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Original Investigation | Cardiology
Evaluation of the Age, Biomarkers, and Clinical History–Bleeding
Risk Scorein Patients With Atrial Fibrillation With Combined
Aspirin and AnticoagulationTherapy Enrolled in the ARISTOTLE and
RE-LY TrialsZiad Hijazi, MD, PhD; Jonas Oldgren, MD, PhD; Johan
Lindbäck, MSc; John H. Alexander, MD, MHS; Marco Alings, MD, PhD;
Raffaele De Caterina, MD, PhD;John W. Eikelboom, MD; Michael D.
Ezekowitz, MBChB, DPhil; Claes Held, MD, PhD; Kurt Huber, MD;
Elaine M. Hylek, MD, MPH; Christopher B. Granger, MD;Renato D.
Lopes, MD, PhD; Dragos Vinereanu, MD, PhD; Agneta Siegbahn, MD,
PhD; Lars Wallentin, MD, PhD
Abstract
IMPORTANCE Most patients with atrial fibrillation (AF) and
coronary artery disease have indicationsfor preventing stroke with
oral anticoagulation therapy and preventing myocardial infarction
andstent thrombosis with platelet inhibition.
OBJECTIVE To evaluate whether the recently developed ABC (age,
biomarkers, and clinical history)–bleeding risk score might be
useful to identify patients with AF with different risks of
bleeding duringconcomitant aspirin and anticoagulation therapy.
DESIGN, SETTING, AND PARTICIPANTS The biomarkers in the
ABC-bleeding risk score (growthdifferentiation factor 15,
hemoglobin, and troponin) were measured in blood samples collected
atrandomization between 2006 and 2010 in the ARISTOTLE (Apixaban
for Reduction in Stroke andOther Thromboembolic Events in Atrial
Fibrillation) trial and between 2005 and 2009 in the
RE-LY(Randomized Evaluation of Long-term Anticoagulation Therapy)
trial, both of which weremultinational randomized clinical trials.
The trials were reported 2011 and 2009, respectively. A totalof 24
349 patients with AF (14 980 patients from the ARISTOTLE trial and
9369 patients from theRE-LY trial) were analyzed in the present
cohort study. The median (interquartile range) length offollow-up
was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3)
years in the RE-LY cohort.Data analysis was performed from February
2018 to June 2019.
EXPOSURES Concomitant aspirin treatment during study
follow-up.
MAIN OUTCOMES AND MEASURES Time to first occurrence of a major
bleeding was determinedaccording to International Society on
Thrombosis and Hemostasis definition. Hazard ratios wereestimated
with Cox models adjusted for ABC-bleeding risk score and randomized
treatment.
RESULTS The median (interquartile range) age was 70 (63-76)
years in the ARISTOTLE cohort and72 (67-77) years in the RE-LY
cohort (5238 patients [35.6%] in the ARISTOTLE cohort and
3086patients [36.4%] in the RE-LY cohort were women). The total
number of patients with a first majorbleeding event was 651 (207
with aspirin and 444 without) in ARISTOTLE and 463 (238 with
aspirinand 225 without) in RE-LY. For both cohorts, in those with a
low ABC-bleeding risk score, the absolutebleeding rate was low even
with concomitant aspirin treatment, whereas in those with a
higherABC-bleeding risk score, the rate of bleeding was higher with
concomitant aspirin compared with oralanticoagulation alone
(ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P < .001;
RE-LY, hazard ratio,1.70; 95% CI, 1.42-2.04; P < .001). Thus, a
low annual ABC-bleeding risk (eg, 0.5% without aspirinuse) would
with concomitant aspirin result in an annual rate of 0.8%, and a
high estimatedABC-bleeding risk (eg, 3.0%) would result in a
substantially higher rate of 5.0%.
(continued)
Key PointsQuestion Is the recently developedABC (age,
biomarkers, and clinical
history)–bleeding risk score for patients
with atrial fibrillation (AF) useful to
identify patients with different risks of
bleeding during concomitant aspirin and
anticoagulation therapy?
Findings This cohort study examined atotal of 24 349 patients
with AF from 2
randomized clinical trials and found that
the ABC-bleeding risk score identified
patients with different risks of bleeding
when combining aspirin and oral
anticoagulation.
Meaning The ABC-bleeding risk scoremay be a useful tool for
decision support
concerning intensity and duration of
combination antithrombotic treatment
in patients with AF and coronary
artery disease.
+ Invited Commentary+ Supplemental contentAuthor affiliations
and article information arelisted at the end of this article.
Open Access. This is an open access article distributed under
the terms of the CC-BY License.
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Abstract (continued)
CONCLUSIONS AND RELEVANCE These findings suggest that the
ABC-bleeding risk scoreidentifies patients with different risks of
bleeding when combining aspirin and oral anticoagulation.The
ABC-bleeding risk score may, therefore, be a useful tool for
decision support concerning intensityand duration of combination
antithrombotic treatment in patients with AF and coronaryartery
disease.
