Copyright 2016 American Medical Association. All rights reserved.
Cardiovascular Biomarker Score and Clinical Outcomes
in Patients With Atrial Fibrillation
A Subanalysis of the ENGAGE AF-TIMI 48
Randomized Clinical Trial
Christian T. Ruff, MD, MPH; Robert P. Giugliano, MD, SM; Eugene Braunwald, MD;
Sabina A. Murphy, MPH; Karen Brown, PhD; Petr Jarolim, MD, PhD; Michele Mercuri, MD, PhD;
Elliott M. Antman, MD; David A. Morrow, MD, MPH
IMPORTANCE Treatment decisions in atrial f ibrillation (AF) are based on clinical assessment
of risk. The CHA
2
DS
2
-VASc (cardiac failure or dysfunc tion, hyper tension, age 65-74 [1 point]
or ⱖ75 years [2 points], diabetes mellitus, and stroke, transient ischemic attack or
thromboembolism [2 points]–vascular disease, and sex category [female]) risk score is
pragmatic and widely used but has only moderate discrimination.
OBJECTIVE To develop and test a cardiovascular biomarker score for indication of risk in
patients with AF.
DESIGN, SETTING, AND PARTICIPANTS The ENGAGE AF-TIMI 48 trial was a randomized,
double-blind, double-dummy clinical trial comparing 2 once-daily edoxaban dose regimens
with warfarin in 21 105 patients with AF at moderate to high risk of stroke. This prespecified
subanalysis was performed in 4880 patients enrolled at randomization in the biomarker
substudy. Cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and
D-dimer levels
were measured at baseline. A multimarker risk score was developed to determine the
probability of stroke, systemic embolic events, or death by assigning tiered points for higher
concentrations of the biomarkers.
MAIN OUTCOMES AND MEASURES Risk score and clinical outcomes based on cardiac troponin I,
N-terminal pro-B-type natriuretic peptide, and
D-dimer levels at baseline.
RESULTS Of the 5002 patients enrolled in the biomarker substudy of the ENGAGE AF-TIMI 48
trial, 4880 patients (97.6%) had all 3 biomarkers available at randomization (1820 [37.3%]
were women; median [interquartile range] age, 71 [64-77] years). After adjustment for the
CHA
2
DS
2
-VASc score, each biomarker was associated with a 2.8-fold to 4.2-fold gradient of
risk comparing the highest vs lowest concentrations across groups of increasing
concentrations (P < .001 for trend for each). The multimarker risk score identified a more
than 15-fold gradient of risk after adjustment for CHA
2
DS
2
-VASc score. When added to the
CHA
2
DS
2
-VASc score, the biomarker score significantly enhanced prognostic accuracy by
improving the C statistic from 0.586 (95% CI, 0.565-0.607) to 0.708 (95% CI, 0.688-0.728)
(P < .001) and reclassification with a net reclassification improvement of 59.4% (P < .001).
CONCLUSIONS AND RELEVANCE A prototype multimarker risk score signif icantly enhanced risk
assessment for stroke, systemic embolic events, or death compared with traditional clinical
risk stratification. Incorporation of biomarkers into clinical decision making to define
therapeutic management in AF warrants consideration.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00781391
JAMA Cardiol. 2016;1(9):999-1006. doi:10.1001/jamacardio.2016.3311
Published online October 5, 2016.
Supplemental content
Author Affiliations: TIMI Study
Group (Ruff, Giugliano, Braunwald,
Murphy, Antman, Morrow);
Cardiovascular Medicine Division,
Brigham and Women’s Hospital and
Harvard Medical School, Boston,
Massachusetts (Ruff, Giugliano,
Braunwald, Murphy, Antman,
Morrow); Daiichi Sankyo Pharma
Development, Edison, New Jersey
(Brown, Mercuri); Department of
Pathology and Laboratory Medicine,
Brigham and Women's Hospital,
Harvard Medical School, Boston,
Massachusetts (Jarolim).
Corresponding Author: Christian T.
