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Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 18, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2016.02.056
Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes The TRACER Trial Pascal Vranckx, MD, PHD,a Harvey D. White, DSC,b Zhen Huang, MS,c Kenneth W. Mahaffey, MD,d Paul W. Armstrong, MD,e Frans Van de Werf, MD,f David J. Moliterno, MD,g Lars Wallentin, MD, PHD,h Claes Held, MD, PHD,h Philip E. Aylward, MD,i Jan H. Cornel, MD, PHD,j Christoph Bode, MD,k Kurt Huber, MD,l José C. Nicolau, MD, PHD,m Witold Ruzyllo, MD,n Robert A. Harrington, MD,d Pierluigi Tricoci, MD, MHS, PHDc
ABSTRACT BACKGROUND The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed. OBJECTIVES This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries). METHODS We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death. RESULTS During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding. CONCLUSIONS In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943) (J Am Coll Cardiol 2016;67:2135–44) © 2016 by the American College of Cardiology Foundation.
From the aHartcentrum Hasselt, Hasselt, Belgium; bGreen Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; cDuke Clinical Research Institute, Durham, North Carolina; dStanford University, Stanford, California; eDivision of CarListen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
diology, University of Alberta, Edmonton, Canada; fDepartment of Cardiology, University of Leuven, Leuven, Belgium; gGill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky;
h
Department of Medical
Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; iSAHMRI, Flinders University and Medical Centre, Adelaide, Australia; jDepartment of Cardiology, Medisch Centrum Alkmaar, Alkmaar, the Netherlands; kInternal Medicine and Cardiology, Universitätsklinikum, Freiburg, Germany; l3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria;
m
Heart Institute (InCor), University of São Paulo Medical School, São Paulo,
Brazil; and the nDepartment of Coronary Artery Disease and Cardiac Catheterization Laboratory, Institute of Cardiology, Warsaw, Poland. The TRACER trial was supported by Merck & Co., Inc. Dr. White has received research grants from Sanofi, Eli Lilly, the National Institutes of Health, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi-Sankyo Pharma Development, George Institute, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics Inc., Elsai Inc., and DalGen Products and
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Clinical Validation of BARC Criteria in ACS Patients
ABBREVIATIONS AND ACRONYMS BARC = Bleeding Academic
A
ntithrombotic and revascularization
laboratory
strategies to reduce the risk of recur-
thresholds of clinical or laboratory severity and cor-
evaluation
but
not
meeting
specific
rent ischemic events in patients with
onary artery bypass graft (CABG)-related bleeding.
non–ST-segment elevation acute coronary
The TRACER (Thrombin Receptor Antagonist for
syndromes (NSTE-ACS) are associated with
Clinical Event Reduction in Acute Coronary Syn-
graft
increased
drome) trial was a contemporary trial testing the
CI = confidence interval
bleeding is a central safety outcome in car-
efficacy and safety of the protease-activated receptor-1
diovascular clinical trials, especially for
antagonist vorapaxar against placebo in patients with
form
antithrombotic strategies and invasive pro-
NSTE-ACS in addition to standard of care, where
GUSTO = Global Use of
cedures (1,2).
treatment decisions were made by the treating physi-
Research Consortium
CABG = coronary artery bypass
eCRF = electronic case report
Strategies to Open Occluded Coronary Arteries
risk
of
bleeding.
Therefore,
SEE PAGE 2145
cian (6,7). The large TRACER dataset provides opportunities to: 1) examine the association of BARC-defined
Many definitions of bleeding exist and are
bleeding with mortality over a long follow-up in a
NSTE-ACS = non–ST-segment
used inconsistently in clinical trials and
broad group of NSTE-ACS patients in whom different
elevation acute coronary
registries, making it difficult to compare re-
types of treatment strategies were adopted (PCI, CABG,
sults across trials. Additionally, the prog-
medical treatment); and 2) compare the BARC defini-
nostic impact of bleeding may depend upon
tion with other established bleeding definitions in
definitions used. In 2011, the Bleeding Aca-
predicting mortality.
HR = hazard ratio
syndrome
PCI = percutaneous coronary intervention
TIMI = Thrombolysis In Myocardial Infarction
demic Research Consortium (BARC) proposed standardized bleeding definitions in
METHODS
patients receiving antithrombotic therapy by implementing a hierarchical approach (3). In patients with
STUDY
ACS following a percutaneous coronary intervention
design have been previously reported (6,7). In brief,
DESIGN. The
(PCI), this consensus classification has been shown
TRACER was a multicenter, global, randomized,
to be independently associated with 1-year mortality,
double-blind, event-driven trial with a minimum
but it has not been validated in a broad population
follow-up of 1 year. The study compared placebo with
with ACS, including patients treated with other
vorapaxar administered as a 40 mg loading dose fol-
treatment strategies (4,5). Furthermore, the prog-
lowed by a daily 2.5 mg maintenance dose in patients
nostic value of certain BARC categories has not been
with NSTE-ACS at high risk for recurrent ischemic
established, such as bleeding requiring medical or
events (6,7). Concomitant treatment was according to
trial’s primary results and
Services; and participates in an advisory board at AstraZeneca. Dr. Mahaffey has received research grants from Amgen, Daiichi, Johnson & Johnson, Medtronic, Merck, St. Jude, and Tenax; has provided consulting or other services for the American College Cardiology, AstraZeneca, BAROnova, Bayer, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, Eli Lilly, Elsevier, Epson, Forest, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Mt. Sinai, Myokardia, Omthera, Portola, Purdue Pharma, Springer Publishing, The Medicines Company, Vindico, and WebMD; and has equity in BioPrint Fitness. Dr. Van de Werf has received a research grant, honoraria for lectures, and advisory board membership from Merck & Co. Dr. Moliterno has served on a Data and Safety Monitoring Board for Janssen Pharmaceuticals; and has received research grants from Merck and AstraZeneca. Dr. Wallentin has received research grants from AstraZeneca, Merck & Co., Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Merck & Co.; honoraria from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Merck & Co.; been a consultant/served on an advisory board from Merck & Co., Regado Biosciences, Evolva, Portola, C.S.L. Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Bristol-Myers Squibb/Pfizer; and received travel support from Bristol-Myers Squibb/Pfizer. Dr. Held has received research grants from AstraZeneca, GlaxoSmithKline, Pfizer/Bristol-Myers Squibb, Roche, and Schering-Plough (now Merck); has served on an advisory board for AstraZeneca; and has served as a consultant for Bayer. Dr. Aylward has received a research grant from Merck & Co., AstraZeneca, Sanofi, and GlaxoSmithKline; and has received honoraria/served on a speaker bureau and advisory board for AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer/ Johnson & Johnson, Servier, and Bristol-Myers Squibb. Dr. Cornel has received consulting fees/honoraria from AstraZeneca, MSD, Eli Lilly, and Bristol-Myers Squibb/Pfizer; and travel support from Bayer and AstraZeneca. Dr. Bode has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Sanofi; and speakers’ and consulting honoraria from Bayer, BristolMyers Squibb, and Daiichi-Sankyo. Dr. Huber has received lecture fees from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Sanofi, and The Medicines Company; and a research grant from AstraZeneca. Dr. Nicolau has received a research grant and consultant/advisory fees from Merck; and research grants and/or personal fees (consultancy, lectures, travel support) from Sanofi, AstraZeneca, Daiichi-Sankyo, Bayer/Johnson & Johnson, and Roche, outside the submitted work. Dr. Harrington has received research grants from Merck & Co., Astra, Sanofi, Bristol-Myers Squibb, The Medicines Company, Portola Pharma, and Regado; has consulted for Merck and The Medicines Company; and has served on advisory boards for Gilead and WebMD. Dr. Tricoci has a consultant agreement and has received a research grant from Merck & Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received December 16, 2015; revised manuscript received February 9, 2016, accepted February 24, 2016.
