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Published in final edited form as:

Circ J. 2016 April 25; 80(5): 1061–1066. doi:10.1253/circj.CJ-16-0239.

Predicting atrial fibrillation and its complications

Alvaro Alonso, MD, PhD and Faye L. Norby, MPH, MS
Division of Epidemiology and Community Health, School of Public Health, University of
Minnesota, MN, USA

Abstract
Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke
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and other complications. Identifying individuals at higher risk of developing AF in the community
is now possible using validated predictive models that take into account clinical variables and
circulating biomarkers. These models have shown adequate performance in racially and ethnically
diverse populations. Similarly, risk stratification schemes predict incidence of ischemic stroke in
persons with AF, assisting clinicians and patients in decisions regarding oral anticoagulation use.
Complementary schemes have been developed to predict the risk of bleeding in AF patients taking
vitamin K antagonists. However, major gaps in our ability to predict AF and its complications
exist. Additional research should refine models for AF prediction and determine their value to
improve population health and clinical outcomes, advance our ability to predict stroke and other
complications in AF patients, and develop predictive models for bleeding events and other adverse
effects in patients using non-vitamin K oral anticoagulants.
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Atrial fibrillation (AF) is a common cardiac arrhythmia affecting >30 million persons
worldwide.1 In addition, AF increases the risk of stroke, heart failure, and overall mortality.2
With the aging of the population, the incidence and prevalence of AF are expected to grow
in future decades as well as the burden from its associated complications.3 The growing
public health significance of AF has spurred efforts to identify individuals at higher risk of
developing this arrhythmia and its complications. Identifying individuals more likely to
develop AF could facilitate targeting of preventive interventions and screening programs,
while risk stratification schemes in AF patients can assist clinicians and patients in treatment
decisions.

This review article provides an overview of the expanding field of AF prediction. We have
structured the text as follows. First, we describe available models for the prediction of
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incident AF in the community and their potential applications. Second, we summarize the
main existing risk schemes for prediction of ischemic stroke in patients with AF,
highlighting some limitations. Third, we discuss prediction of bleeding and other
complications in patients with AF. We end by highlighting areas that demand additional

Corresponding author: Alvaro Alonso, MD, PhD. Division of Epidemiology and Community Health, School of Public Health,
University of Minnesota, 1300 S 2nd St, Suite 300, Minneapolis, MN 55454, USA. Phone: +1 612 626 8597. [email protected].
DISCLOSURES
Dr. Alonso reports grant support from the American Heart Association and the National Institutes of Health. Ms. Norby reports no
disclosures.
 Alonso and Norby Page 2

research. To inform the review, we searched PubMed through December 31, 2015 using the
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search terms “atrial fibrillation” AND “prediction”. We considered publications mostly from
the past 5 years, though we did not exclude frequently referenced older publications, and
selected those considered relevant. Though related to the topic, we do not discuss the
extensive work on prediction of AF recurrence after electrical cardioversion or catheter
ablation, or on AF prediction in the context of specific clinical contexts, such as
postoperative AF after cardiac surgery.

PREDICTION OF AF IN THE COMMUNITY

Risk scores and equations for AF prediction
Over the last few years, several risk scores and equations for the prediction of AF in the
general population have been developed, published, and validated. Table 1 enumerates in
chronological order the published scores, the variables included, the characteristics of the
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derivation and validation samples, if any, and the performance of the model (discrimination
and calibration). Discrimination refers to the ability of the model to separate subjects who
develop the outcome from those who do not, while calibration refers to the agreement
between observed outcomes and predictions.4