Ruff, MD, MPH, TIMI Study Group,
Cardiovascular Division, Brigham and
Women's Hospital, Harvard Medical
School, 350 Longwood Ave, First
Floor Offices, Boston, MA 02115
(cruff@partners.org).
Research
JAMA Cardiology | Original Investigation
(Reprinted) 999
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 08/26/2022
Copyright 2016 American Medical Association. All rights reserved.
A
trial fibrillation (AF) predisposes patients to an in-
creased risk of embolic stroke and is associated with
higher rates of stroke and mortality compared with si-
nus rhythm.
1-3
Current risk stratification schemes rely on a com-
bination of demographic and clinical characteristics to deter-
mine the probability of thromboembolism. The most
commonly used and validated risk scores are CHADS
2
(con-
gestive heart failure, hypertension, age ≥75 years, diabetes, and
stroke or transient ischemic attack (TIA) [2 points]) and
CHA
2
DS
2
-VASc (cardiac failure or dysfunction, hypertension,
age 65-74 [1 point] or ≥75 years [2 points], diabetes mellitus,
and stroke, TIA or thromboembolism [2 points]–vascular dis-
ease, and sex category [female]), which are based on clinical
variables.
4,5
Although clinical risk scores, particularly CHA
2
DS
2
-
VASc, are useful in identifying patients with low risk of throm-
boembolism who are unlikely to benefit from anticoagula-
tion, the scores were not developed to determine the
probability of mortality.
6
It is important to stratify risk for both
thromboembolism and mortality because this expanded out-
come is the most relevant to clinicians and, most important,
patients. This end point is analogous to myocardial infarction
and death or heart failure hospitalization and death—
composite outcomes routinely assessed in other disease areas.
In addition, mortality is reduced with anticoagulation and thus
“modifiable” by therapy; therefore, it is important to incor-
porate mortality into risk prognostic schemes used to qualify
whether patients may benefit from anticoagulation. There has
been considerable interest in determining whether the addi-
tion of biomarkers to clinical risk scores enhances prognostic
accuracy for thromboembolism and mortality.
7,8
An emerging body of research has demonstrated that vari-
ous markers of inflammation, coagulation activity, hemody-
namic stress, myocardial injury, and renal dysfunction are as-
sociated with an increased risk of adverse events in patients
with AF.
7
In several large, contemporary, phase 3 trials
9-13
in-
vestigating non–vitamin K antagonist oral anticoagulants vs
warfarin in patients with AF, cardiac troponin, N-terminal pro-
B-type natriuretic peptide (NT-proBNP), and
D-dimer have been
shown to be powerful predictors of stroke and mortality that
significantly enhance prognostic ability when they were added
individually to clinical risk scores. There is also evidence
9,14
that further improvement in risk stratification is achieved when
biomarkers are used in combination.
Therefore, we developed a multimarker risk score using
biomarkers collected in the ENGAGE AF-TIMI 48 trial
15,16
com-
paring 2 once-daily dose regimens of edoxaban with warfarin
in patients with AF at moderate to high risk of stroke. We evalu-
ated whether the performance of this multimarker risk score
alone and in combination with the CHA
2
DS
2
-VASc score im-
proved on current approaches to risk-stratify patients with AF.
Methods
Study Population
The ENGAGE AF-TIMI 48 trial
17
has been described
previously.
15,16
A total of 21 105 patients with documented AF
and a CHADS
2
risk score of 2 or higher were eligible for enroll-
ment. Patients were randomly assigned (1:1:1) to receive war-
farin (dose adjusted to an international normalized ratio of 2.0
to 3.0), higher-dose edoxaban (60 mg/d with dose reduction
to 30 mg/d in selected patients), or lower-dose edoxaban
(30 mg/d with dose reduction to 15 mg/d in selected pa-
tients). Individuals included in this analysis were enrolled in
the biomarker substudy at randomization. The substudy popu-
lation consisted of the first approximately 5000 patients at
selected sites who elected to participate in the biomarker sub-
study, with a final population of 5002 patients. Written in-
formed consent for participation in the trial, including the
biomarker substudy, was approved by the governing institu-
tional review board/ethics committee at each site and ob-
tained from each participating patient. Brigham and Wo-
men’s Hospital Human Research Committee reviewed and
approved the protocol overseeing the TIMI Study Group as the
Coordinating Center for the trial.