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Clinical Validation of BARC Criteria in ACS Patients
the applicable practice guidelines (e.g., North Amer-
hemoglobin levels, hematocrit levels, and blood
ican, European) (8,9). Subjects who discontinued
transfusions. For patients who underwent CABG
study treatment for any reason were followed for
surgery during the index hospitalization, the eCRF
occurrence of clinical events.
contained data on the occurrence of bleeding and its
The TRACER trial complied with the Declaration of
characteristics. All suspected bleeding events were
Helsinki and was approved by the appropriate na-
prospectively assessed and adjudicated according to
tional and institutional regulatory authorities and
the Thrombolysis In Myocardial Infarction (TIMI)
ethics committees. All patients provided written
classification and the GUSTO (Global Use of Strate-
informed consent. ENDPOINT
DEFINITIONS
gies to Open Occluded Coronary Arteries) classifiFOLLOW-UP. The
cation (10,11). Protocol-defined bleeding and efficacy
main outcome measure for this analysis was all-cause
endpoints included in the primary outcome mea-
mortality. All suspected bleeding events in the
sure were adjudicated by a central clinical events
TRACER trial were systematically identified via an
committee. The BARC consensus document was
integrated
investigator-reported
published while TRACER was being conducted.
events along with central review of relevant data in
BARC bleeding definition criteria were retrospec-
the electronic case report form (eCRF). The eCRF
tively derived using an algorithm on the basis of the
contained information on localization, imaging tests,
adjudicated data points collected during the clinical
assessment
AND
of
CENTRAL ILLUSTRATION BARC Criteria in ACS Patients Without ST-Segment Elevation: Clinical Validation
Vranckx, P. et al. J Am Coll Cardiol. 2016;67(18):2135–44.
This study evaluated the impact of bleeding classified with the BARC scale on mortality in a cohort of patients with non–ST-segment-elevation acute coronary syndrome (N ¼ 12,944) treated according to current clinical practice and enrolled in the TRACER trial. The bleeds classified as BARC grades 2, 3, or 4 were independently associated with an increased risk of mortality, which gradually rose up to 1 year following a bleeding event with an escalating BARC-graded severity of bleeding observed for noncoronary artery bypass graft–related bleeding. The hazard of death associated with BARC grade 3 criteria was similar in magnitude compared with TIMI (major or minor) and GUSTO (moderate or severe) bleeding criteria. The BARC criteria captured a higher proportion of major bleeding compared with both the GUSTO and the TIMI scales alone. ACS ¼ acute coronary syndrome; BARC ¼ Bleeding Academic Research Consortium; GUSTO ¼ Global Strategies for Opening Occluded Coronary Arteries; TIMI ¼ Thrombolysis In Myocardial Infarction; TRACER ¼ Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome.
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Clinical Validation of BARC Criteria in ACS Patients
quality of data collection was assessed according to
T A B L E 1 Baseline Demographic Characteristics
current regulatory standards (12).
BARC Grades 2–4 (n ¼ 1,975)
BARC Grades 0–1 (n ¼ 10,969)
Age, yrs* N
STATISTICAL ANALYSIS. The analysis population
included all randomized subjects in the TRACER trial. Bleeding events post-randomization to last follow-up
1,975
10,969
67.0 9.8
63.9 9.9
were classified as BARC bleeding categories on the
67.0 (60.0–74.0)
63.0 (57.0–71.0)
basis of the algorithm described in Online Table 2.
33.0, 92.0
29.0, 94.0
The first event of each BARC bleeding category for a
599/1,975 (30.3)
3,033/10,969 (27.7)
subject was included in the analyses described later.
1,702/1,973 (86.3)
9,337/10,936 (85.4)
Black
43/1,973 (2.2)
269/10,936 (2.5)
with and without BARC 2, 3, and 4 bleeding.
Asian
169/1,973 (8.6)
887/10,936 (8.1)
Other race
59/1,973 (3.0)
443/10,936 (4.1)
1,969
10,916
mortality post-bleeding were estimated by the Kaplan-
81.3 18.7
82.7 17.7
Meier method. Mortality rates at 30 days, 1 year, and
80.0 (69.0–92.0)
80.7 (70.0–92.7)
2 years post-bleeding were estimated among subjects
27.0, 181.0
31.8, 190.3
with bleeding events according to the BARC, TIMI, and
200/1,969 (10.2)
787/10,916 (7.2)
Mean SD Median (IQR) Range, min, max Female Race*†
Baseline characteristics were reported for subjects
White
All p values were calculated according to multivariate Cox modeling that included randomized treatment and baseline covariates. Cumulative event rates of
Body weight, kg N Mean SD Median (IQR) Range, min, max <60 kg 2
BMI, kg/m N
GUSTO classifications. Event curves were created to describe the incidence and timing to death post-
1,964
10,888
28.3 5.5
28.6 5.2
27.5 (24.6–30.9)
27.8 (25.1–31.2)
13.8, 58.3
13.8, 74.3
North America
643/1,975 (32.6)
2,761/10,969 (25.2)
were estimated by Cox regression models, in which
Latin America
104/1,975 (5.3)
744/10,969 (6.8)
Europe I
788/1,975 (39.9)
5,051/10,969 (46.0)
bleeding was included as a time-varying covariate in
Europe II
170/1,975 (8.6)
1,317/10,969 (12.0)
Asia
152/1,975 (7.7)
784/10,969 (7.1)
Australia/New Zealand
118/1,975 (6.0)
312/10,969 (2.8)
Hypertension
1,454/1,975 (73.6)
7,674/10,964 (70.0)
might change over time. As a post-randomization risk
Hyperlipidemia
1,287/1,975 (65.2)
6,775/10,961 (61.8)
factor, bleeding occurred in different subjects at
Diabetes mellitus*
605/1,975 (30.6)
3,465/10,963 (31.6)
different times. The bleeding status of all subjects
Former smoker*
455/1,974 (23.0)
3,081/10,963 (28.1)
Current smoker*
731/1,974 (37.0)
3,455/10,963 (31.5)
60/1,871 (3.2)
130/10,390 (1.3)
bleeding.” A subject remained in this category until a
327/1,871 (17.5)
1,150/10,390 (11.1)
bleeding event had occurred and was then reclassified
1,484/1,871 (79.3)
9,110/10,390 (87.7)
as “bleeding.” Prior knowledge suggested that the risk
Mean SD Median (IQR) Range, min, max Region*
bleeding. To evaluate the association between various bleeding classifications and mortality, hazard ratios (HRs) of mortality and 95% confidence intervals (CIs)
addition to the baseline characteristics (as listed in Table 1) and randomized treatment. The time-varying aspect of bleeding was 2-fold: the effect of bleeding and the status of bleeding for a subject, both of which
Cardiovascular risk factors
Renal inefficiency CrCl, ml/min* <30 30–60 $60
Continued on the next page
was examined at each time point since randomization, where everyone was first classified as “no
for mortality following a bleeding event differed in the short and long term; therefore, a piecewise hazard
events committee review. Bleeding definitions are
function was built representing periods within day 30,
provided in Online Table 1 (3). BARC grade 5 is fatal
day 31 to 1 year, and 1 year to 2 years post-bleeding.