The first published risk score was derived in 4764 mostly white participants in the
Framingham Heart Study (FHS), and used basic demographic and clinical variables to
predict the 10-year risk of AF.5 The discrimination of the model, assessed with the C-
statistic, was good (0.78, 95% confidence interval (CI) 0.76, 0.80). This score was
subsequently validated in four different cohorts: the Age, Gene/Environment Susceptibility-
Reykjavik (AGES) study, Atherosclerosis Risk in Communities (ARIC) study,
Cardiovascular Health Study (CHS), and the Multi-Ethnic Study of Atherosclerosis
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(MESA).6–8 In these external cohorts, the discrimination of the model was acceptable,
ranging from 0.67 in African American participants in CHS to 0.75 in the racially diverse
MESA cohort. In most populations, however, the model required recalibration to adjust the
predicted probabilities to the actual risk of AF in the different cohorts. Independently, the
ARIC study also developed a 10-year risk score for AF prediction among 14,546 study
participants 45–64 years of age.7 In contrast to the FHS AF risk score, the ARIC model was
based on a bi-racial cohort, including whites and African Americans. Given the well-
established lower risk of AF among non-whites compared to whites,9, 10 attention to race in
AF prediction is relevant and the application of scores developed in a specific racial/ethnic
group to another should be done carefully. The discrimination of the ARIC model was
similar to the FHS AF risk score (C-statistic 0.78). The ARIC model, however, has not been
applied in any external cohorts and, therefore, its validity outside the ARIC population is
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uncertain. More recently, the Women’s Health Study (WHS), a cohort of mostly white,
healthy women, derived and validated a 10-year model among 19,940 participants.11 The
model had good discrimination (C-statistic 0.72) and excellent calibration in the WHS
cohort, but has not been validated in external populations and its applicability to men is
unknown.

The FHS, ARIC, and WHS risk scores and predictive models were derived in single cohorts,
and restricted in terms of race/ethnicity (FHS), age (ARIC), or sex (WHS), which may

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reduce generalizability to other populations. To address this limitation, the Cohorts for
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Aging and Research in Genomic Epidemiology (CHARGE)-AF consortium derived a new

predictive model pooling data from 18,556 participants in the FHS, CHS and ARIC studies
to predict the 5-year risk of AF. This model was then validated in 7,672 participants from the
AGES and Rotterdam studies, showing acceptable discrimination.12 The CHARGE-AF
model, which included demographic and clinical information readily available in clinical
settings, had good discrimination in the derivation cohorts (C-statistic 0.77, 95%CI 0.75,
0.78) and acceptable in AGES (0.66, 95% 0.63, 0.70) and the Rotterdam study (0.71, 95%
0.66, 0.75).12 The CHARGE-AF risk model has been validated in two additional cohorts. In
the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study, the
model had excellent discrimination (C-statistic 0.81, 95% 0.75, 0.85) but it overestimated
the risk of AF, requiring recalibration.13 Similarly, the CHARGE-AF model had good
discrimination in the MESA cohort (C-statistic 0.78, 95%CI 0.74, 0.81), but also
overestimated AF risk, particularly among those with the highest observed risk.8
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Finally, some studies have suggested that scores derived for prediction of stroke in patients
with AF, such as the CHADS2 and CHA2DS2-VASc, could be also applied in AF
prediction.14, 15 In fact, most of the elements included in these scores (age, diabetes,
hypertension, heart failure, vascular disease) are well established risk factors for AF.
However, these scores perform worse than AF-specific predictive models (as assessed with
c-statistics, for example) and are not adequately calibrated to predict AF, failing to provide
estimates of actual predicted AF risk over a particular time period.8

AF prediction beyond clinical variables

Extensions of these models have evaluated whether information on blood biomarkers,
echocardiographic and electrocardiographic (ECG) measurements, or genetic variants would
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improve prediction of AF beyond the information provided by clinical variables.

