56 (0.952.57)

0.0200.039 21 (1.02) 1.77 (0.993.17) 1.72 (0.953.09)

0.040 17 (1.69) 3.04 (1.645.64) 2.88 (1.535.42)

NT-proBNP quartile

group (ng/L)

387 21 (0.64) 0.2383 0.4499

387800 28 (0.85) 1.72 (0.933.18) 1.62 (0.883.00)

8011402 24 (0.73) 1.49 (0.762.91) 1.31 (0.662.56)

1402 30 (0.94) 1.93 (0.983.82) 1.53 (0.763.08)

Composite thromboembolic

outcome

Troponin I group

(g/L)

0.010 114 (2.00) 0.0001 0.0001

0.0100.019 167 (3.93) 1.73 (1.362.21) 1.63 (1.282.08)

0.0200.039 112 (5.43) 2.11 (1.612.76) 1.83 (1.392.41)

0.040 89 (8.85) 3.43 (2.574.56) 2.77 (2.063.72)

NT-proBNP quartile

group (ng/L)

387 58 (1.78) 0.0001 0.0001

387800 97 (2.95) 1.78 (1.262.53) 1.66 (1.172.36)

8011402 112 (3.40) 2.06 (1.442.94) 1.81 (1.262.58)

1402 215 (6.76) 3.55 (2.515.02) 2.79 (1.963.98)

Major bleed Troponin I group

(g/L)

0.010 98 (1.72) 0.0009 0.0040

0.0100.019 125 (2.94) 1.48 (1.131.93) 1.45 (1.111.90)

0.0200.039 67 (3.25) 1.50 (1.092.07) 1.45 (1.052.01)

0.040 44 (4.38) 2.01 (1.392.90) 1.89 (1.302.75)

NT-proBNP quartile

group (ng/L)

387 66 (2.03) 0.1503 0.5272

387800 74 (2.25) 1.12 (0.781.62) 1.07 (0.741.54)

8011402 80 (2.43) 1.16 (0.791.70) 1.07 (0.731.57)

1402 114 (3.58) 1.47 (1.012.15) 1.28 (0.871.88)

Six thousand ninety-two patients had values for all covariates and were included in the Cox regressions. Numbers of patients in each group were as follows: troponin

I group 12663, group 22006, group 31023, and group 4497. For NT-proBNP; Q11547, Q21547, Q31544, and Q41551. NT-proBNP indicates

N-terminal pro-B-type natriuretic peptide; and HR, hazard ratio.

*Adding NT-proBNP to multivariable analysis of troponin I, and troponin I to multivariable analysis of NT-proBNP, respectively.

Stroke, systemic embolism, pulmonary embolism, myocardial infarction, vascular death (excluding hemorrhagic death).



8/12

raised risk of stroke or systemic embolism, mortality, and

other cardiovascular events. The levels of these biomarkers

added prognostic information beyond currently used clinical

risk scores, eg, the CHADS2 or CHA2DS2-VASc risk scores.

Elevation of troponin was initially identified as a sensitive

indicator of myocardial damage and myocardial infarction

and also as an indicator of raised risk of reinfarction and

mortality in patients with acute coronary syndromes.5,6,22 At a

later stage, slight elevations of troponin were observed in a

proportion of patients with stable coronary artery disease and

also associated with a worse outcome.8 In advanced heart

failure, elevated troponin is associated with progressive left

ventricular dysfunction and increased mortality.9 Recently,

more sensitive assays have identified detectable troponin

levels also in elderly healthy men, predicting coronary heart

disease events and mortality independent of conventional

major coronary risk factors.12

The prognostic value of natriuretic peptides has previouslybeen established for a variety of cardiovascular diseases.

Even in community-based populations without heart failure,

natriuretic peptide levels predict risk of death and cardiovas-

cular events.11,23 BNP and NT-proBNP are also prognostic of

short- and long-term mortality in patients with acute coronary

syndromes24,25 and stable coronary artery disease.7 Elevated

levels of BNP also provide prognostic information in acute

decompensated heart failure26 and in chronic heart failure.10

The simultaneous use of both cardiac biomarkers has dis-

played even further improvements in risk stratification in

patients with acute coronary syndromes.27 Our findings in the

present RE-LY substudy extend these observations to a novel

population by demonstrating the prognostic importance of

troponin I and NT-proBNP in patients with AF.