bleeding and was not included in the analyses of the
Wald chi-square tests were carried out to examine
relationship with all-cause mortality. Subjects with
whether the HRs were consistent across these pe-
BARC grade 5 were analyzed according to the bleeding
riods. In subjects who had more than 1 bleed during
events before the fatal bleeding event.
follow-up, the subsequent bleeds were included in
The TRACER protocol required that all enrolled
the analyses and analyzed in the same way as the
patients return for study visits at 30 days; at 4, 8, and
initial one. Goodness-of-fit tests of -2 log likelihood
12 months; and then every 6 months thereafter. Pa-
were used to evaluate the improved model perfor-
tients who prematurely discontinued treatment were
mance comparing models with and without bleeding.
followed by telephone at the same intervals. During
These analyses were carried out for bleeding events
follow-up visits, patients underwent a complete
according to BARC, TIMI, and GUSTO classifications.
clinical evaluation. The TRACER trial was part of an investigational
new
drug
application;
therefore,
All statistical tests were 2-sided with a significance level of 0.05; p values are not adjusted for multiple
Vranckx et al.
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Clinical Validation of BARC Criteria in ACS Patients
comparisons. SAS software, version 9.2 (SAS Institute, Cary, North Carolina) was used for statistical analyses.
T A B L E 1 Continued
BARC Grades 2–4 (n ¼ 1,975)
RESULTS
BARC Grades 0–1 (n ¼ 10,969)
Cardiovascular disease history Prior myocardial infarction
579/1,974 (29.3)
3,212/10,964 (29.3)
in 37 countries. Approximately 9 of 10 patients
Prior percutaneous coronary intervention*
451/1,975 (22.8)
2,639/10,959 (24.1)
(n ¼ 11,399; 88%) underwent coronary angiography;
Prior CABG
278/1,975 (14.1)
1,265/10,964 (11.5)
7,075 (54%) patients received a coronary stent; and
Stroke*
115/1,975 (5.8)
438/10,964 (4.0)
1,312 (10%) patients were treated with CABG. The cu-
Peripheral arterial disease
173/1,975 (8.8)
763/10,962 (7.0)
mulative incidence of a BARC bleed of grade 2 or
Positive troponin or CK-MB
A total of 12,944 patients were enrolled at 818 sites
higher from randomization to last follow-up was 15.3% (n ¼ 1,975); 3.7% (n ¼ 484) of patients had a TIMI major or minor bleed and 4.0% (n ¼ 514) of patients had a bleed according to GUSTO severe or moderate
1,852/1,965 (94.2) 10,198/10,892 (93.6)
Electrocardiogram findings ST-segment depression ST-segment elevation Symmetric T-wave inversions
652/1,975 (33.0)
3,547/10,969 (32.3)
99/1,975 (5.0)
637/10,969 (5.8)
425/1,975 (21.5)
2,488/10,969 (22.7)
TIMI risk score‡
criteria. The cumulative incidence of bleeding ac-
0–2
8/1,975 (0.4)
59/10,969 (0.5)
cording to BARC criteria is shown in Online Figure 1.
3–4
928/1,975 (47.0)
5,770/10,969 (52.6)
Baseline demographic characteristics for patients with (BARC 2, 3, or 4) or without (BARC 0 or 1) bleeding are reported in Table 1. Patients with actionable bleeding were older, more frequently from North America, more likely to be current smokers, and have reduced renal function, higher Killip class,
5–7
1,039/1,975 (52.6) 5,140/10,969 (46.9)
Baseline hemoglobin, g/dl* N Mean SD Median (IQR) Range, min, max
1,967
10,902
13.7 1.7
14.0 1.6
13.9 (12.7–14.9)
14.1 (13.0–15.1)
6.0, 20.0
4.3, 20.8
Killip class*§
and a history of prior stroke. Use of glycoprotein IIb/IIIa
I
inhibitors at baseline was also more common in pa-
II
95/1,970 (4.8)
399/10,862 (3.7)
tients with BARC actionable bleeding.
III–IV
42/1,970 (2.1)
88/10,862 (0.8)
Use or intent to use glycoprotein IIb/IIIa at randomization*
476/1,975 (24.1)
2,234/10,969 (20.4)
Use or intent to use direct thrombin inhibitor at randomization
345/1,975 (17.5)
1,811/10,969 (16.5)
1,734/1,975 (87.8)
9,573/10,969 (87.3)
1,120/1,917 (58.4)
6,403/10,598 (60.4)
BLEEDING EVENTS AND MORTALITY. In the 12,944
patients analyzed, there were 652 (5.0%) deaths at 2 years, with 196 (1.5%) deaths occurring within the first 30 days after randomization. The cumulative mortality rates post-bleeding by BARC, TIMI, and GUSTO categories are shown in the Central Illustration.
1,833/1,970 (93.0) 10,375/10,862 (95.5)
Randomization/stratification factors
Antiplatelet at randomization Thienopyridine at baseline* Aspirin dose at baseline, mg
The crude mortality rates were comparable among
#100
patients with BARC grade 3, GUSTO moderate or se-
100–300
vere, and TIMI minor or major bleeding (Table 2).
$300
The association between BARC bleeding and mortality was significant in the 30 days following bleeding and at 1 year post-bleeding (Table 3). In the interval beyond 1 year from bleeding, the hazard decreased and was no longer significant. The hazard of mortality increased progressively with higher non-CABG BARC grades (p for trend <0.0001 within 30 days and be-
135/1,917 (7.0)
914/10,598 (8.6)
662/1,917 (34.5)
3,281/10,598 (31.0)
Values are n/N (%) unless otherwise indicated. *p < 0.05 according to the multivariate Cox modeling of BARC bleeding $2 vs. <2 controlling for randomized treatment and the baseline covariates. †Race or ethnic group was reported by investigators after interviews with patients. ‡The TIMI risk score ranges from 0 to 7, with higher scores indicating greater risk. §According to the Killip classification, class II indicates cardiac S3 or rales on #50% of the lung fields, class III indicates rales on >50% of the lung fields, and class IV indicates signs of cardiogenic shock. BARC ¼ Bleeding Academic Research Consortium; BMI ¼ body mass index; CABG ¼ coronary artery bypass graft; CK-MB ¼ creatinine kinase-myocardial band; CrCl ¼ creatinine clearance; IQR ¼ interquartile range; SD ¼ standard deviation; TIMI ¼ Thrombolysis In Myocardial Infarction.
tween 30 days and 1 year) (Table 2). BARC grade 4 (bleeding following CABG), as a separate grade,
increase in the hazard was observed with BARC
contained a more than 10-fold increase in hazard up to
grades 3 or 4, TIMI major or minor, and GUSTO
30 days but not beyond. The inclusion of BARC
moderate or severe bleeding.
bleeding in a multivariable model predicting mortality significantly improved the goodness of fit (Table 4).