Blood biomarkers—The predictive value of a diverse array of circulating biomarkers,

including markers of inflammation (high-sensitivity C-reactive protein, fibrinogen),16–18
atrial overload (atrial and B-type natriuretic peptides),16–18 myocardial ischemia (high-
sensitivity troponin T and I),17, 19, 20 cardiac fibrosis (galectin-3),21 and others (soluble ST2,
growth differentiation factor-15),20 has been assessed in the literature. Of these, only
natriuretic peptides have consistently demonstrated added predictive value beyond
information on clinical variables across multiple populations. For instance, in the CHARGE-
AF pooled analysis, which included five separate cohorts, B-type natriuretic peptides but not
C-reactive protein helped in risk reclassification of individuals, as measured by the net
reclassification index (NRI).16 Similar observations have been made in the FHS,22 the
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Malmö Diet and Cancer Study,18 the MESA cohort,8 and in the Gutenberg Health Study.17

Electrocardiography—Some of the existing AF risk scores and models include ECG-

derived variables, such as the PR interval in the FHS AF score, the ARIC score, and the
CHARGE-AF model, or ECG-based left ventricular hypertrophy in the ARIC score and the
CHARGE-AF model.5, 7, 12 Their added predictive value beyond clinical variables, however,
is only marginal. Other ECG measurements considered as potential predictors of AF include

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P wave indices. A pooled analysis of the FHS and ARIC cohorts found that even though P
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wave indices such as P wave duration, area, and terminal force were associated with the
incidence of AF, their contribution to risk prediction on top of established risk factors was
minimal.23 Information on atrial ectopy assessed through longer term heart rhythm
monitoring, however, could improve AF prediction. An analysis of 1260 participants in the
CHS cohort found that information on premature atrial contractions count from 24-hour
Holter monitoring led to clinically significant improvements in AF prediction beyond the
information provided by the FHS AF score (C-statistic of 0.65 in the FHS AF score alone vs
0.72 after adding atrial ectopy information to the statistical model).24

Imaging—Information on cardiac structure and function obtained from

echocardiographic studies, such as left atrial diameter, left ventricular function, left
ventricular mass, or left ventricular wall thickness, have not demonstrated benefit in the
prediction of AF once demographic and clinical information is considered.5, 25 Whether
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more novel measures of echocardiography-based left atrial function (e.g. left atrial strain by
speckle tracking, tissue Doppler imaging-derived atrial conduction time)26, 27 or other
cardiac imaging modalities (e.g. periatrial epicardial adipose tissue from computerized
tomography)28 can be used for AF prediction remains to be determined.

Genetics—Recent research has identified several common genetic variants associated

with the risk of AF.29 The added value of information on these genetic variants to predict AF
has been explored in at least two different populations. The WHS cohort found that a genetic
risk score, calculated with information on 12 single nucleotide polymorphisms previously
associated with AF, significantly improved prediction, measured with change in C-statistic
and continuous NRI, beyond a clinical risk score in approximately 20,000 women: the C-
statistic increased from 0.72 to 0.74, while the continuous NRI was 0.49 (95%CI 0.30–
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0.67).11 In a similar analysis among 27,471 participants of the Malmö Diet and Cancer
Study, however, a genetic risk score also based on 12 single nucleotide polymorphisms only
minimally improved risk prediction (C-statistic changed from 0.735 to 0.738).30 Notably,
none of these analyses considered information on natriuretic peptides, which are possibly the
strongest biomarkers for AF risk. Future studies should evaluate whether genetic
information improves our ability to predict AF on top of clinical variables and established
AF circulating biomarkers.

Applications of models for AF prediction

Available risk scores, though imperfect, may play a role in identifying individuals at higher
risk of developing AF, particularly the externally validated FHS and CHARGE-AF models.
A follow-up question is whether this information has any clinical or public health
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implications. We think of two major areas in which these scores could be useful: as aids for
selection of high-risk participants to screening programs and primary prevention trials, and
as benchmarks for the testing of potential novel biomarkers of AF risk.