At present, risk stratification in AF is based on clinical

variables, with the CHADS2 risk score being the most widely

used. Although easy to apply, all clinical risk scores including

the novel CHA2DS2-VASc score have, at best, only a modest

discriminating ability for the individual patients, in this respectnot very different from CHADS2 risk score, with C-statistics in

CumulativeHazardRate

0.00

0.05

0.10

0.15

0.20

Months

0 6 12 18 24 30

Numbers at Risk

266320061023497

26481985994480

26181947

970464

24071736853420

17381292612291

714558217120

0.040 g/L

0.020-0.039 g/L

0.010-0.019 g/L


9/12

the range from 0.54 to 0.65.28 We demonstrated the additive

value of troponin I and NT-proBNP to CHADS2 score by

stratifying the RE-LY biomarker cohort based on cardiac bio-

markers and CHADS2 score (Figure 3A). Within every

CHADS2 score stratum, there was also a further gradation of

thromboembolic risk in relation to the troponin I and NT-

proBNP levels. Even in low-risk patients with a CHADS2 score

of 0 to 1, any increase in troponin I (0.020 g/L) doubled the

risk, and highly elevated troponin I levels (0.040 g/L) raised

the risk 5-fold, surpassing the annual risk of patients with a

CHADS2 score of 2 and undetectable troponin I levels. The

incremental information from NT-proBNP levels was similar,

with a 2.5-fold increase in risk when comparing patients with

the highest and lowest quartiles of NT-proBNP within the group

of patients with CHADS2 score of 0 to 1 (Figure 3B). The

significantly improved C-statistics and IDI support the improve-

ment of risk prediction of thromboembolic events when adding

cardiac biomarkers to the CHADS2 and the CHA2DS2-VASc

risk scores.

A CHADS2 score 2 is currently the generally accepted

indication for treatment with oral anticoagulants in AF

patients.29 Therefore, it is noteworthy that, in the present

population, a group with low CHADS2 score of 0 to 1 andelevated levels of any or both of these cardiac biomarkers had

a higher annual rate of a composite of thromboembolic events

than patients with higher CHADS2 scores and undetectable

troponin I and/or low NT-proBNP levels. Conversely, pa-

tients without elevated cardiac biomarkers might have sub-

stantially lower risk than perceived by the CHADS2 score.

Similar findings were shown in relation to the novel

CHA2DS2-VASc risk score. Patients with high CHADS2 or

CHA2DS2-VASc risk score and elevated cardiac biomarkers

remain at high risk for thromboembolic events despite pre-

ventive treatment with effective oral anticoagulants. Such

patients might be considered for intensified pharmacological

treatment with angiotensin-converting enzyme inhibitors, an-

giotensin receptor blockers or statins, ablation therapy, left

atrial appendage closure devices, left atrial volume reduction,

and, perhaps, also myocardial perfusion stress test or coro-

nary angiogram for further risk stratification and potential

percutaneous coronary interventions.

The results of this study also document an association

between elevated troponin I levels and risk of major bleeding.

In AF, several of the variables in scores for estimating stroke

risk are the same components used for assessing bleeding

risk.30 There are some previous studies in acute coronary

syndrome populations linking peak troponin I levels tosubsequent increase of bleeding rate.31 The causality is

Figure 3. Stroke, systemic embolism, pulmonary embolism, myocardial infarction, vascular death (excluding hemorrhagic death) in rela-tion to troponin I levels and CHADS2 scores (A), NT-proBNP levels and CHADS2-scores (B), and troponin I and NT-proBNP levels (C).Total number of patients given in each bar.



10/12

unknown, but elevated troponin I levels might contribute to

the identification of a more fragile AF subpopulation more

likely to bleed during anticoagulation. The NT-proBNP levelswere not related to major bleeding risk in the present analysis.

The mechanism for the prognostic value of elevated troponin

I levels in patients with AF can currently only be an area for

speculation. In acute coronary syndrome, troponin levels reflect

necrosis of myocytes as a consequence of myocardial ischemia.