The timing of a BARC 2, 3, or 4 bleed (during the index stay, including bleeding events related to
TIMI major or minor bleeding and GUSTO moderate
instrumentation or trauma; within 7 days of discharge;
or severe bleeding were also significantly associated
and beyond 7 days after discharge) did not affect the
with
mortality
(Tables
to
relationship with mortality (Online Figure 2). Finally,
BARC bleeding, the relationship with mortality was
transfusion was not independently associated with
significant up to 1 year after bleeding, but not there-
mortality and did not confer additional prognostic
after. In comparing the 3 scales, a similar degree of
value on top of BARC criteria (Online Table 3).
3
and
4).
Similar
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Clinical Validation of BARC Criteria in ACS Patients
T A B L E 2 Cumulative Mortality After Bleeding
30 Days Post-Bleeding
Crude Rate
1 Yr Post-Bleeding
Kaplan-Meier Estimated Rate
Crude Rate
Kaplan-Meier Estimated Rate
2 Yrs Post-Bleeding
Crude Rate
Kaplan-Meier Estimated Rate
BARC Grade 1
17/1,584 (1.1)
1.1 (0.6–1.6)
59/1,584 (3.7)
4.2 (3.2–5.2)
73/1,584 (4.6)
6.1 (4.6–7.6)
Grade 2
19/1,320 (1.4)
1.5 (0.9–2.1)
71/1,320 (5.4)
6 (4.6–7.4)
83/1,320 (6.3)
8.2 (6.3–10.1)
Grade 3a
15/344 (4.4)
4.4 (2.2–6.6)
43/344 (12.5)
14.2 (10.2–18.2)
52/344 (15.1)
19.8 (14.6–25)
Grade 3b
30/250 (12.0)
12.2 (8.1–16.3)
50/250 (20.0)
21.3 (16–26.6)
51/250 (20.4)
22.5 (16.8–28.2)
Grade 3c
23/68 (33.8)
33.9 (22.6–45.2)
30/68 (44.1)
48.4 (35–61.8)
30/68 (44.1)
48.4 (35–61.8)
Grade 4
14/155 (9.0)
9.1 (4.6–13.6)
22/155 (14.2)
14.5 (8.9–20.1)
22/155 (14.2)
14.5 (8.9–20.1)
Grades 2–4
80/1,975 (4.1)
4.1 (3.2–5.0)
180/1,975 (9.1)
9.9 (8.5–11.3)
200/1,975 (10.1)
12.3 (10.6–14)
Grades 3, 4
74/773 (9.6)
9.7 (7.6–11.8)
133/773 (17.2)
18.5 (15.6–21.4)
143/773 (18.5)
21.4 (18.1-24.7)
54/280 (19.3)
19.4 (14.8–24)
76/280 (27.1)
28.3 (22.8–33.8)
78/280 (27.9)
30.0 (24.2–35.8)
76/783 (9.7)
9.8 (7.7–11.9)
134/783 (17.1)
18.3 (15.5–21.1)
146/783 (18.6)
21.4 (18.2–24.6)
Major
56/406 (13.8)
13.9 (10.5–17.3)
84/406 (20.7)
21.7 (17.6–25.8)
85/406 (20.9)
22.4 (18–26.8)
Major or minor
64/625 (10.2)
10.3 (7.9–12.7)
106/625 (17.0)
18.1 (14.9–21.3)
111/625 (17.8)
20.0 (16.5–23.5)
GUSTO Severe Moderate or severe TIMI
Values are n/N (%) or % (IQR). GUSTO ¼ Global Use of Strategies to Open Occluded Coronary Arteries; other abbreviations as in Table 1.
COMPARISON OF BLEEDING DEFINITIONS. In the dis-
classification of severity is necessary. The BARC
tribution of bleeding using BARC, TIMI major/minor,
consensus document proposed a hierarchical grading
and GUSTO moderate/severe criteria (Table 5), only
system to classify bleeding events in cardiovascular
one-half of BARC 3 bleeds were concomitantly
investigations (3), but validation (especially on its
captured in both the TIMI minor or major and GUSTO
prognostic implication) is required. We studied the
moderate or severe categories. Of the remaining BARC
impact of bleeding classified with the BARC scale on
3 bleeds, approximately 30% were captured as GUSTO
mortality in a cohort of patients with NSTE-ACS
moderate or severe only (but not TIMI major or minor)
treated according to current clinical practice and
and approximately 20% were captured as TIMI major
enrolled in the TRACER trial. We concluded that
or minor only (but not GUSTO moderate or severe).
bleeds classified as BARC grades 2, 3, or 4 were
There were 159 bleeds that were not classified by
independently associated with an increased risk of
BARC criteria. Those were CABG-related bleeds that
mortality. Blood transfusion for bleeding was not an
were classified as GUSTO moderate or severe but did
independent predictor for mortality after full adjust-
not meet the BARC CABG definition. In fact, trans-
ment for all available variables and bleeding. There
fusion and hemodynamic instability, key elements of
was a gradual increase in the risk of mortality up to
the GUSTO criteria, are not part of the BARC 4 criteria.
1 year following a bleeding event with an increasing
To understand the additive predictive value of
BARC-graded severity of bleeding.
bleeding grades on mortality, we first created a
The strengths of our analysis relied on the
multivariable model to predict 1-year mortality using
extended follow-up, the well-described and contem-
baseline characteristics and then added various
porary NSTE-ACS patient population, and the pro-
bleeding classifications to assess to what degree the
spective collection and blinded adjudication of
inclusion of bleeding scales in the mortality model
bleeding events. TRACER patients were largely
would improve the prediction capability of the
included with positive biomarkers and then treated
model. The inclusion of BARC 2, 3, or 4 and of BARC
with a variety of strategies according to modern
3 or 4 criteria to the baseline model significantly
standards of care and physicians’ choices. More than
increased the predictive value of the model (Table 4),
90% of patients in TRACER had positive troponin,
to a similar degree as TIMI minor or major bleeding
90% underwent diagnostic angiography, and nearly
and GUSTO moderate or severe bleeding.
60% underwent PCI. One of 10 patients had CABG
DISCUSSION
during the index hospitalization.