JAMA Network Open. 2020;3(9):e2015943.
doi:10.1001/jamanetworkopen.2020.15943
Introduction
In patients with atrial fibrillation (AF) and coronary artery
disease (CAD), there are indications forpreventing stroke with oral
anticoagulation therapy and preventing myocardial infarction (MI)
andstent thrombosis with platelet inhibition.1,2 However, as the
antithrombotic therapy intensifies, therisk of major bleeding
increases.3 This is a well-known, and rather frequently
encountered, dilemmain clinical practice, because approximately 20%
to 30% of patients with AF also have concomitantCAD.4-6
International guidelines1,2 recommend an individual risk-benefit
assessment to tailor theantithrombotic treatment and its duration
to an optimally balanced risk of ischemic events vs risk
ofbleeding. However, current bleeding risk scores provide limited
guidance in the setting of AF andconcomitant CAD.5 Recently, the
ABC (age, biomarkers, and clinical history)–bleeding risk score
wasdeveloped and validated in patients with AF receiving oral
anticoagulation therapy for estimation ofmajor bleeding events.7
The biomarker-based ABC-bleeding risk score outperformed other
riskscores based on clinical variables, such as the HAS-BLED
(hypertension, abnormal renal and liverfunction, stroke, bleeding,
labile international normalized ratio, elderly, drugs or alcohol)
score.Importantly, the ABC-bleeding risk score was also shown to be
well-calibrated in several cohorts ofpatients with AF.7,8 The
ABC-bleeding score has, therefore, been mentioned in the recent
EuropeanAF and Dual Antiplatelet Therapy guidelines1,2 as a
possible tool to estimate risk of major bleeding inpatients with
AF. In this cohort study, we evaluated whether the ABC-bleeding
risk score might beuseful to identify patients with different risks
of bleeding during concomitant antiplatelet (aspirin)and
anticoagulation therapy based on 9369 patients from the RE-LY
(Randomized Evaluation ofLong-term Anticoagulation Therapy) trial9
and 14 980 patients with AF from the ARISTOTLE(Apixaban for
Reduction in Stroke and Other Thromboembolic Events in Atrial
Fibrillation) trial.10 Wehypothesized that the biomarker-based
ABC-bleeding risk score can differentiate between thebleeding risk
in patients with AF taking oral anticoagulation and concomitant
aspirin.
Methods
The ARISTOTLE trial randomized 18 201 patients with AF and an
increased risk of stroke to warfarinor apixaban and was reported in
2011.10,11 Biomarker samples were available at baseline for 14
697participants, with a median (interquartile range) length of
follow-up of 1.8 (1.3-2.3) years. The RE-LYtrial randomized 18 113
patients with AF to dabigatran or warfarin and was reported in
2009.9,12
Biomarker samples were available at baseline for 8468
participants, with a median (interquartilerange) length of
follow-up of 2.0 (1.6-2.3) years. Overall, both the ARISTOTLE and
RE-LY biomarkercohorts were representative of each respective study
cohort and have been described in detailelsewhere.13,14
Institutional review board or ethics committee approval was
obtained at all sites forboth trials, and all patients provided
written informed consent, including consent for the
biomarkersubstudy program. This study follows the Strengthening the
Reporting of Observational Studies inEpidemiology (STROBE)
reporting guideline.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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Outcome AssessmentIn both the ARISTOTLE and the RE-LY trials,
the primary safety outcome was major bleeding definedaccording to
the International Society on Thrombosis and Hemostasis.9,10 Blinded
clinical eventcommittees reviewed and centrally adjudicated the
outcome events.
Biochemical MethodsIn both the ARISTOTLE and RE-LY studies,
blood samples were collected at randomization into EDTAtubes and
immediately centrifuged, frozen in aliquots, and stored at −70 °C
until analyzed centrallyat the Uppsala Clinical Research Center
laboratory in Uppsala, Sweden. High-sensitive cardiactroponin T and
N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were
analyzed withhigh-sensitivity immunoassays on the Cobas Analytics
e601 (Roche Diagnostics), and growthdifferentiation factor–15
(GDF-15) levels were detected with the Elecsys growth
differentiationfactor–15 precommercial assay kit P03 with the same
standardization as the recently introducedroutine reagent (Roche
Diagnostics). All analyses were performed according to the
instructions of themanufacturer and have been described
elsewhere.15-17
Statistical AnalysisAll patients with no missing values for the
variables included in the ABC-bleeding score (prior strokeor
transient ischemic attack, age, high-sensitive cardiac troponin,
and N-terminal prohormone ofbrain natriuretic peptide) measured at
baseline were included in the analyses. The ABC-bleedingscore was
defined in this study as the estimated 1-year major bleeding
risk.