In patients with chronic heart failure, stable coronary disease,

apparently healthy elderly individuals, or as in this cohort of

stable AF patients, there might be alternative explanations such

as the increased ventricular rate that might lead to oxygen

demand/mismatch and myocardial ischemia, volume and pres-

sure overload, changes in microvascular blood flow, atrial

calcium overload, oxidative stress, or alterations in tissue struc-

ture.29,32,33 The pathogenesis of thrombi in AF involves poorly

contractile atrium,34 hypercoagulable state,35 and endothelial

dysfunction.36 Troponin release in AF patients may be con-

nected to several of these mechanisms associated with myocar-

dial dysfunction, apoptosis, inflammation, and fibrosis in the

atrial and ventricular musculature, as well. The higher proportion

of patients with troponin elevation in permanent AF as an

indicator of increased AF burden and a more advanced cardiac

disease supports this hypothesis and also the relation to major

bleeding events.

The mechanism for the prognostic value of elevated

NT-proBNP levels in AF seems easier to understand. Ele-

vated natriuretic peptides reflect the myocyte response toincreased wall tension. This is usually seen in settings of left

ventricular systolic or diastolic dysfunction, ventricular hy-

pertrophy,37 increasing age, and female sex.38 An acute

coronary syndrome, renal dysfunction, and high-output statesmay cause elevation of NT-proBNP as well.39 Concerning

natriuretic peptides in AF, NT-proBNP level is a predictor of

future development of AF, independent of other risk factors,

including echocardiographic parameters in older adults.40 In

accordance with the present results, the levels of NT-proBNP

have previously been shown to be elevated in patients with

AF, either with or without structural heart disease in compar-

ison with matched controls in sinus rhythm.41 After restora-

tion of sinus rhythm, either by cardioversion or ablation

therapy, the level of natriuretic peptides falls rapidly.42,43

Therefore, there are arguments for NT-proBNP being of atrial

origin in AF,44 in contrast to the pathophysiology of heart

failure, where it is derived mainly from the ventricles.45 Some

studies support this by indicating that atrial stretch is a source

of BNP in patients with AF.46 The level of natriuretic peptides

in AF may therefore, to some extent reflect, atrial dysfunc-

tion, which is an established marker of atrial thrombus

formation,34 and thereby provide a plausible mechanism for

the prognostic importance of elevated NT-proBNP levels and

thromboembolic events as shown in the present study.

There are several limitations of this study. The findings

concern a population with nonvalvular AF with at least 1 risk

factor for stroke. To extend and apply the results to AF

patients without any clinical stroke risk factors, further

studies in other AF populations are warranted. Furthermore,the study design, with all study participants receiving oral

Table 3. Receiver Operating Characteristics for Stroke or Systemic Embolism, and the Composite of Stroke, Systemic Embolism,

Pulmonary Embolism, Myocardial Infarction, Vascular Death (Excluding Hemorrhagic Death)

Model

Stroke and Systemic Embolism Composite Thromboembolic Outcome*

C-statistic P Value IDI Relative IDI, % C-statistic P Value IDI Relative IDI, %

Troponin I 0.605 Referent 0.640 Referent

NT-proBNP 0.598 0.640

Troponin INT-proBNP 0.631 0.0228 0.0027 67 0.676 0.0001 0.0126 57

CHADS2 0.614 Referent 0.596 Referent

Troponin I 0.646 0.0398 0.0033 70 0.667 0.0001 0.0200 239

NT-proBNP 0.637 0.1157 0.0036 76 0.662 0.0001 0.0177 211


CHA2DS2-VASc 0.618 Referent 0.612 Referent

Troponin I 0.647 0.0492 0.0033 59 0.674 0.0001 0.0195 152

NT-proBNP 0.633 0.2393 0.0035 63 0.668 0.0001 0.0160 125


CV risk factors 0.679 Referent 0.679 Referent

Troponin I 0.690 0.2620 0.0032 24 0.703 0.0007 0.0165 49

NT-proBNP 0.692 0.1486 0.0041 30 0.707 0.0001 0.0136 40


NT-proBNP indicates N-terminal pro-B-type natriuretic peptide; IDI, integrated discrimination improvement; CV, cardiovascular; AF, atrial fibrillation; TIA, transient

ischemic attack.

*Stroke, systemic embolism, pulmonary embolism, myocardial infarction, vascular death (excl hemorrhagic death).

All P0.01.