The interest in developing screening programs for identification of asymptomatic AF is

growing.31 AF is responsible for a substantial proportion of strokes, and in a number of
cases, stroke is the first clinical manifestation of AF.32 Identifying individuals with

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asymptomatic AF offers a unique preventive opportunity if AF diagnosis is followed by

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adequate antithrombotic therapy. Restricting screening programs to individuals more likely

to have AF—as identified by one of the validated risk scores—would make those programs
more cost-effective. A similar rationale can be applied to the selection of participants for
primary prevention trials of AF. Currently, there are no established interventions for the
primary prevention of AF. Trials testing such interventions will have to be conducted in
subgroups at higher risk of AF, which will lead to more efficient designs.

Validated risk scores, particularly those including circulating natriuretic peptides as

predictors, can also be used as benchmarks against which novel biomarkers purported to
improve AF prediction can be compared. In this era of “precision medicine,” rigorous
comparisons with extensively validated risk scores are needed to avoid the hype that
frequently surrounds the discovery of novel markers of disease. For example, as summarized
above, adequate testing against a model including natriuretic peptides (BNP or NT-proBNP)
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showed that inflammatory markers such as CRP, despite being associated with increased risk
of AF in observational studies, are not particularly useful in AF prediction.8, 16

PREDICTING STROKE IN PERSONS WITH AF

Cardioembolic stroke is a major complication of AF. Fortunately, oral anticoagulation, either
using vitamin K antagonists or the newer direct oral anticoagulants, has consistently
demonstrated a reduction in the risk of ischemic stroke in persons with AF.33 Oral
anticoagulation, however, is not exempt from complications. Thus, identifying patients with
a higher stroke risk, more likely to benefit from oral anticoagulation, is imperative in AF
treatment. Over the last 15 years several scores and risk stratification schemes have been
developed (Table 2).34–37 Of these, the CHADS2 and CHA2DS2-VASc scores have gained
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the most acceptance, being included in AF treatment guidelines from different professional
organizations across the world.33, 38, 39 Predictors consistently associated with the risk of
stroke in AF patients in the different risk scores include older age, female sex, prior stroke,
hypertension, diabetes, and heart failure.

Despite current recommendations suggesting the use of the CHA2DS2-VASc score for stroke
risk stratification in AF patients, the evidence supporting this score above others is mixed.
Studies that have compared multiple risk scores in the same population have not found
meaningful and consistent differences between the various scores. An analysis of 2720
patients with AF from Olmsted County, Minnesota, in the United States, tested nine different
stratification schemes, reporting similar performance across the models.40 Other studies in
larger populations have reported one scoring system does better than the rest, but these
differences tend not to be clinically relevant and lack consistency across populations.41, 42
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Overall, all scores offer limited discrimination ability (c-statistic <0.7) and, in the end,
decisions to use one approach over another should balance simplicity, availability of data
required for the score calculation, and predictive ability.43 Finally, though some published
studies suggest that circulating biomarkers (e.g. creatinine, troponin, natriuretic peptides, D-
dimer) may improve stroke prediction in AF patients, few of these observations have been
replicated in multiple populations.44–46

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PREDICTING BLEEDING AND OTHER COMPLICATIONS IN PERSONS

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WITH AF
Even though oral anticoagulation in AF reduces the risk of ischemic stroke and systemic
thromboembolism, this benefit is accompanied by an increased bleeding risk. Identifying
individuals at higher risk of bleeding complications when using oral anticoagulants may
facilitate personalized treatments. To date, at least four risk scores for the assessment of
bleeding risk in patients with AF treated with vitamin K antagonists have been published
(summarized in Table 3).47–50 Variables consistently associated with increased bleeding risk
in this patient population include older age, renal disease, and a history of prior bleeding,
with anemia, cancer, and hypertension included in several of the scores. As with the scores
used for stroke risk stratification, the existing bleeding predictive models have only
moderate discrimination and do not differ significantly from each other when applied to the
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same population.51–53 Of note, these scores have been developed for the prediction of
bleeding among persons with AF using vitamin K antagonists. Given the different bleeding
profile of the newer direct oral anticoagulants (NOACs) compared to vitamin K antagonists,
future research should develop bleeding risk scores specifically for patients using NOACs.