The consistency of the ABC-bleeding score with concomitant
aspirin use was assessed using aCox regression model. The model
included aspirin use and the estimated 1-year ABC-bleeding risk asa
restricted cubic spline, with 4 knots placed at the 5th, 35th,
65th, and 95th sample percentiles,and the interaction between
aspirin status and the linear part of the ABC-bleeding risk. If the
test ofthe interaction was not significant, a model excluding the
interaction term was fitted to estimate therelative hazard of
bleeding according to aspirin use. The fitted model was also used
to estimate theabsolute increase in bleeding for 2 examples of low
(0.5%) and high (3.0%) ABC-bleeding riskswithout aspirin. These
examples were chosen because there are no established cutoffs for
low orhigh annual major bleeding risks in patients with AF;
previously, risks below 1% and above 2% havebeen indicated,
although not established.18
In the ARISTOTLE trial, aspirin use was recorded continuously
during follow-up and wastherefore included as a time-updated
covariate in the model. In the RE-LY trial, a patient wasassumed to
be taking aspirin if she or he was taking aspirin at any time
during follow-up. The modelsdid not include any further adjustment
for confounders because the ABC-bleeding risk score
alreadyincorporates the main risk factors for major bleeding and
further adjustment would not be expectedto improve the model.7
Nevertheless, in a sensitivity analysis of the ARISTOTLE data, a
Cox regression model includingpotential baseline and time-updated
confounders was fitted. Baseline variables included age,
sex,diabetes, hypertension, history of MI, history of peripheral
arterial disease, and history of vasculardisease. Postrandomization
variables included whether the patient was currently taking the
studydrug, MI, angina, percutaneous coronary intervention, coronary
stenting, nonmajor bleeding andinteractions between prior MI and
nonmajor bleeding, MI and nonmajor bleeding, study drug andangina,
study drug and percutaneous coronary intervention, and nonmajor
bleeding. The resultswere materially unaltered compared with the
unadjusted model; therefore, we only present theresults from the
simpler model. Furthermore, the 3-way interaction between the
ABC-bleeding riskscore, aspirin use, and study treatment was
evaluated by fitting a Cox model including theABC-bleeding risk
score, a treatment combination variable (aspirin or no aspirin in
combination withwarfarin or apixaban in ARISTOTLE, and warfarin or
dabigatran [110 mg or 150 mg] in RE-LY) and theinteraction between
the ABC-bleeding risk score and the treatment combination
variable.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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Results from all models are presented graphically as plots of
hazard ratios (HRs) with anarbitrary reference point set to 2.0%
1-year ABC-bleeding risk in the no-aspirin group. TheABC-bleeding
and HAS-BLED risk scores were calculated according to
previouslydescribed methods.7
All tests were 2-sided, with P < .05 denoting statistical
significance. All analyses were doneusing R statistical software
version 3.6.1 (R Project for Statistical Computing). Data analysis
wasperformed from February 2018 to June 2019.
Results
Baseline CharacteristicsA total of 24 349 patients with AF were
analyzed in the present cohort study. The median(interquartile
range) age was 70 (63-76) years in the ARISTOTLE cohort and 72
(67-77) years in theRE-LY cohort; 5238 patients (35.6%) in the
ARISTOTLE cohort and 3086 patients (36.4%) in theRE-LY cohort were
women. The characteristics according to concomitant aspirin use or
no aspirin useare shown in Table 1 for the ARISTOTLE and RE-LY
cohort. The proportion of patients takingconcomitant aspirin was
31.0% (4638 patients) at day 1 in the ARISTOTLE cohort and
approximately20% on any day after day 1.4 In the RE-LY cohort, the
proportion of patients taking concomitantaspirin at any time during
follow-up was 36.4% (3413 patients). In both cohorts, a higher
proportionof patients receiving concomitant aspirin had vascular
disease (eg, prior MI, CAD, or peripheral arterydisease). The
presence of diabetes was also more common in patients with
concomitant aspirin.Patients with prior vitamin K antagonist use
were more common in the group withoutconcomitant aspirin.
Risk of Major Bleeding With Concomitant Aspirin Use and
ABC-Bleeding Risk ScoreARISTOTLE CohortThe total number of patients
with a first major bleeding event was 651 (207 while taking aspirin
and444 while not taking aspirin) during 24 903 person-years of
follow-up. The annual rate of majorbleeding during follow-up was
higher in patients taking aspirin than in those not taking
aspirin(4.04% vs 2.24%) (Table 2). The bottom quarter of the
patients had an estimated ABC-bleeding riskless than 1.1% annually.
In these patients, the absolute bleeding risk was low even with
concomitantaspirin treatment (Figure 1A). In those in the top
quarter with an ABC-bleeding risk greater than2.5%, the absolute
risk of bleeding was higher with concomitant aspirin compared with
oralanticoagulation alone (Figure 1A). The P value for the test of
the null hypothesis of no multiplicativeinteraction was .07. In a
model without the interaction term, adjusted for ABC-bleeding risk
score andrandomized treatment, concomitant aspirin treatment
increased bleeding significantly (HR, 1.65;95% CI, 1.40-1.95; P
< .001). Thus, a low ABC-bleeding risk score without aspirin
(eg, 0.5% annually)would with concomitant aspirin result in an
annual rate of 0.8%, and a high estimated ABC-bleedingrisk score
without aspirin (eg, 3.0% annually) would result in a substantially
higher absolute annualrate for major bleeding of 5.0%.
The observed event rate for major bleeding as a function of the
ABC-bleeding score by thedifferent combinations of antithrombotic
treatment is shown in Figure 2. At low estimated bleedingrisk with
the ABC-bleeding score, the model showed good calibration. With
higher estimatedbleeding risk, concomitant use of aspirin conferred
higher than estimated bleeding rates.