Biomarker Testing
Blood samples for determination of cardiac troponin I, NT-
proBNP, and
D-dimer levels werecollected at randomization and
stored at −20°C or colder and then shipped frozen to the TIMI
Clinical Trials Laboratory, where they were stored at −80°C or
colder until thawed and analyzed by personnel blinded to treat-
ment allocation and clinical outcomes. Cardiac troponin I was
measured (EDTA plasma) using a commercially available sen-
sitive assay (TnI-Ultra; Siemens Healthcare Diagnostics) with a
lower limit of detection of 0.006 ng/mL and an established 99th
percentile reference limit of 0.04 ng/mL, with a coefficient of
variation of 10% at a concentration of 0.03 ng/mL.
18
The NT-
proBNP levels were measured (EDTA plasma) using a sand-
wich immunoassay (proBNP II; Roche Diagnostics) with an ana-
lytical range of 5 to 35 000 pg/mL and a coefficient of variation
of 4.6% at a concentration of 44 pg/mL.
19
D-dimer was mea-
sured (citrated plasma) using an immunoturbidimetric assay
(STA-Liatest D-DI; Diagnostica Stago) with a reportable range
0.22 to 4.00 μg/mL and an intrarun coefficient of variation of
2.6% at a concentration of 2.29 μg/mL.
20
Outcomes
The primary outcome for this analysis was the composite of
all-cause stroke (ischemic and hemorrhagic), systemic em-
Key Points
Question Can a cardiovascular biomarker score improve risk
prediction in patients with atrial f ibrillation?
Findings In this prespecified subanalysis of 4880 patients
enrolled in the biomarker study of the ENGAGE AF-TIMI 48 trial,
a multimarker risk score determined by using troponin I,
N-terminal pro-B-type natriuretic peptide, and
D-dimer levels at
baseline identified a more than 15-fold gradient of risk for stroke,
systemic embolic events, or death after adjustment for the
CHA
2
DS
2
-VASc score. Use of the multimarker risk score
significantly enhanced prognostic accuracy and reclassification.
Meaning Incorporation of biomarkers into clinical decision making
to define therapeutic management in atrial fibrillation warrants
consideration.
Research Original Investigation Biomarker Scores and Outcomes in Patients With Atrial Fibrillation
1000 JAMA Cardiology December 2016 Volume 1, Number 9 (Reprinted) jamacardiology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 08/26/2022
Copyright 2016 American Medical Association. All rights reserved.
bolic event (SEE), and all-cause mortality. We chose a com-
posite outcome because, although most clinical risk scores were
initially developed to indicate the probability of thromboem-
bolic events, the scores also serve as indicators of mortality,
and anticoagulation has been demonstrated to reduce
mortality.
21
Moreover, the increased number of events was de-
sirable to support statistical power for individual stratified
analyses. As a sensitivity analysis, we also examined stroke and
SEE separately from all-cause mortality. An independent clini-
cal end point committee unaware of randomized treatment as-
signment or biomarker levels adjudicated all events for the en-
tire trial.
Statistical Analysis
The evaluation of the prognostic ability of cardiac biomark-
ers in the ENGAGE AF-TIMI 48 trial was prespecified. Descrip-
tive statistics of baseline characteristics are given as numbers
and percentages, medians with 25th and 75th percentiles, or
means (SDs). All analyses were performed in the intention-to-
treat population and were restricted to patients who had all 3
biomarkers available. Biomarker levels were stratified by quar-
tiles with the exception of troponin because a substantial por-
tion of patients (49.6%) had a troponin level below the limit
of detection for the TnI-Ultra assay (<0.006 ng/mL), and there
is a clinically established 99th percentile reference limit (≥0.04
ng/mL). Troponin levels were therefore stratified as follows:
less than the limit of detection, tertiles above the limit of de-
tection but less than the 99th percentile reference limit, and
the 99th percentile limit or higher.