AF is associated with an increased risk of other cardiovascular complications beyond

ischemic stroke, such as heart failure or myocardial infarction.54 A limited number of
published studies have developed models for the prediction of these and other endpoints in
persons with AF. For example, investigators from the FHS developed a predictive model
including information on age, body mass index, left ventricular hypertrophy, diabetes,
cardiac murmur, and prior myocardial infarction.55 Though this and other models can help
identify individuals at a particular higher risk of AF-related complications, the clinical
implications of the information provided from those models are unclear since they do not
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translate directly into specific changes in the management of these patients.

NEXT STEPS IN PREDICTION OF AF AND ITS COMPLICATIONS

As summarized in this review, over the last 15 years we have made great advances in our
ability to predict AF and its complications. However, a number of areas require additional
research.

The discriminative ability of models for prediction of AF needs improvement. Additional

work should determine whether novel biomarkers, imaging techniques, and genomic
markers can refine the existing predictive models. Also, current models predict 5- or 10-year
risk of AF in the community. Future efforts may be directed to the development of models
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for the prediction of lifetime risk of AF and models that predict AF using information
obtained from the electronic health records. The usefulness of these predictive models to
implement preventive strategies and screening programs that lead to improved population
health and clinical outcomes has not been determined.

The CHA2DS2-VASc, HAS-BLED and other scores are widely recommended for the risk
stratification of persons with AF. However, multiple studies conducted in diverse settings
have demonstrated that these scores have limited ability to separate those who will develop

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ischemic stroke or other AF-related complications from those who will not. In order to treat
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the right patients at the right time with the right therapies, additional work needs to build
upon the existing scores and improve them.

Finally, with the advent of new therapies for the prevention of cardioembolic stroke in AF,
such as NOACs and left atrial appendage closure devices, new models for the prediction of
complications among persons receiving these novel treatments need to be developed.

Acknowledgments
FUNDING

This work was supported by grant 16EIA26410001 from the American Heart Association, and grant R01-
HL122200 from the National Institutes of Health.
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Table 1

Risk scores and equations for the prediction of atrial fibrillation in the community

Risk model Variables Derivation Performance Validation in external populations Performance

FHS (10-year Age, sex, body mass 4764 participants, C-statistic (95%CI): AGES:64238 participants, 100% white, C-statistic (95%CI): 0.67 (0.64, 0.71)
risk) 5 index, systolic blood 100% white, 55% 0.78 (0.76–0.80) 63% women, mean age 76 Recalibrated χ2 = 16.2 (p = 0.06)
Alonso and Norby

pressure, treatment for women, 45–95 years of χ2 = 4.2 (p = 0.09)

hypertension, PR age, mean age 61
interval, cardiac murmur,
heart failure

CHS:6 5410 participants, 16% African- C-statistic (95%CI): 0.68 (0.66, 0.70) in whites, 0.66
American, 84% white, 60% women, 65 (0.61, 0.71) in African Americans
and older, mean age 75 Recalibrated χ2 = 46.1 (p < 0.001) in whites and 10.6
(p = 0.31) in African Americans

ARIC:7 14,546 participants, 27% C-statistic: 0.68 overall, 0.69 in whites, 0.65 in
African-American, 73% white, 55% African Americans
women, 45–64 years of age

MESA:8 6663 participants, 38% white, C-statistic (95%CI): 0.75 (0.72, 0.77) overall, 0.75
28% African-American, 22% Hispanic, (0.72, 0.78) in whites, 0.74 (0.70, 0.78 in non-whites
12% Chinese-American, 53% women, χ2 = 57.4 (p < 0.001) overall, χ2 = 8.1 (p = 0.53) in
45–84 years of age, mean age 62 whites, χ2 = 73.9 (p <0.001) in non-whites