RE-LY CohortThe total number of patients with first major
bleeding events was 463 (238 with aspirin and 225without) during 16
212 person-years of follow-up. The annual rate of major bleeding
during follow-upwas higher in patients with aspirin than without
aspirin (4.18% vs 2.14%) (Table 2). Overall, the resultsin the
RE-LY cohort were similar to those of the ARISTOTLE cohort. The
bottom quarter of thepatients had an estimated ABC-bleeding risk
less than 1.3%, whereas the top quarter had an
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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ABC-bleeding risk greater than 2.8%. The relative hazard of
major bleeding associated with aspirinuse was similar across the
full range of the ABC-bleeding risk score (Figure 1B; P for
interaction = 0.2).In Cox models adjusted for ABC-bleeding risk
score and randomized treatment, concomitant aspirintreatment
increased bleeding significantly (HR, 1.70; 95% CI, 1.42-2.04; P
< .001). Thus, a lowABC-bleeding risk score without aspirin (eg,
0.5% annually) would with concomitant aspirin result in
Table 1. Baseline Characteristics in the ARISTOTLE Cohort by
Aspirin Status on Day 1 (Day of Randomization) and in the RE-LY
Cohort by Aspirin StatusDuring Follow-up, Anytime During the Study,
Including Biomarkers Used in the ABC-Bleeding Score
Variable
Patients, No. (%)
ARISTOTLE RE-LY
No aspirin (n = 10 342) Aspirin (n = 4638) No aspirin (n = 5956)
Aspirin (n = 3413)Randomized treatment: warfarin 5193 (50.2) 2289
(49.4) 1985 (33.3) 1144 (33.5)
Received dabigatran
110 mg NA NA 1972 (33.1) 1137 (33.3)
150 mg NA NA 1999 (33.6) 1132 (33.2)
Age, y, median (IQR) 70.0 (62.0-76.0) 70.0 (63.0-76.0) 72.0
(67.0-77.0) 72.0 (67.0-78.0)
Female 3769 (36.4) 1562 (33.7) 2275 (38.2) 1133 (33.2)
Body mass index, median (IQR)a 28.5 (25.3-32.5) 28.6 (25.3-32.8)
28.0 (25.1-31.6) 27.9 (25.1-31.2)
Missing values, No. 49 22 3 4
Systolic blood pressure, mm Hg, median (IQR) 130.0 (120.0-140.0)
130.0 (120.0-140.0) 130.0 (120.0-142.0) 130.0 (120.0-140.0)
Missing values, No. 25 8 8 5
Diabetes 2454 (23.7) 1243 (26.8) 1196 (20.1) 883 (25.9)
Hypertension 8961 (86.6) 4153 (89.5) 4660 (78.2) 2731 (80.0)
Current smoker 870 (8.4) 349 (7.5) 467 (7.8) 254 (7.4)
Missing values, No. 12 2
Alcohol 264 (2.6) 114 (2.5) 866 (14.5) 456 (13.4)
Permanent or persistent atrial fibrillation 8865 (85.7) 3846
(82.9) 4255 (71.5) 2078 (60.9)
Missing values, No. 3 0 2 2
Prior stroke or transient ischemic attack 1948 (18.8) 861 (18.6)
1159 (19.5) 664 (19.5)
Prior bleeding 1701 (16.4) 736 (15.9) 678 (11.4) 505 (14.8)
Anemia 665 (6.4) 342 (7.4) 678 (11.4) 505 (14.8)
Missing values, No. 6 5 0 0
Heart failure 3115 (30.1) 1536 (33.1) 1685 (28.3) 1026
(30.1)
Missing values, No. 0 0 1 0
Prior myocardial infarction 1008 (9.7) 918 (19.8) 747 (12.5) 842
(24.7)
Missing values, No. 1 0 0 0
Prior peripheral arterial disease 456 (4.4) 274 (5.9) 186 (3.1)
159 (4.7)
Missing values, No. 1 0 1 0
Prior vascular disease 2028 (19.6) 1695 (36.5) 882 (14.8) 937
(27.5)
Warfarin within 7 d of randomization 6455 (62.5) 1582 (34.2)
4397 (73.8) 1609 (47.1)
Missing values, No. 18 11 0 0
Estimated glomerular filtration rate, mL/min, median (IQR) 74.5
(57.0-96.0) 73.1 (56.1-93.8) 65.5 (54.5-77.4) 63.7 (52.7-76.4)
Missing values, No. 37 15 68 23
Growth differentiation factor 15, ng/L, median (IQR) 1348.0
(965.0-1992.0) 1464.0 (1005.0-2216.0) 1476.0 (1092.0-2124.0) 1592.0
(1142.2-2338.0)
Missing values, No. 117 65 467 251
High-sensitive cardiac troponin T, ng/L, median (IQR) 10.7
(7.4-16.3) 11.6 (7.8-17.6) 11.7 (7.5-18.8) 13.1 (8.2-20.6)
Missing values, No. 49 34 417 233
Hemoglobin, g/dL, median (IQR) 14.3 (13.2-15.3) 14.2 (13.1-15.3)
14.3 (13.3-15.3) 14.2 (13.1-15.3)
Missing values, No. 53 17 100 59
Abbreviations: ABC, age, biomarkers, and clinical history;
ARISTOTLE, Apixaban forReduction in Stroke and Other Thromboembolic
Events in Atrial Fibrillation; IQR,interquartile range; NA, not
applicable; RE-LY, Randomized Evaluation of
Long-termAnticoagulation Therapy.
SI conversion factor: To convert hemoglobin to grams per liter,
multiply by 10.0.a Body mass index is calculated as weight in
kilograms divided by height in
meters squared.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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an annual rate of 0.85%, and a high estimated ABC-bleeding risk
score without aspirin, (eg, 3.0%annually) would result in a
substantially higher annual rate for major bleeding of 5.1%.