Event rates are expressed per 100 patient-years. Hazard ra-
tios (HRs) for the individual biomarkers as well as the bio-
marker scores were determined using the Cox proportional haz-
ards regression model with and without multivariable
adjustment for the CHA
2
DS
2
-VASc risk score. Testing for trend
of survivor functions was conducted. A multimarker score was
constructed by assigning tiered integer values to each bio-
marker group by rounding each HR adjusted for the CHA
2
DS
2
-
VASc score to the nearest whole number. Formal interaction
terms were analyzed in a Cox proportional hazards regres-
sion model to test for a treatment interaction with the bio-
marker risk score. The prognostic accuracy of the biomarker
and CHA
2
DS
2
-VASc scores were compared using the area un-
der the curve derived from receiver operating characteristic
curves (C statistic).
22
To further assess the discriminatory per-
formance (C statistic) in our data set, bootstrapping methods
with replacement for 100 replications were performed. The
ability of the multimarker risk score to enhance discrimina-
tion and correctly reclassify patients was additionally tested
with the integrated discrimination improvement (IDI) and the
category-free net reclassification improvement (NRI).
23,24
The
IDI measures enhancement in average sensitivity gained with-
out forgoing specificity from the addition of the biomarker risk
score to the CHA
2
DS
2
-VASc score. As an integral, the IDI grades
the biomarker risk score’s performance in improving overall
sensitivity and specificity. The NRI is the probability that pa-
tients were appropriately assigned to a higher or lower risk and
evaluates whether there is an additive benefit gained from re-
classifying patients into different categories with the addi-
tion of the biomarker risk score. The NRI quantifies the de-
gree to which adding the biomarker risk score to the CHA
2
DS
2
-
VASc score drives correct movement between categories.
Analyses were performed with SAS, version 9.3 (SAS Institute
Inc) and Stata, version 13.1 (StataCorp LP).
Results
Biomarker Levels and Association with Outcomes
Of the 5002 patients enrolled in the biomarker substudy of the
ENGAGE AF-TIMI 48 trial, 4880 patients (97.6%) had all 3 bio-
markers available at randomization (1820 [37.3%] were wom-
en; median [interquartile range] age, 71 [64-77] years). Base-
line characteristics between patients included in this analysis
and all other patients in the ENGAGE AF-TIMI 48 trial were gen-
erally similar (eTable 1 in the Supplement).
The distribution of each biomarker and the association
between biomarker levels and event rates are reported in
Table 1. There was a graded association between increasing
individual biomarker levels and the rate of stroke, SEE, or
death (P < .001 for trend for each). The same pattern was
observed for the individual components of the composite
end point, including stroke and SEE (Table 1). After adjust-
ment for the CHA
2
DS
2
-VASc score, there remained a 2.8-fold
to 4.2-fold gradient of risk comparing the highest vs lowest
concentrations across groups of increasing concentrations of
individual biomarker levels for stroke, SEE, or death
(Figure 1). There was a similar significant gradient for stroke
and SEE alone (1.6-fold to 3.9-fold; P < .03 for each) compar-
ing the highest vs lowest concentrations after adjustment for
the CHA
2
DS
2
-VASc score.
Multimarker Risk Score
A multimarker score was constructed by assigning tiered in-
teger values to each biomarker group (eTable 2 in the Supple-
ment). The biomarker risk score had a range of 0 to 11 and was
calculated for each patient by summing the integer values as-
signed for the 3 biomarker levels for that patient. The distri-
butions of CHA
2
DS
2
-VASc and biomarker scores are shown in
eFigure 1A and B in the Supplement, respectively.