ARIC (10-year Age, race, height, 14,546 participants, C-statistic: 0.78 None
risk) 7 smoking, systolic blood 27% African-American, χ2 = 10.0 (p = 0.35)
pressure, treatment for 73% white, 55%
hypertension, cardiac women, 45–64 years of
murmur, ECG-based left age
ventricular hypertrophy,
ECG-based left atrial
enlargement, diabetes,
coronary heart disease,
heart failure

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WHS (10-year Age, weight, height, 19,940 participants, C-statistic (95%CI): None
risk) 11 systolic blood pressure, 100% white, 100% 0.72 (0.68–0.75)
alcohol use, smoking women, median age 53 χ2 = 8.1 (p = 0.43)

CHARGE-AF 18,556 participants, C-statistic (95%CI): AGES:12 4469 participants, 100% white, C-statistic (95%CI): 0.66 (0.63, 0.70)
(5-year risk) 12 81% white, 19% 0.77 (0.75–0.78) 60% women, mean age 76 Recalibrated χ2 = 12.6 (p = 0.18)
African-American, 57% χ2 = 9.3 (p = 0.41)
women, 46–94 years of
age, mean age 65

Rotterdam Study:12 3203 participants, C-statistic (95%CI): 0.71 (0.66, 0.75)

100% white, 59% women, mean age 72 Recalibrated χ2 = 16.4 (p = 0.06)

EPIC-Norfolk:13 24,020 participants, C-statistic (95%CI): 0.81 (0.75, 0.85)

>99% white, 55% women, 39–79 years χ2 = 142.2 (p < 0.001)
of age, mean age 59 Recalibrated χ2 = 13.3 (p = 0.15)
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Risk model Variables Derivation Performance Validation in external populations Performance

MESA:8 6663 participants, 38% white, C-statistic (95%CI): 0.78 (0.74, 0.81) overall, 0.76
28% African-American, 22% Hispanic, (0.72, 0.81) in whites, 0.78 (0.72, 0.83 in non-whites
12% Chinese-American, 53% women, χ2 = 25.6 (p = 0.002) overall, χ2 = 14.6 (p = 0.10) in
45–84 years of age, mean age 62 whites, χ2 = 12.3 (p = 0.20) in non-whites

AGES: Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC: Atherosclerosis Risk in Communities Study; CHARGE-AF: Cohorts for Aging and Research in Genomic Epidemiology—Atrial
Alonso and Norby

Fibrillation; CHS: Cardiovascular Health Study; CI: Confidence interval; EPIC: European Prospective Investigation into Cancer and Nutrition; FHS: Framingham Heart Study; MESA: Multi-Ethnic Study
of Atherosclerosis; WHS: Women’s Health Study

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Table 2

Risk stratification schemes for stroke prediction in AF patients

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Risk score CHADS2 34 CHA2DS2-VASc 35 Framingham 36 ATRIA 37

Variables Heart failure Heart failure Age Age

Hypertension Hypertension Female sex Female sex
Age Age Systolic blood pressure Diabetes
Diabetes Diabetes Prior stroke / TIA Heart failure
Prior stroke / TIA Female sex Diabetes Hypertension
Prior stroke / TIA Proteinuria
Vascular disease Reduced kidney function or ESRD
Prior stroke

ESRD: End-stage renal disease; TIA: transient ischemic stroke

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Table 3

Risk stratification schemes for bleeding prediction in AF patients using vitamin K antagonists
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Risk score HEMORR2HAGES 47 HAS-BLED 48 ATRIA 49 ORBIT-AF 50

Variables Age Age Age Age

Hepatic / renal disease Abnormal renal / liver function Renal disease Abnormal kidney function
Hypertension Hypertension Hypertension Prior bleeding
Prior bleeding Prior bleeding Prior bleeding Anemia
Stroke Stroke Anemia Antiplatelet use (heart failure) (cancer)
Alcohol abuse Drugs/alcohol (COPD) (hip fracture / osteoporosis)
Anemia Labile INR (smoking)
Cancer
Reduced platelet count / function
Genetic factors
Fall risk

INR: International Normalized Ratio

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