Bleeds are not equal and do not carry the same
bleeding scales used for the main safety analysis and
hazard for mortality over time; therefore, accurate
reporting in the TRACER trial. The TIMI definition
The TIMI and GUSTO criteria were the prespecified
Vranckx et al.
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Clinical Validation of BARC Criteria in ACS Patients
T A B L E 3 Association of Bleeding and Mortality
HR (95% CI)* p Value
p Value for Testing Same HR
30 Days Post-Bleeding
31 Days–1 Yr Post-Bleeding
1–2 Years Post-Bleeding
Grades 2–4 vs. <2
7.35 (5.59–9.68) <0.0001
2.56 (2.02–3.25) <0.0001
1.24 (0.75–2.04) 0.4043
<0.0001
<0.0001
<0.0001
Grades 3, 4 vs. <3
14.25 (10.72–18.94) <0.0001
3.36 (2.51–4.51) <0.0001
1.64 (0.86–3.14) 0.1340
<0.0001
0.0446
<0.0001
Grade 1
1.74 (1.06–2.86) 0.0282
1.06 (0.75–1.49) 0.7377
1.13 (0.65–1.97) 0.6683
0.1010
0.8454
0.2751
Grade 2
2.23 (1.38–3.61) 0.0011
1.70 (1.25–2.32) 0.0008
1.00 (0.52–1.90) 0.9950
0.3431
0.1379
0.1582
Grade 3a
4.54 (2.68–7.70) <0.0001
2.61 (1.75–3.89) <0.0001
3.10 (1.56–6.16) 0.0012
0.0948
0.6611
0.5749
Grade 3b
11.60 (7.47–18.03) <0.0001
3.26 (2.03–5.23) <0.0001
0.56 (0.08–4.06) 0.5697
<0.0001
0.0893
<0.0001
0.000 0.9902
<0.0001
0.9882
0.0021
<0.0001
0.9598
0.0003
Bleeding Categories
Day 30, 1 Yr 1 Yr, 2 Yrs Day 30, 1 Yr, 2 Yrs
BARC
Compared with grade 0
Grade 3c Grade 4
58.07 (34.39–98.04) 10.75 (5.04–22.94) <0.0001 <0.0001 10.05 (5.41–18.69) <0.0001
1.11 (0.45–2.71) 0.8204
0.000 0.9601
<0.0001
<0.0001
0.0357
Major or minor vs. not major/minor
16.30 (12.08–21.99) <0.0001
3.25 (2.31–4.56) <0.0001
0.99 (4.41–2.44) ¼0.9897
<0.0001
0.0248
<0.0001
Major vs. not major
22.65 (16.49–31.09) <0.0001
3.08 (2.02–468) <0.0001
0.31 (0.04–2.22) 0.2426
<0.0001
0.0248
<0.0001
2.72 (1.52–4.87) 0.0007
1.37 (0.86–2.19) 0.1808
0.39 (0.10–1.60) 0.1908
0.0638
0.0943
0.0219
Minor
7.29 (2.95–18.00) <0.0001
1.89 (0.69–5.18) 0.2139
0.000 0.9527
0.0479
0.9498
0.1410
Major
22.43 (13.54–37.15) <0.0001
6.16 (3.55–10.69) <0.0001
1.34 (0.19–9.67) ¼0.7720
0.0005
0.1437
0.0002
Moderate or severe vs. not moderate/severe
14.20 (0.69–18.88) <0.0001
3.09 (2.30–4.16) <0.0001
1.75 (0.96–3.18) 0.0658
<0.0001
0.8970
<0.0001
Severe vs. not severe
29.25 (21.07–40.62) <0.0001
4.12 (2.61–6.50) <0.0001
0.96 (0.24–3.88) 0.9494
<0.0001
0.0501
<0.0001
Mild
0.95 (0.46–2.00) 0.9003
0.74 (0.44–1.26) 0.2697
0.72 (0.26–1.96) 0.5201
0.5821
0.9585
0.8422
Moderate
7.43 (4.01–13.76) <0.0001
3.70 (2.22–6.19) <0.0001
0.00 (0.00–0.00) 0.9505
0.0790
0.9446
0.2132
28.45 (16.88–47.93) <0.0001
6.74 (3.54–12.82) <0.0001
1.70 (0.24–12.24) 0.5999
0.0005
0.1918
0.0002
Test of trend across grades 1, 2, 3a–3c TIMI
Compared with no TIMI bleeding Needing medical attention
GUSTO
Compared with no GUSTO bleeding
Severe
*HR is estimated by Cox regression model of all-cause mortality with bleeding class as a time-varying factor and with different HR estimated at 30 days, 1 yr, and 2 yrs postbleeding, adjusted for baseline covariates and randomized treatment. Baseline covariates are: demographics (age, sex, race, region, body weight, BMI), cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, smoking), renal inefficiency, cardiovascular disease history (prior myocardial infarction, percutaneous coronary intervention, CABG, stroke, peripheral arterial disease), features on presentation (heart rate, blood pressure, ST-segment deviation, Killip class), and treatment received (glycoprotein IIb/IIIa inhibitor, aspirin dose, and thienopyridine use). BARC grade 5 is fatal bleeding. Subjects with BARC grade 5 bleeding were analyzed on the basis of bleeding assessments before the fatal event. CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.
integrates mainly laboratory-based data, whereas the
the TIMI and GUSTO scales (5). The hazard of death
GUSTO definition is largely clinically based (10,11).
associated with BARC grade 3 criteria was similar in
For this analysis, all bleeding events were reclassified
magnitude compared with TIMI (major or minor) and
according to the BARC hierarchical bleeding scale
GUSTO (moderate or severe) bleeding criteria. How-
(grade 2, 3, or 4) using data prospectively collected as
ever, our analysis demonstrated that BARC classifica-
part of the clinical event committee adjudication for
tion is potentially able to capture a larger proportion
2141
2142
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Clinical Validation of BARC Criteria in ACS Patients
that the impact of bleeding on the risk of death is
T A B L E 4 Mortality Models: Improvement in Goodness of Fit*
Change in -2log Likelihood vs. Baseline Model†
Covariates
increased only for a certain period after the event (13). Degrees of Freedom
p Value
Baseline þ BARC
The vast majority of bleeding events occurred early after randomization. However, in the current analysis we could not demonstrate a differential hazard for
$2
10,326–10,136 ¼ 190
3
<0.0001
$3
10,326–10,054 ¼ 272
3
<0.0001
mortality by BARC-graded bleeding occurring during
Baseline þ TIMI major
10,326–10,100 ¼ 226
3
<0.0010
the index stay, including the majority of instru-
Baseline þ TIMI major or minor
10,326–10,096 ¼ 230
3
<0.0001
mented and traumatic bleeds, and after discharge.
Baseline þ GUSTO severe
10,326–10,090 ¼ 236
3
<0.0001
Interestingly, in TRACER, even BARC 1 bleeds—
Baseline þ GUSTO moderate or severe
10,326–10,074 ¼ 252
3
<0.0001
recently shown to be associated with decreased shortand
long-term
quality
of
life
(14)—carried
an
increased hazard of death up to 30 days.