Sensitivity Analyses According to Different Oral Anticoagulant
TherapiesAlthough limited by a smaller number of events,
sensitivity analyses were performed in relation todifferent oral
anticoagulant therapies. The results were similar between the
ARISTOTLE cohort(warfarin, HR, 1.62 [95% CI, 1.30-2.02]; apixaban,
HR, 1.69 [95% CI, 1.32-2.18]) (Figure 3A) and theRE-LY cohort
(warfarin, HR, 1.77 [95% CI, 1.29-2.42]; dabigatran 110 mg, HR,
1.50 [95% CI, 1.08-2.07];dabigatran 150 mg, HR, 1.84 [95% CI,
1.34-2.52]) (Figure 3B).
Comparison With the HAS-BLED Score and Discriminatory ValueThe
risk of major bleeding according to the HAS-BLED score in patients
with oral anticoagulationtaking aspirin compared with those not
taking aspirin are shown in eFigure in the Supplement.
Thediscriminatory ability to estimate the risk of major bleeding in
patients with AF treated with oralanticoagulation and concomitant
aspirin was 0.62 and 0.63 for the HAS-BLED score in theARISTOTLE
and RE-LY cohorts, and 0.68 and 0.72 for the ABC-bleeding score,
respectively.Additionally, the information gained from these risk
scores was also assessed in models containingboth scores (eTable in
the Supplement). This showed that the ABC-bleeding risk score
remainedsignificant in the model, whereas the HAS-BLED score was no
longer significant (eFigure in theSupplement).
Discussion
The main findings in this study are that the ABC-bleeding risk
score is able to stratify patients with AFreceiving the combination
of aspirin and oral anticoagulation according to their risk of
bleeding. Alow estimated risk of major bleeding according to the
ABC-bleeding risk score showed a low bleedingrisk even with
concomitant aspirin treatment, whereas a higher ABC-bleeding risk
score wasassociated with higher bleeding risk. These findings
suggest that the ABC-bleeding risk score may bea useful tool for
decision support concerning intensity and duration of combination
antithrombotictreatment in patients with AF and CAD to improve the
risk-benefit balance with differentantithrombotic strategies.
The added value of biomarkers for improved risk estimation in
patients with AF have so far beenrather consistent in several
cohorts, including randomized clinical trial cohorts, as well as
lessselected observational registry cohorts.19-21 The ABC-bleeding
risk score, which includes the mostrelevant variables, including
both biomarkers and clinical data, was developed and validated
usingrobust methods and very large cohorts of patients with
AF.7,22,23 The ABC-bleeding risk scoreoutperforms traditional risk
scores for stroke, death, and major bleeding, in comparison with
riskscores based on clinical variables. In addition, the
ABC-bleeding risk score has shown to be wellcalibrated, with
estimated risk aligning well with observed risk during
follow-up.7,22,23 Biomarkers
Table 2. Event Rates of Major Bleeding
Groupa Patients, No. Events, No. Person-years, No.Incidence
rate/100person-years (95% CI)
ARISTOTLE
No aspirin 11 943 444 19 781 2.24 (2.04-2.46)
Aspirin 4987 207 5122 4.04 (3.51-4.63)
Total 14 697 651 24 903 2.61 (2.42-2.82)
RE-LY
No aspirin 5372 225 10 519 2.14 (1.87-2.44)
Aspirin 3096 238 5693 4.18 (3.67-4.75)
Total 8468 463 16 212 2.86 (2.60-3.13)
Abbreviations: ARISTOTLE, Apixaban for Reduction inStroke and
Other Thromboembolic Events in AtrialFibrillation; RE-LY,
Randomized Evaluation of Long-term Anticoagulation Therapy.a
ARISTOTLE data are based on time-updated aspirin
data. RE-LY data are based on aspirin data fromanytime during
the study.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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and the ABC-bleeding risk scores in patients with AF have,
therefore, been suggested as potentialnew tools for improved risk
estimation in the latest European guidelines for management of
AF.1
Similarly, the European Dual Antiplatelet Therapy guidelines
refer to, among others, theABC-bleeding risk score as a possible
tool to estimate bleeding risk in patients with AF with
anindication for added antiplatelet therapy to assess the bleeding
risk and make informed decisionsregarding the intensity and
duration of concomitant antiplatelet therapy.2 Patients with AF and
CADconsidered to have a high ischemic risk (eg, because of acute
coronary syndrome or other anatomicalor procedural characteristics)
should, according to the guidelines, be considered for a more
intenseand prolonged antithrombotic strategy. If these patients are
considered to have a high risk ofbleeding, a less intense and
shorter duration of concomitant antiplatelet therapy is suggested
in theguidelines. To our knowledge, the present study is the first
to evaluate the ABC-bleeding risk scorein patients with AF and
chronic CAD receiving concomitant single-antiplatelet therapy vs
oral
Figure 1. Relative Hazard of Major Bleeding Comparing Patients
With OralAnticoagulation Taking Aspirin With Patients Not Taking
Aspirinby Estimated 1-Year Risk According to the ABC (Age,
Biomarkers,and Clinical History)–Bleeding Risk Score
10
3
1
0.3
0.1
0.03
Rela
tive
haza
rd
1-y ABC bleeding risk0 0.02 0.04 0.06 0.08 0.10
AspirinNo aspirin
ARISTOTLE cohortA
10
30
3
1
0.3
0.1
0.03
Rela
tive
haza
rd
1-y ABC bleeding risk0 0.02 0.04 0.06 0.08 0.10
AspirinNo aspirin
RE-LY cohortB
Graphs show relative hazards (lines) and 95% CIs (shaded areas)
for theARISTOTLE (Apixaban for Reduction in Stroke and Other
ThromboembolicEvents in Atrial Fibrillation) (A) and RE-LY
(Randomized Evaluation of Long-termAnticoagulation Therapy) (B)
cohorts. The bottom of each panel shows thedistribution of the
patients with ABC-bleeding risk scores as a density plot foreach
group at baseline.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
JAMA Network Open. 2020;3(9):e2015943.