CVs risk factors: Adjusted for study treatment, use of (prestudy) anticoagulant treatment at randomization and established risk factors for cardiovascular disease,

ie, age, sex, body mass index, smoking status, sitting systolic blood pressure, sitting heart rate, AF duration, AF type, creatinine clearance, diabetes, coronary artery

disease, previous stroke/systemic embolism/TIA, heart failure, hypertension, treatment at randomization with aspirin, angiotensin-converting enzyme inhibitors or

angiotensin II receptor blockers, and statins.



11/12

anticoagulants, does not allow final conclusions concerning

the optimal cutoff value of cardiac biomarkers as a decision-

support tool for improved selections of AF patients for oral

anticoagulation. The mechanisms behind the release and

origin of NT-proBNP in AF patients without congestive

heart failure need further clarification, and the exact

mechanisms behind troponin elevations and their relations

to events such as stroke and bleeding in AF, as well.

Although the current troponin I assay has shown robust

analytic performance in patients who have coronary artery

disease and are older,12,14 newly developed assays with

even higher sensitivity and precision might provide even

better identification of patients at increased risk and with a

potential benefit of oral anticoagulation.

ConclusionElevated levels of troponin I and NT-proBNP are common in

patients with AF and at least 1 risk factor for stroke and

associated with an increase in the risk for stroke or systemic

embolism and vascular events. The prognostic informationfrom the troponin I and NT-proBNP levels are independent of

and additive to established clinical risk factors such as the

CHADS2 and CHA2DS2-VASc risk scores.

Source of FundingThe RE-LY trial w as funded by Boehringer IngelheimPharmaceuticals.

DisclosuresAll authors have completed and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest. Dr Hijazi reports receivinglecture fees and an institutional research grant from Boehringer-Ingelheim. Dr Oldgren reports receiving consulting and lecture fees, and

grant support from Boehringer Ingelheim, and consultant and lecturefees from Bayer and Bristol-Myers Squibb. Ms Andersson reports noconflicts of interest. Dr Connolly reports receiving consulting fees,lecture fees, and grant support from Boehringer Ingelheim. Dr Ezekow-itz reports receiving consulting fees, lecture fees, and grant support fromBoehringer Ingelheim and Aryx Therapeutics; consulting fees fromSanofi-aventis; and lecture fees and grant support from Portola Phar-maceuticals. Dr Hohnloser reports receiving consulting fees and lecturefees from Boehringer Ingelheim, St. Jude Medical, and Sanofi-aventis,and lecture fees from Cardiome. Dr Reilly is an employee of BoehringerIngelheim. Dr Vinereanu reports receiving lecture fees and grant supportfrom Boehringer Ingelheim. Dr Siegbahn reports consulting fees, lecturefees, and grant support from Boehringer Ingelheim; lecture fees andgrants from Eli Lilly; and grant support from AstraZeneca. Dr Yusufreports receiving consulting fees, lecture fees, and grant support fromBoehringer Ingelheim; and consulting fees from AstraZeneca, Bristol-Myers Squibb, and Sanofi-aventis. Dr Wallentin reports receivingconsulting and lecture fees, honoraria, and research grants from Boeh-ringer Ingelheim; research grants from AstraZeneca, Bristol-MyersSquibb, GlaxoSmithKline, and Schering-Plough; honoraria from Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, andSchering-Plough; consultant fees from Athera Biotechnologies, Astra-Zeneca, Eli Lilly, GlaxoSmithKline, and Regado Biotechnologies; andlecture fees from AstraZeneca and Eli Lilly.

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CLINICAL PERSPECTIVETroponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are widely available biomarker analyses for

diagnosis and prognostication of cardiac diseases. We demonstrated that elevated levels of troponin I and NT-proBNP were

common in patients with atrial fibrillation, with troponin elevations observed in 25% of the patients and NT-proBNP

elevations in almost 75% of the patients. Elevated levels of any or both of these cardiac biomarkers provided incremental

prognostic information to the currently used CHADS2 and CHA2DS2-VASc risk scores. Beyond clinical risk factors, an

elevated level of troponin I or NT-proBNP identifies patients with a doubled risk for stroke or systemic embolism, and up

to 6-fold increased risk of vascular death. Determination of troponin I or NT-proBNP may be used to improve risk

prediction in patients with atrial fibrillation beyond currently used clinical risk scores.


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