PracticeUpdate: Cardiology

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Cardiovascular biomarker score improves risk
prediction in patients with atrial fibrillation
Comment by T. Jared Bunch MD
Stroke is a major worldwide source of morbidity and mortality with incidence rates that continue to climb
dramatically in middle-lower income countries and elderly populations.1,2 Atrial fibrillation (AF) is associated with
more disabling and severe strokes compared with strokes from other causes, resulting in significantly higher
rates of disability and mortality.3 AF is felt to be a preventable cause of stroke due to the availability of highly
effective anticoagulation therapies.
Stroke risk stratification for anticoagulation
use in AF patients is traditionally based
on validated clinical risk scores. The
most commonly used risk scores are CHADS2
(congestive heart failure, hypertension, age
≥75 years, diabetes, and stroke or transient
ischemic attack [2 points]) andCHA2DS2-VASc
(cardiac failure or dysfunction, hypertension,
age 65–74 [1 point] or ≥75 years [2 points],
diabetes mellitus, and stroke, transient
ischaemic attack, or thromboembolism [2
points]–vascular disease, and sex [female
gender]). These scores are derived from
relatively broad static clinical components.
As AF is often a risk marker of a dynamic
systemic vascular disease state, of which
stroke is a consequence, 4 it is not surprising
that the broad risk stratification scores based
on static baseline clinical variables perform
poorly for stroke prediction.5 In fact, the vast
majority of these risk assessment tools have
a C-statistic from 0.5 to 0.6, including both
CHADS2 and CHA2DS2-VASc – a statistical
finding suggestive of a predictive accuracy only
slightly better than chance.5
The key to improving stroke prediction and
all other untoward outcomes associated with
AF is finding tools that better diagnose and
define the underlying systemic vascular dis-
ease state. Since AF is a chronic progressive
disease state in most patients, these tools need
to be dynamic to redefine risk with disease
evolution. Biomarkers that accurately measure
contemporary vascular inflammation, vascu-
lar stiffness and/or reactivity, adverse cardiac
response and remodelling to exposure to el-
evated filling pressures, and local and systemic
hypercoagulability may provide the dynamic
resource necessary to truly define stroke risk
across broad AF populations.
The ENGAGEAF-TIMI 48 trial was a ran-
domised, prospective trial of 21,105 patients
comparing edoxaban with warfarin in AF pa-
tients at moderate to high risk of stroke. This
study included a biomarker substudy of 4880
patients in which troponin I, NT-proBNP, and
D-dimer levels were measured at study enroll-
ment.6 These biomarkers were analysed indi-
vidually and then collectively in a biomarker
risk score as to their association with incident
stroke, thromboembolism, and death. The
biomarker scores were then compared with
CHA2DS2-VASc scores to determine which
had better prognostic accuracy.
First, for both D-dimer and NT-proBNP
separated in quartiles and for troponin I
separated in tertiles, there was a graded as-
sociation with increasing serum levels and
risk of stroke, thromboembolism, and death
(P < 0.001 for all). More importantly, after
adjustment for CHA2DS 2-VASc scores, the
multivariate hazard ratios remained significant
for each biomarker ranging, from 1.22 to 1.39
in the lower serum levels to 2.83 to 4.16 in the
higher serum levels.
Next in this study, the prognostic accuracy
of the CHA2DS2-VASc system was reassessed,
and the C-statistic was 0.586; again suggestive
of predictive utility only slightly better than
chance. If a single biomarker is added to the
CHA 2DS2-VASc scoring system, this C-sta-
tistic increased to 0.647 to 0.674. The three-
component biomarker scored performed better
than CHA 2DS2-VASc and CHA2DS 2-VASc
with any one of the individual biomarkers, with
a C-statistic of 0.700. Adding CHA2DS2-VASc
to the three-component biomarker score only
very marginally improved the diagnostic ac-
curacy (C-statistic, 0.708).
This study brings up a necessary question.
Why do we continue to use risk scores such
as CHADS2 or CHA2DS2-VASc that have very
limited utility and a prognostic accuracy that
is modestly better than flipping a coin? First,
these scores are easy to remember and have
become part of standard-of-care nomencla-
ture, consensus guidelines, and medical edu-
cation. In other words, they are entrenched
in our clinical practice. Second, these scores
are derived from simple clinical demographics
that can be collected by any physician or clinic
and are not reliant on sometimes expensive
testing such as testing for biomarkers or ad-
vanced cardiac imaging. Finally, since neither
scoring system works well, society consensus
guidelines have evolved to recommended anti-
coagulation in nearly all AF patients (CHADS2
and CHA2DS2-VASc score ≥1). Since most AF
patients are treated, the prognostic accuracy
of the risk scores becomes less significant. 7
Long-term anticoagulation exposure is not
without significant risks. Macro- and micro-
bleeds can have devastating effects on organ
function, leading to higher rates of mortality,
disease-related morbidities, and disability.