doi:10.1001/jamanetworkopen.2020.15943 (Reprinted) September 16,
2020 7/13
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anticoagulation, and our findings support that the ABC-bleeding
risk score is useful for estimatingbleeding risk in such
patients.
The landmark non–vitamin K antagonist oral anticoagulant (NOAC)
trials24 have showed thatpatients taking NOACs have similar or
lower risks of major bleeding in comparison with patientstaking
warfarin. Furthermore, substudies from these NOAC trials have shown
that the risk of majorbleeding increases with concomitant use of
aspirin, although with preserved safety with NOACscompared with
warfarin; for example, even if the risk of major bleeding increases
with concomitantantiplatelet therapy in both the NOAC as well as
the warfarin groups, the relative risk is still lower
withNOACs.4,25-27 Nonetheless, in some patients, the risk of
ischemic events may warrant a moreaggressive antithrombotic
treatment strategy. Recent randomized clinical trials have
repeatedlyhighlighted the changing balance between benefits and
risks with increasing intensity ofantithrombotic treatment. For
instance, the COMPASS trial,28 which compared the use of
dualtherapy (low-dose rivaroxaban in combination with aspirin) with
single-antithrombotic therapy(aspirin alone) in patients with
stable CAD without AF, found that the combination of
low-doserivaroxaban with aspirin significantly reduced the risk of
ischemic cardiovascular events. However,this comes at a cost of
increased risk of major bleeding events. A similar pattern is also
evident earlyafter coronary events (ie, percutaneous coronary
interventions and/or acute coronary syndromes)when comparing
triple- and dual-antithrombotic therapy strategies in patients with
AF.29,30 Thesestudies consistently show that the risk of clinically
relevant, as well as major, bleeding events aresubstantially lower
with less-aggressive antithrombotic treatment strategies (ie, dual-
vs triple-antithrombotic therapy).29,30 However, this might, to
varying degrees, come at the price of anincreased risk of ischemic
events, including stent thrombosis.29-31 Risk score models that
improve therisk stratification concerning bleeding events would
thus be useful to better identify patients for
Figure 2. One-Year Risk of Major Bleeding Rate as a Function of
the ABC(Age, Biomarkers, and Clinical History)–Bleeding Score by
DifferentTreatment Combinations
32
2
4
8
16
0.10
0.25
0.50
1
Obs
erve
d ev
ent r
ate,
%/y
1-y ABC bleeding risk, %0.5 1 2 4 8
Warfarin with aspirinWarfarin without aspirinApixaban with
aspirinApixaban without aspirin
Lines denote hazard ratios. Shaded areas denote 95% CIs. The
solid black lineindicates perfect calibration. The bottom of the
graph shows the distribution ofthe patients with ABC-bleeding risk
scores as a density plot for each group atbaseline.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
JAMA Network Open. 2020;3(9):e2015943.
doi:10.1001/jamanetworkopen.2020.15943 (Reprinted) September 16,
2020 8/13
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whom more intensive antithrombotic therapy is suitable. By
providing an individualized treatmentstrategy, these models would
also improve patient outcomes.
In the present study, we expanded on previous findings by
showing that the biomarker-basedABC-bleeding risk score
successfully identifies patients with different risks of bleeding
whencombining single-antiplatelet therapy with aspirin and oral
anticoagulation. The ABC-bleeding riskscore may, therefore, be a
useful tool for decision support concerning the intensity and
duration ofcombination antithrombotic treatment in patients with AF
and stable CAD. However, it is importantto keep in mind that
concomitant use of aspirin will offset the calibration of the
ABC-bleeding score,because the observed risk of bleeding will
increase by adding concomitant antiplatelet therapy.
LimitationsThis study has limitations that should be addressed.