*After including bleeding classifications. †Bigger changes indicate more improved fit.
Finally, this analysis provides a first validation of
Abbreviations as in Tables 1 and 2.
BARC 4 grade (CABG-related) bleeding in a large of clinically significant bleeding than either the GUSTO
cohort of patients with ACS (1,312 patients underwent
or TIMI scales. We showed that TIMI major or minor
CABG during the index hospitalization). We observed
criteria only capture about 70% of bleeds meeting
that BARC 4–defined CABG-related bleeding carried a
BARC 3 criteria, whereas GUSTO moderate or severe
high 30-day HR, similar to BARC 3b grade, but leveled
criteria capture approximately 80% of BARC 3
off thereafter.
bleeding. The similar prognostic significance of the 3
Our findings complement the results from TRITON-
scales, but with a more inclusive set of criteria in the
TIMI 38 (Trial to Assess Improvement in Therapeutic
BARC scale, may make BARC a more desirable bleeding
Outcomes by Optimizing Platelet Inhibition with
scale given the possibility to capture more bleeding.
Prasugrel–Thrombolysis In Myocardial Infarction 38)
Not surprisingly, BARC 3C (intracranial) bleeding
and PRODIGY (Prolonging Dual Antiplatelet Treat-
events were associated with the worst prognosis.
ment After Grading Stent-Induced Intimal Hyperpla-
Blood transfusion for bleeding was not an indepen-
sia) (5,15). In both trials, which were confined to
dent predictor for mortality after full adjustment for
patients presenting with ACS undergoing an early
baseline variables, treatment regimen, and BARC-
invasive treatment strategy, the impact of bleeding
graded bleeding.
on mortality was restricted to more serious bleeding
The increase in mortality was significant up to 1
events. Focusing on the time dependency of this
year after a BARC actionable bleeding, whereas the
relationship, the associated HR was similar for
relationship between bleeding and mortality became
bleeding events occurring during the index hospital-
weaker and nonsignificant beyond 1 year from the
ization—clustering the instrumented bleeds—or post-
bleed. The reason for this finding is not entirely clear,
discharge. This finding points to the detrimental
but it is possible that patients at a higher risk of
nature of a major bleed per se, regardless of the
mortality have a fatal outcome relatively early after a
timing of the index procedure or randomization. The
bleed so those who survive beyond 1 year represent a
decline in the hazard for mortality late after a first
lower risk group. On the other hand, it may also be
serious non-CABG bleeding event is biologically
T A B L E 5 Distribution of All Bleeding Events*
TIMI Major/Minor and GUSTO Severe/Moderate
TIMI Major/Minor but not GUSTO Severe/Moderate
GUSTO Severe/Moderate but not TIMI Major/Minor
Other TIMI and GUSTO Categories
Total
159 (3.21)
64 (1.29)
223 (4.50)
Not classified by BARC
0 (0.00)
0 (0.00)
BARC 1
0 (0.00)
0 (0.00)
0 (0.00)
2,183 (44.09)
2,183 (44.09)
BARC 2
0 (0.00)
0 (0.00)
0 (0.00)
1,591 (32.13)
1,591 (32.13)
BARC 3a
103 (2.08)
120 (2.42)
155 (3.13)
0 (0.00)
378 (7.63)
BARC 3b
206 (4.16)
19 (0.38)
40 (0.81)
0 (0.00)
265 (5.35)
72 (1.45)
0 (0.00)
0 (0.00)
23 (0.46)
95 (1.92)
7 (0.14)
0 (0.00)
0 (0.00)
166 (3.35)
BARC 3c BARC 4 BARC 5 Total
159 (3.21) 0 (0.00) 540 (10.91)
Values are n (%). *By BARC, TIMI, and GUSTO bleeding definitions. Abbreviations as in Tables 1 and 2.
0 (0.00) 146 (2.95)
0 (0.00) 354 (7.15)
50 (1.01)
50 (1.01)
3,911 (78.99)
4,951 (100.00)
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Clinical Validation of BARC Criteria in ACS Patients
plausible and may explain the attenuation in the
the initial treatment strategy, BARC bleeding grades
hazard beyond 1 year in our analysis.
independently and incrementally predicted 1-year
In TRACER, we could not detect any additional risk
mortality. BARC grade 3 had a hazard of death similar
for 30-day or 1-year mortality with blood transfusion
to that provided by TIMI and GUSTO scales, but could
for bleeding beyond the BARC serious (grade 3 or 4)
capture more bleeding than TIMI major or minor or
events. Use of transfusion is highly variable, and local
GUSTO moderate or severe criteria only. These data
policy may differ across centers and providers, which
add to the clinical validity of the BARC classification
may explain this finding. Information on policy and
that, by integrating elements of both GUSTO and TIMI
guidance adopted in the use of blood transfusion was
scales, may be helpful to standardize bleeding
not collected.
endpoint definitions in clinical investigations and
STUDY LIMITATIONS. The most relevant limitation
may thus be used in addition to or in substitution of
of the present analysis is the different timing of
these 2 scales.
the adjudication of bleeding. More specifically, bleeding according to BARC criteria was derived
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
retrospectively, although it was on the basis of
Pierluigi Tricoci, Duke Clinical Research Institute,
prospectively collected data by a central adjudica-
Box 3850, 2400 Pratt Street, Durham, North Car-
tion committee.
olina 27705. E-mail: [email protected].
Although TRACER did not have significant exclusion criteria on the basis of the presumed risk of
PERSPECTIVES
bleeding, patients with active bleeding, hemorrhagic diathesis, or history of intracranial hemorrhage at any time were excluded. Patients with concomitant or foreseeable need for oral anticoagulation were not included in the trial. Even after adjustment, the possibility of residual confounding remains for the relationship between bleeding and mortality. For the outcome analysis, models were adjusted for baseline variables but not for post-randomization factors, such as recurrent myocardial infarction or reinterventions during follow-up.
COMPETENCY IN PRACTICE-BASED LEARNING: In patients with non–ST-segment elevation acute coronary syndromes, bleeding is a composite endpoint associated with a risk of mortality over the course of the subsequent year. The Bleeding Academic Research Consortium criteria capture most overt bleeding events and therefore form a meaningful tool for assessment of the safety of antithrombotic therapy. TRANSLATIONAL OUTLOOK: Further studies are needed to develop methods for integrated assessment of both safety and
CONCLUSIONS
efficacy to reflect the net clinical benefit of antithrombotic in-
In this validation of the BARC hierarchical classifica-
terventions in randomized trials and clinical practice.
tion in patients with a recent NSTE-ACS, regardless of
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9. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of nonST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598–660. 10. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329:673–82.
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Clinical Validation of BARC Criteria in ACS Patients
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A PPE NDI X For supplemental tables and figures, please see the online version of this article.