The rate of stroke, SEE, or death ranged from 1.2% per
year in patients with a biomarker score of 0 to 21.1% per year
in patients with a biomarker score of 10 to 11—a greater than
17-fold range. In contrast, using the CHA
2
DS
2
-VASc score, the
rate of the same end point ranged from 2.2% in patients with
a CHA
2
DS
2
-VASc score of 2 to 9.9% per year in patients with
a CHA
2
DS
2
-VASc score of 8 to 9—a greater than 4-fold range
(Figure 2). The biomarker score identified more than a
15-fold gradient of risk after adjustment for the CHA
2
DS
2
-
VASc score (eFigure 2 in the Supplement). There was an
approximately 7-fold gradient of risk for stroke and SEE
alone after adjustment for the CHA
2
DS
2
-VASc score (6.5;
95%, CI 2.1-19.9) (comparing a biomarker risk score of ≥10 to
a biomarker risk score of 0). Annual rates of stroke, SEE, or
death according to biomarker and CHA
2
DS
2
-VASc scores are
shown in Figure 3. Although event rates increased with
higher levels of both scores, a greater relative increase in risk
Biomarker Scores and Outcomes in Patients With Atrial Fibrillation Original Investigation Research
jamacardiology.com (Reprinted) JAMA Cardiology December 2016 Volume 1, Number 9 1001
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 08/26/2022
Copyright 2016 American Medical Association. All rights reserved.
was observed with the biomarker score. There was no inter-
action between vitamin K antagonist–naive vs –experienced
status at randomization or study treatment (edoxaban vs
warfarin) and the predictive performance of the biomarker
or CHA
2
DS
2
-VASc score.
Prognostic Discrimination and Reclassification
Biomarkers significantly improved discrimination for
stroke, SEE, or death when added individually to the
CHA
2
DS
2
-VASc score (Table 2). The biomarker risk score
alone had significantly greater prognostic accuracy than the
CHA
2
DS
2
-VASc score, with a C statistic of 0.700 (95% CI,
0.679-0.720) compared with 0.586 (95% CI, 0.565-0.607)
(P < .001) (Table 2). Bootstrapping methods resulted in
similar C statistics, with a biomarker score of 0.700 (95% CI,
0.681-0.718) and a CHA
2
DS
2
-VASc score of 0.586 (95% CI,
0.568-0.605). Adding the biomarker score to the CHA
2
DS
2
-
VASc score incrementally increased the C statistic to 0.708
(95% CI, 0.688-0.728) (bootstrapping C statistic, 0.708;
95% CI, 0.687-0.729) compared with the biomarker score
alone (P = .01), with a relative IDI improvement of 590%
(P < .001). Combining the biomarker and CHA
2
DS
2
-VASc
scores also significantly enhanced reclassification compared
with the CHA
2
DS
2
-VASc score alone; the NRI was 59.4%
(P < .001), with events contributing 32.4% and nonevents
contributing 27%.
In a sensitivity analysis, the biomarker score was inde-
pendently associated with stroke or SEE (without including all-
cause mortality) after adjustment for the CHA
2
DS
2
-VASc score.
The C statistic for the CHA
2
DS
2
-VASc score was 0.584 (95% CI,
0.547-0.620), and the addition of the biomarker score pro-
vided significant improvement in discrimination (C statistic,
0.661; 95% CI, 0.627-0.696; P < .001) and reclassification (NRI,
0.318; P < .001) (eTable 3 in the Supplement). Again, boot-
strapping methods resulted in similar C statistics: biomarker
score, 0.635 (95% CI, 0.600-0.670); CHA
2
DS
2
-VASc score, 0.584
(95% CI, 0.557-0.610); and CHA
2
DS
2
-VASc plus biomarker
score, 0.661 (95% CI, 0.627-0.696).