The patients in the ARISTOTLE trial wereclinically stable, and the
biomarkers used in the ABC-bleeding risk score, in particular
troponin, will beaffected in patients with acute coronary
syndromes. Thus, the ABC-bleeding risk score shouldpreferably be
assessed at a later time point, such as during routine outpatient
postdischargecheck-up, for the most accurate ABC-bleeding risk
estimation. Because antiplatelet therapy was notrandomized, there
may be confounding by indication, and thus evaluation of ischemic
risks was notperformed. For the ARISTOTLE data, it was possible to
use an advanced statistical model in whichaspirin was used as a
time-updated covariable. In the RE-LY cohort, the status of
concomitantantiplatelet therapy was defined as any time during the
study and may not completely reflect themedication during study
follow-up. Nevertheless, the results were very consistent between
the 2cohorts. Furthermore, as with every risk score, a prospective
evaluation of the risk score such as the
Figure 3. Relative Risk of Major Bleeding by Study Treatment
10
30
3
1
0.3
0.1
0.03
Rela
tive
haza
rd
1-y ABC bleeding risk
1-y ABC bleeding risk
Warfarin
0 0.02 0.04 0.06 0.08 0.10
1-y ABC bleeding risk
Apixaban
ARISTOTLE trialA
0 0.02 0.04 0.06 0.08 0.10
30
10
3
1
0.1
0.3
0.03
Rela
tive
haza
rd
WarfarinRE-LY trialB
0 0.02 0.04 0.06 0.08 0.10
1-y ABC bleeding risk
Dabigatran 150 mg
0 0.02 0.04 0.06 0.08 0.10
1-y ABC bleeding risk
Dabigatran 110 mg
0 0.02 0.04 0.06 0.08 0.10
AspirinNo aspirin
Graphs show data for the ARISTOTLE (Apixaban for Reduction in
Stroke and OtherThromboembolic Events in Atrial Fibrillation) (A)
and RE-LY (Randomized Evaluation ofLong-term Anticoagulation
Therapy) (B) cohorts. Lines denote hazard ratios. Shaded
areas denote 95% CIs. The bottom of each panel shows the
distribution of the patientsABC (age, biomarkers, and clinical
history)–bleeding risk scores as a density plot for eachgroup at
baseline.
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
JAMA Network Open. 2020;3(9):e2015943.
doi:10.1001/jamanetworkopen.2020.15943 (Reprinted) September 16,
2020 9/13
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(NHT) User on 06/05/2021
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ongoing ABC-AF study (ClinicalTrials.gov identifier NCT03753490)
is desirable to fully assess the clinicalusefulness of the
ABC-bleeding score for better tailoring of antithrombotic treatment
strategies.
Conclusions
The ABC-bleeding risk score accurately identifies patients with
different risks of bleeding whencombining aspirin and oral
anticoagulation; low ABC-bleeding risk scores were associated with
lowbleeding risk, and higher ABC-bleeding risk scores were
associated with higher bleeding risk. Thesedata suggest that the
ABC-bleeding risk score may provide useful information concerning
intensityand duration of combination antithrombotic treatment in
patients with AF and stable CAD.
ARTICLE INFORMATIONAccepted for Publication: June 24, 2020.
Published: September 16, 2020.
doi:10.1001/jamanetworkopen.2020.15943
Open Access: This is an open access article distributed under
the terms of the CC-BY License. © 2020 Hijazi Z et al.JAMA Network
Open.
Corresponding Author: Ziad Hijazi, MD, PhD, Uppsala Clinical
Research Center, Uppsala University, UppsalaScience Park, SE-752 37
Uppsala, Sweden ([email protected]).
Author Affiliations: Department of Medical Sciences, Cardiology,
Uppsala University, Uppsala, Sweden (Hijazi,Oldgren, Held,
Wallentin); Uppsala Clinical Research Center, Uppsala University,
Uppsala, Sweden (Hijazi, Oldgren,Lindbäck, Held, Siegbahn,
Wallentin); Duke Clinical Research Institute, Duke Medicine,
Durham, North Carolina(Alexander, Granger, Lopes); University
Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
(Alings);University Cardiology Division, University of Pisa, Pisa,
Italy (De Caterina); Population Health Research Institute,Hamilton,
Ontario, Canada (Eikelboom); Sidney Kimmel Medical College, Thomas
Jefferson University,Philadelphia, Pennsylvania (Ezekowitz);
Cardiovascular Medicine, Lankenau Institute for Medical
Research,Wynnewood, Pennsylvania (Ezekowitz); Wilhelminenhospital,
3rd Department of Medicine, Cardiology andIntensive Care Medicine,
Medical Faculty, Sigmund Freud University, Vienna, Austria (Huber);
CardiovascularMedicine, Boston University School of Medicine,
Boston, Massachusetts (Hylek); University and EmergencyHospital,
University of Medicine and Pharmacy Carol Davila, Bucharest,
Romania (Vinereanu); Clinical Chemistry,Department of Medical
Sciences, Uppsala University, Uppsala, Sweden (Siegbahn).
Author Contributions: Dr Hijazi and Mr Lindbäck had full access
to all of the data in the study and takeresponsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Hijazi, Oldgren, Lindbäck, Eikelboom,
Ezekowitz, Hylek, Granger, Vinereanu, Wallentin.
Acquisition, analysis, or interpretation of data: Hijazi,
Oldgren, Lindbäck, Alexander, Alings, De Caterina,Eikelboom,
Ezekowitz, Held, Huber, Hylek, Lopes, Vinereanu, Siegbahn,
Wallentin.
Drafting of the manuscript: Hijazi.
Critical revision of the manuscript for important intellectual
content: All authors.
Statistical analysis: Lindbäck.
Obtained funding: Hijazi, Oldgren, Eikelboom, Siegbahn,
Wallentin.
Administrative, technical, or material support: Ezekowitz,
Siegbahn, Wallentin.
Supervision: Oldgren, De Caterina, Ezekowitz, Hylek, Vinereanu,
Siegbahn, Wallentin.