VOL. 67, NO. 18, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2016.02.056
Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes The TRACER Trial Pascal Vranckx, MD, PHD,a Harvey D. White, DSC,b Zhen Huang, MS,c Kenneth W. Mahaffey, MD,d Paul W. Armstrong, MD,e Frans Van de Werf, MD,f David J. Moliterno, MD,g Lars Wallentin, MD, PHD,h Claes Held, MD, PHD,h Philip E. Aylward, MD,i Jan H. Cornel, MD, PHD,j Christoph Bode, MD,k Kurt Huber, MD,l José C. Nicolau, MD, PHD,m Witold Ruzyllo, MD,n Robert A. Harrington, MD,d Pierluigi Tricoci, MD, MHS, PHDc
ABSTRACT BACKGROUND The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed. OBJECTIVES This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries). METHODS We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death. RESULTS During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding. CONCLUSIONS In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943) (J Am Coll Cardiol 2016;67:2135–44) © 2016 by the American College of Cardiology Foundation.
From the aHartcentrum Hasselt, Hasselt, Belgium; bGreen Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand; cDuke Clinical Research Institute, Durham, North Carolina; dStanford University, Stanford, California; eDivision of CarListen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
diology, University of Alberta, Edmonton, Canada; fDepartment of Cardiology, University of Leuven, Leuven, Belgium; gGill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky;
h
Department of Medical
Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; iSAHMRI, Flinders University and Medical Centre, Adelaide, Australia; jDepartment of Cardiology, Medisch Centrum Alkmaar, Alkmaar, the Netherlands; kInternal Medicine and Cardiology, Universitätsklinikum, Freiburg, Germany; l3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria;
m
Heart Institute (InCor), University of São Paulo Medical School, São Paulo,
Brazil; and the nDepartment of Coronary Artery Disease and Cardiac Catheterization Laboratory, Institute of Cardiology, Warsaw, Poland. The TRACER trial was supported by Merck & Co., Inc. Dr. White has received research grants from Sanofi, Eli Lilly, the National Institutes of Health, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi-Sankyo Pharma Development, George Institute, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics Inc., Elsai Inc., and DalGen Products and
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Clinical Validation of BARC Criteria in ACS Patients
ABBREVIATIONS AND ACRONYMS BARC = Bleeding Academic
A
ntithrombotic and revascularization
laboratory
strategies to reduce the risk of recur-
thresholds of clinical or laboratory severity and cor-
evaluation
but
not
meeting
specific
rent ischemic events in patients with
onary artery bypass graft (CABG)-related bleeding.
non–ST-segment elevation acute coronary
The TRACER (Thrombin Receptor Antagonist for
syndromes (NSTE-ACS) are associated with
Clinical Event Reduction in Acute Coronary Syn-
graft
increased
drome) trial was a contemporary trial testing the
CI = confidence interval
bleeding is a central safety outcome in car-
efficacy and safety of the protease-activated receptor-1
diovascular clinical trials, especially for
antagonist vorapaxar against placebo in patients with
form
antithrombotic strategies and invasive pro-
NSTE-ACS in addition to standard of care, where
GUSTO = Global Use of
cedures (1,2).
treatment decisions were made by the treating physi-
Research Consortium
CABG = coronary artery bypass
eCRF = electronic case report
Strategies to Open Occluded Coronary Arteries
risk
of
bleeding.
Therefore,
SEE PAGE 2145
cian (6,7). The large TRACER dataset provides opportunities to: 1) examine the association of BARC-defined
Many definitions of bleeding exist and are
bleeding with mortality over a long follow-up in a
NSTE-ACS = non–ST-segment
used inconsistently in clinical trials and
broad group of NSTE-ACS patients in whom different
elevation acute coronary
registries, making it difficult to compare re-
types of treatment strategies were adopted (PCI, CABG,
sults across trials. Additionally, the prog-
medical treatment); and 2) compare the BARC defini-
nostic impact of bleeding may depend upon
tion with other established bleeding definitions in
definitions used. In 2011, the Bleeding Aca-
predicting mortality.
HR = hazard ratio
syndrome
PCI = percutaneous coronary intervention
TIMI = Thrombolysis In Myocardial Infarction
demic Research Consortium (BARC) proposed standardized bleeding definitions in
METHODS
patients receiving antithrombotic therapy by implementing a hierarchical approach (3). In patients with
STUDY
ACS following a percutaneous coronary intervention
design have been previously reported (6,7). In brief,
DESIGN. The
(PCI), this consensus classification has been shown
TRACER was a multicenter, global, randomized,
to be independently associated with 1-year mortality,
double-blind, event-driven trial with a minimum
but it has not been validated in a broad population
follow-up of 1 year. The study compared placebo with
with ACS, including patients treated with other
vorapaxar administered as a 40 mg loading dose fol-
treatment strategies (4,5). Furthermore, the prog-
lowed by a daily 2.5 mg maintenance dose in patients
nostic value of certain BARC categories has not been
with NSTE-ACS at high risk for recurrent ischemic
established, such as bleeding requiring medical or
events (6,7). Concomitant treatment was according to
trial’s primary results and
Services; and participates in an advisory board at AstraZeneca. Dr. Mahaffey has received research grants from Amgen, Daiichi, Johnson & Johnson, Medtronic, Merck, St. Jude, and Tenax; has provided consulting or other services for the American College Cardiology, AstraZeneca, BAROnova, Bayer, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, Eli Lilly, Elsevier, Epson, Forest, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Mt. Sinai, Myokardia, Omthera, Portola, Purdue Pharma, Springer Publishing, The Medicines Company, Vindico, and WebMD; and has equity in BioPrint Fitness. Dr. Van de Werf has received a research grant, honoraria for lectures, and advisory board membership from Merck & Co. Dr. Moliterno has served on a Data and Safety Monitoring Board for Janssen Pharmaceuticals; and has received research grants from Merck and AstraZeneca. Dr. Wallentin has received research grants from AstraZeneca, Merck & Co., Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Merck & Co.; honoraria from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Merck & Co.; been a consultant/served on an advisory board from Merck & Co., Regado Biosciences, Evolva, Portola, C.S.L. Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Bristol-Myers Squibb/Pfizer; and received travel support from Bristol-Myers Squibb/Pfizer. Dr. Held has received research grants from AstraZeneca, GlaxoSmithKline, Pfizer/Bristol-Myers Squibb, Roche, and Schering-Plough (now Merck); has served on an advisory board for AstraZeneca; and has served as a consultant for Bayer. Dr. Aylward has received a research grant from Merck & Co., AstraZeneca, Sanofi, and GlaxoSmithKline; and has received honoraria/served on a speaker bureau and advisory board for AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer/ Johnson & Johnson, Servier, and Bristol-Myers Squibb. Dr. Cornel has received consulting fees/honoraria from AstraZeneca, MSD, Eli Lilly, and Bristol-Myers Squibb/Pfizer; and travel support from Bayer and AstraZeneca. Dr. Bode has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Sanofi; and speakers’ and consulting honoraria from Bayer, BristolMyers Squibb, and Daiichi-Sankyo. Dr. Huber has received lecture fees from AstraZeneca, Daiichi-Sankyo, Eli Lilly, Sanofi, and The Medicines Company; and a research grant from AstraZeneca. Dr. Nicolau has received a research grant and consultant/advisory fees from Merck; and research grants and/or personal fees (consultancy, lectures, travel support) from Sanofi, AstraZeneca, Daiichi-Sankyo, Bayer/Johnson & Johnson, and Roche, outside the submitted work. Dr. Harrington has received research grants from Merck & Co., Astra, Sanofi, Bristol-Myers Squibb, The Medicines Company, Portola Pharma, and Regado; has consulted for Merck and The Medicines Company; and has served on advisory boards for Gilead and WebMD. Dr. Tricoci has a consultant agreement and has received a research grant from Merck & Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received December 16, 2015; revised manuscript received February 9, 2016, accepted February 24, 2016.