Risks of both bleeding and stroke evolve over
time and both increase with aging. As AF pa-
tients age, anticoagulation underuse is more
often a problem than overuse; a problematic
trend that has persisted even after the in-
troduction of direct oral anticoagulants.8 If
risk scores have a greater prognostic utility
for both stroke and bleeding risks, physi-
cian decisions to use anticoagulation will
likely increase and improve, and guide-
line recommendations can become more
focused and helpful. However, in order
to reach these improvements, we have to
be willing to move beyond CHADS2 and
CHA2DS2-VASc risk scores and question
our current models and understanding of
AF and stroke.
In the meantime, based on the results of
this study clinicians should consider the
additive value of biomarkers. For example,
in further risk-stratifying a female patient
at low-moderate risk (CHA2DS 2-VASc
score of 1 or 2) an elevated NT-proBNP
and troponin I will raise the risk to moder-
ate. In contrast, if these levels are low then
the patient is low-risk. Another considera-
tion is using these serum biomarkers in a
patient at moderate risk of both bleeding
and stroke to try to further investigate the
risk-benefit ratio of anticoagulation.
References
1. Feigin VL, Lawes CM, Bennett DA, et al.
Lancet Neurol 2009;8(4):355-369.
PIIS1474-4422(09)70025-0/abstract
2. Yiin GS, Howard DP, Paul NL, et al.
Circulation 2014;130(15):1236-1244.
3. Lin HJ, Wolf PA, Kelly-Hayes M, et al.
Stroke 1996;27(10):1760-1764.
4. Bunch TJ, May HT. Eur Heart J In press.
5. Lip GY, Nieuwlaat R, Pisters R, et al.
Chest 2010;137(2):263-272.
6. Ruff CT, Giugliano RP, Braunwald E, et al.
JAMA Cardiol In press.
7. Kirchhof P, Benussi S, Kotecha D, et al. Eur
Heart J 2016; In press.
8. Alamneh EA, Chalmers L, Bereznicki LR.
Am J Cardiovasc Drugs 2016;16(3):183-200.
Dr Bunch is
Medical Director of
Electrophysiology for
Intermountain Healthcare,
Intermountain Heart
Institute, Intermountain
Medical Center in Utah.
Cardiovascular biomarker
score and clinical outcomes in
patients with atrial fibrillation:
a subanalysis of the ENGAGE
AF-TIMI 48 randomized clinical
trial
JAMA Cardiology
Take-home message
• This study investigated the feasibility of
adding biomarkers to the current system
for determining risk when making treatment
decisions for patients with atrial fibrillation
(AF). The authors determined the baseline
levels for D-dimers, cTnI, and NT-proBNP in
patients enrolled in the double-blind, double-
dummy ENGAGE AF-TIMI 48 clinical trial for
AF patients at moderate to high risk for stroke.
All three of the biomarkers were present in
4880 of the 5002 patients enrolled and were
linked to increased risk (2.8- to 4.2-fold; P
< 0.001 for all three). When combined with
the current method for determining risk, the
CHA2DS2-VASc score, there was a significant
improvement in risk prediction, with a 59.4%
net improvement in reclassification.
• Usingmultiple biomarkers significantly improved
the accuracy of risk assessment for patients with
AF compared with the current scoring system.
The authors recommend considering the
inclusion of biomarkerswhenmaking therapeutic
decisions for patients with AF.
Abstract
IMPORTANCE Treatment decisions in atrial fibrillation
(AF) are based on clinical assessment of risk. The
CHA2DS2-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]) risk
score is pragmatic and widely used but has only
moderate discrimination.
OBJECTIVE To develop and test a cardiovascular bio-
marker 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 as-
signing 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 CHA2DS2-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 <0.001 for trend for each). The
multimarker risk score identified a more than 15-
fold gradient of risk after adjustment for CHA2DS2-
VASc score. When added to the CHA2DS2-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<0.001) and reclassification with a
net reclassification improvement of 59.4% (P<0.001).
CONCLUSIONS AND RELEVANCE A prototype
multimarker risk score significantly 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.
JAMA Cardiol 2016 Oct 05;[Epub ahead of print],
Ruff CT, Giugliano RP, Braunwald E, et al.
This study brings up a necessary
question. Why do we continue to use
risk scores such as CHADS 2 or
CHA2DS2-VASc that have very limited
utility and a prognostic accuracy
that is modestly better than flipping
a coin?
ARRHYTHMIAS/HEART RHYTHM DISORDERS
VOL. 1 • No. 3 • 2016
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