Figure 1. Risk of Stroke, Systemic Embolic Event (SEE), and Death
Associated With Individual Biomarker Levels
0.5 5210
HR (95% CI)
1
Reduced
Risk of Event
Increased
Risk of Event
Quartile 2 1.22 (0.95-1.59)
Quartile 3 1.85 (1.46-2.35)
Quartile 4 2.83 (2.27-3.54)
HR (95% CI)
d-Dimer
Tertile 1 1.40 (1.08-1.80)
Tertile 2 2.03 (1.63-2.52)
Tertile 3 2.80 (2.28-3.43)
>99th Percentile 4.07 (3.12-5.30)
Tnl-Ultra
Quartile 2 1.39 (1.05-1.86)
Quartile 3 1.96 (1.50-2.57)
Quartile 4 4.16 (3.25-5.33)
NT-proBNP
Referent quartile 1 for D-dimer and N-terminal pro-B-type natriuretic peptide
(NT-proBNP) and less than the limit of detection for the TnI-Ultra assay
(Siemens Healthcare Diagnostics). Hazard ratios (HRs) are adjusted for the
CHA
2
DS
2
-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point]
or ⱖ75 years [2 points], diabetes mellitus, and stroke, transient ischemic
attack or thromboembolism [2 points]–vascular disease, and sex category
[female]) score.
Table 1. Association of Biomarker Levels With Outcomes
Variable
Event Rates per 100 Patient-years, No. (%)
Stroke, SEE,
or Death
Stroke
or SEE
Ischemic
Stroke
Hemorrhagic
Stroke Death
D-dimer, μg/mL
a
Q1: 0-0.26 113 (2.85) 52 (1.31) 40 (1.01) 9 (0.22) 83 (2.06)
Q2: 0.27-0.39 118 (3.68) 42 (1.31) 34 (1.06) 7 (0.22) 100 (3.07)
Q3: 0.40-0.67 172 (5.66) 56 (1.85) 45 (1.48) 10 (0.33) 140 (4.53)
Q4: 0.68-16.00 266 (8.89) 69 (2.32) 50 (1.67) 17 (0.56) 230 (7.49)
P value for trend <.001 <.001 .006 .01 <.001
TnI-Ultra, ng/mL
b
<LOD: <0.006 204 (3.04) 93 (1.39) 69 (1.03) 23 (0.34) 156 (2.29)
T1: 0.006-0.008 85 (4.45) 35 (1.84) 31 (1.62) 2 (0.10) 63 (3.23)
T2: 0.009-0.014 136 (6.50) 36 (1.72) 28 (1.34) 24 (0.38) 117 (5.50)
T3: 0.015-0.039 168 (8.85) 38 (2.01) 27 (1.42) 8 (0.42) 149 (7.69)
≥99th percentile:
≥0.04
76 (12.92) 17 (2.91) 14 (2.40) 2 (0.33) 68 (11.21)
P value for trend <.001 .003 .008 .64 <.001
NT-proBNP, pg/mL
c
Q1: 0-370 80 (2.31) 24 (0.69) 16 (0.46) 6 (0.17) 65 (1.85)
Q2: 371-776 113 (3.34) 43 (1.27) 35 (1.03) 8 (0.23) 88 (2.56)
Q3: 777-1360 157 (4.75) 61 (1.85) 48 (1.45) 10 (0.30) 122 (3.61)
Q4: 1361-18993 319 (10.45) 91 (2.99) 70 (2.29) 19 (0.62) 278 (8.90)
P value for trend <.001 <.001 <.001 .002 <.001
Abbreviations: LOD, level of
detection; NT-proBNP, N-terminal
pro-B-type natriuretic peptide;
Q, quartile; SEE, systemic embolic
event; T, tertile.
a
For Q1, data were available from
1413 patients; Q2, 1167; Q3, 1124;
and Q4, 1176.
b
TnI-Ultra is a commercially available
sensitive assay manufactured by
Siemens Healthcare Diagnostics.
For less than the LOD, data were
available from 2421 patients;
T1, 697; T2, 782; T3, 739; and
greater than the 99th percentile,
241.
c
For Q1, data were available from
1227 patients; Q2, 1218; Q3, 1217;
and Q4, 1218.
Research Original Investigation Biomarker Scores and Outcomes in Patients With Atrial Fibrillation
1002 JAMA Cardiology December 2016 Volume 1, Number 9 (Reprinted) jamacardiology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 08/26/2022
Copyright 2016 American Medical Association. All rights reserved.