Conflict of Interest Disclosures: Dr Hijazi reported receiving
lecture fees from Boehringer Ingelheim, Bristol-Myers
Squibb/Pfizer, and Roche Diagnostics and consulting fees from
Boehringer Ingelheim, Bristol-Myers Squibb,Merck Sharp & Dohme,
Pfizer, and Roche Diagnostics. Dr Oldgren reported receiving
institutional research grantsand fees paid to his institution for
advisory boards and lectures from Roche Diagnostics; fees paid to
his institutionfor advisory boards, study steering committees, and
lectures from AstraZeneca, Bayer, BMS, BoehringerIngelheim, Pfizer,
and Sanofi; and fees paid to his institution for advisory boards,
safety committees, and lecturesfrom Daichii-Sankyo. Dr Alexander
reported receiving institutional research grants and consulting
fees andhonoraria from Bayer, Bristol-Myers Squibb, CryoLife, and
XaTek and consulting fees and honoraria from Pfizer andPortola. Dr
Alings reported receiving consulting fees from Bayer, Boehringer
Ingelheim, Bristol-Myers Squibb,Daiichi Sankyo, and Milestone
Pharmaceuticals; personal fees from Pfizer; and a nonpersonal study
grant fromSanofi. Dr De Caterina reported receiving grants for
congress organizations and personal fees and honoraria for
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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2020 10/13
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lecturing and advisory board participations from Amgen,
Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer,
Daiichi-Sankyo, Novartis, Protola, Roche, and Sanofi. Dr Eikelboom
reported receiving institutional researchgrants and honoraria from
AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers
Squibb/Pfizer, Daiichi-Sankyo, Eli Lilly, Glaxo Smith Kline,
Janssen, and Sanofi. Dr Held reported receiving an institutional
research grantfrom GlaxoSmithKline, honoraria from Pfizer, and
consultant and advisory board fees from AstraZeneca,
Bayer,Boehringer Ingelheim, and Coala Life. Dr Granger reported
receiving research grants and consulting and speakerfees from
Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceutica
Products, LP, and Pfizer; researchgrants from Daichii-Sankyo,
AKROS, Apple, AstraZeneca, GlaxoSmithKline, US Food & Drug
Administration,Medtronic Foundation, and Novartis Pharmaceutical
Company; and consulting and speaker fees from Abbvie,Bayer Corp US,
Boston Scientific Corp, CeleCor Therapeutics, Correvio, Espero
BioPharma, Medscape, MedtronicInc, Merck, National Institutes of
Health, NovoNordisk, Rhoshan Pharmaceuticals, and Roche
Diagnostics. DrLopes reported receiving research grants and
consulting fees from Bristol-Myers Squibb,
GlaxoSmithKline,Medtronic PLC, Pfizer, and Sanofi and consulting
fees from Bayer, Boehringer Ingelheim, Daichii-Sankyo, Merck,and
Portola. Dr Vinereanu reported receiving grants and personal fees
from Bayer, Boehringer Ingelheim, andPfizer. Dr Siegbahn reported
receiving institutional research grants from AstraZeneca,
Boehringer Ingelheim,Bristol-Myers Squibb/Pfizer, GlaxoSmithKline,
and Roche Diagnostics and consultancy fees from Olink Proteomics.Dr
Wallentin reported receiving institutional research grants from
AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer,
GlaxoSmithKline, Roche Diagnostics, and Merck & Co and
consulting fees from Abbott andholding 2 patents involving GDF-15
licensed to Roche Diagnostics (EP2047275B1 and US8951742B2). No
otherdisclosures were reported.
Funding/Support: The ARISTOTLE trial was funded by Bristol-Myers
Squibb and Pfizer, Inc, and coordinated bythe Duke Clinical
Research Institute and Uppsala Clinical Research Center. The RE-LY
trial was funded byBoehringer-Ingelheim and was coordinated by the
Population Health Research Institute, Hamilton, Ontario,Canada, and
Uppsala Clinical Research Center, Uppsala, Sweden. The current
analyses were supported by grantRB13-0197 from the Swedish
Foundation for Strategic Research. Roche Diagnostics provided the
GDF-15 assay freeof charge. Dr Hijazi receives research grants from
the Swedish Society for Medical Research (S17-0133) and theSwedish
Heart-Lung Foundation (20170718).
Role of the Funder/Sponsor: The funding sources were given the
opportunity to review and comment on the finalversion of the
manuscript. The funding sources did not take part in the design and
conduct of the study; collection,management, analysis, and
interpretation of the data; preparation and approval of the
manuscript; or the decisionto submit the manuscript for
publication.
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SUPPLEMENT.eFigure. Relative Hazard of Major Bleeding Comparing
Patients With Oral Anticoagulation on Aspirin (ASA) WithPatients
Not on ASA in ARISTOTLE and RE-LY by Estimated HAS-BLED RiskeTable.
ANOVA Table for the Cox Regression Model Including Aspirin, the
ABC-Bleeding and HAS-BLED Scores,and the Interaction Between
Aspirin and the Respective Bleeding Risk Scores
JAMA Network Open | Cardiology ABC-Bleeding Risk Score and
Antithrombotic Therapy in Patients With AF
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doi:10.1001/jamanetworkopen.2020.15943 (Reprinted) September 16,
2020 13/13
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