Discussion
Clinical practice guidelines
1,2
endorse risk stratification as cen-
tral to the management of AF since risk stratification pro-
vides the framework to guide physicians and patients with re-
spect to the most important decision they must make: whether
an individual patient’s risk of thromboembolism is high enough
to warrant indefinite anticoagulation therapy and the obli-
gate associated bleeding risk. The CHA
2
DS
2
-VASc score is com-
monly used for this purpose owing to its ability to more accu-
rately identify low-risk patientswho are unlikely to benefit from
anticoagulant therapy compared with the CHADS
2
score.
25
The
CHA
2
DS
2
-VASc score, like others that rely solely on clinical fac-
tors, has only modest prognostic ability. In addition, CHA
2
DS
2
-
VASc and other clinical risk scores were developed to deter-
mine the risk of thromboembolism rather than its composite
with mortality. We believe the composite is an important out-
come for risk stratification since both thromboembolism and
mortality are reduced with effective anticoagulation and, from
a patient’s perspective, they want to be stroke free and alive.
21
However, clinical risk scores are simple to use, which has made
them attractive to clinicians. Our analyses sought to address
2 important questions. Can risk stratification be improved by
the incorporation of a biomarker score? Would such an im-
provement be clinically meaningful to warrant the additional
complexity and expense of measuring biomarkers?
Prior work
9-13
has established that individual biomarkers
are associated with a gradient of risk for stroke and mortality
even after adjusting for CHA
2
DS
2
-VASc risk factors. The re-
cently developed ABC stroke risk score
26
demonstrated that
2 biomarkers—troponin and NT-proBNP—added to age and his-
tory of stroke or TIA performed significantly better than
CHA
2
DS
2
-VASc in determining the probability of stroke or sys-
temic embolism. This finding supports the premise that there
is important independent information regarding underlying
risk captured in this manner. We have extended these find-
ings and provided proof of principle that a multimarker score
developed by assigning tiered points for higher concentra-
tions of troponin, NT-proBNP, and
D-dimer significantly im-
proved risk prediction compared with the addition of indi-
vidual biomarkers alone. Although each biomarker was
Figure 3. Rate of Stroke, Systemic Embolic Event (SEE), or Death
Stratified by CHA
2
DS
2
-VASc (Cardiac Failure or Dysfunction,
Hypertension, Age 65-74 [1 Point] or ≥75 Years [2 Points], Diabetes
Mellitus, and Stroke, Transient Ischemic Attack or Thromboembolism
[2 Points]–Vascular Disease, and Sex Category [Female]) and
Biomarker Scores
16
12
8
14
10
6
4
2
0
5-8 23
Events per 100 Person-years, %
CHA
2
DS
2
-VASc
4
0-4
5-7 8-11
Biomarker score
Simultaneous categorization of risk using the established risk and biomarker
scores demonstrates that an elevated biomarker score identified patients with
a CHA
2
DS
2
-VASc score of 2 who were at higher risk than patients with a
CHA
2
DS
2
-VASc score of 5 to 8 with a low biomarker score.
Figure 2. Rate of Stroke, Systemic Embolic Events, and Death Stratified by CHA
2
DS
2
-VASc (Cardiac Failure
or Dysfunction, Hypertension, Age 65-74 [1 Point] or ≥75 Years [2 Points], Diabetes Mellitus, and Stroke,
Transient Ischemic Attack or Thromboembolism [2 Points]–Vascular Disease, and Sex Category [Female])
and Biomarker Scores
25
20
15
10
5
25
20
15
10
5
0
2 567
8-9
4
Events per 100 Person-years, %
CHA
2
DS
2
-VASc Score
3
P < .001 for trend
0
0 3 4 5 6 7 8 9 10-112
Events per 100 Person-years, %
Biomarker Score
1
P < .001 for trend
The unadjusted rate of stroke,
systemic embolism, or death
increased in a significant graded
fashion with both the established risk
score and the biomarker score.
Biomarker Scores and Outcomes in Patients With Atrial Fibrillation Original Investigation Research
jamacardiology.com (Reprinted) JAMA Cardiology December 2016 Volume 1, Number 9 1003
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 08/26/2022