Vranckx et al.
JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2135–44
Clinical Validation of BARC Criteria in ACS Patients
the applicable practice guidelines (e.g., North Amer-
hemoglobin levels, hematocrit levels, and blood
ican, European) (8,9). Subjects who discontinued
transfusions. For patients who underwent CABG
study treatment for any reason were followed for
surgery during the index hospitalization, the eCRF
occurrence of clinical events.
contained data on the occurrence of bleeding and its
The TRACER trial complied with the Declaration of
characteristics. All suspected bleeding events were
Helsinki and was approved by the appropriate na-
prospectively assessed and adjudicated according to
tional and institutional regulatory authorities and
the Thrombolysis In Myocardial Infarction (TIMI)
ethics committees. All patients provided written
classification and the GUSTO (Global Use of Strate-
informed consent. ENDPOINT
DEFINITIONS
gies to Open Occluded Coronary Arteries) classifiFOLLOW-UP. The
cation (10,11). Protocol-defined bleeding and efficacy
main outcome measure for this analysis was all-cause
endpoints included in the primary outcome mea-
mortality. All suspected bleeding events in the
sure were adjudicated by a central clinical events
TRACER trial were systematically identified via an
committee. The BARC consensus document was
integrated
investigator-reported
published while TRACER was being conducted.
events along with central review of relevant data in
BARC bleeding definition criteria were retrospec-
the electronic case report form (eCRF). The eCRF
tively derived using an algorithm on the basis of the
contained information on localization, imaging tests,
adjudicated data points collected during the clinical
assessment
AND
of
CENTRAL ILLUSTRATION BARC Criteria in ACS Patients Without ST-Segment Elevation: Clinical Validation
Vranckx, P. et al. J Am Coll Cardiol. 2016;67(18):2135–44.
This study evaluated the impact of bleeding classified with the BARC scale on mortality in a cohort of patients with non–ST-segment-elevation acute coronary syndrome (N ¼ 12,944) treated according to current clinical practice and enrolled in the TRACER trial. The bleeds classified as BARC grades 2, 3, or 4 were independently associated with an increased risk of mortality, which gradually rose up to 1 year following a bleeding event with an escalating BARC-graded severity of bleeding observed for noncoronary artery bypass graft–related bleeding. The hazard of death associated with BARC grade 3 criteria was similar in magnitude compared with TIMI (major or minor) and GUSTO (moderate or severe) bleeding criteria. The BARC criteria captured a higher proportion of major bleeding compared with both the GUSTO and the TIMI scales alone. ACS ¼ acute coronary syndrome; BARC ¼ Bleeding Academic Research Consortium; GUSTO ¼ Global Strategies for Opening Occluded Coronary Arteries; TIMI ¼ Thrombolysis In Myocardial Infarction; TRACER ¼ Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome.
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JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2135–44
Clinical Validation of BARC Criteria in ACS Patients
quality of data collection was assessed according to
T A B L E 1 Baseline Demographic Characteristics
current regulatory standards (12).
BARC Grades 2–4 (n ¼ 1,975)
BARC Grades 0–1 (n ¼ 10,969)
Age, yrs* N
STATISTICAL ANALYSIS. The analysis population
included all randomized subjects in the TRACER trial. Bleeding events post-randomization to last follow-up
1,975
10,969
67.0 9.8
63.9 9.9
were classified as BARC bleeding categories on the
67.0 (60.0–74.0)
63.0 (57.0–71.0)
basis of the algorithm described in Online Table 2.
33.0, 92.0
29.0, 94.0
The first event of each BARC bleeding category for a
599/1,975 (30.3)
3,033/10,969 (27.7)
subject was included in the analyses described later.
1,702/1,973 (86.3)
9,337/10,936 (85.4)
Black
43/1,973 (2.2)
269/10,936 (2.5)
with and without BARC 2, 3, and 4 bleeding.
Asian
169/1,973 (8.6)
887/10,936 (8.1)
Other race
59/1,973 (3.0)
443/10,936 (4.1)
1,969
10,916
mortality post-bleeding were estimated by the Kaplan-
81.3 18.7
82.7 17.7
Meier method. Mortality rates at 30 days, 1 year, and
80.0 (69.0–92.0)
80.7 (70.0–92.7)
2 years post-bleeding were estimated among subjects
27.0, 181.0
31.8, 190.3
with bleeding events according to the BARC, TIMI, and
200/1,969 (10.2)
787/10,916 (7.2)
Mean SD Median (IQR) Range, min, max Female Race*†
Baseline characteristics were reported for subjects
White
All p values were calculated according to multivariate Cox modeling that included randomized treatment and baseline covariates. Cumulative event rates of
Body weight, kg N Mean SD Median (IQR) Range, min, max <60 kg 2
BMI, kg/m N
GUSTO classifications. Event curves were created to describe the incidence and timing to death post-
1,964
10,888
28.3 5.5
28.6 5.2
27.5 (24.6–30.9)
27.8 (25.1–31.2)
13.8, 58.3
13.8, 74.3
North America
643/1,975 (32.6)
2,761/10,969 (25.2)
were estimated by Cox regression models, in which
Latin America
104/1,975 (5.3)
744/10,969 (6.8)
Europe I
788/1,975 (39.9)
5,051/10,969 (46.0)
bleeding was included as a time-varying covariate in
Europe II
170/1,975 (8.6)
1,317/10,969 (12.0)
Asia
152/1,975 (7.7)
784/10,969 (7.1)
Australia/New Zealand
118/1,975 (6.0)
312/10,969 (2.8)
Hypertension
1,454/1,975 (73.6)
7,674/10,964 (70.0)
might change over time. As a post-randomization risk
Hyperlipidemia
1,287/1,975 (65.2)
6,775/10,961 (61.8)
factor, bleeding occurred in different subjects at
Diabetes mellitus*
605/1,975 (30.6)
3,465/10,963 (31.6)
different times. The bleeding status of all subjects
Former smoker*
455/1,974 (23.0)
3,081/10,963 (28.1)
Current smoker*
731/1,974 (37.0)
3,455/10,963 (31.5)
60/1,871 (3.2)
130/10,390 (1.3)
bleeding.” A subject remained in this category until a
327/1,871 (17.5)
1,150/10,390 (11.1)
bleeding event had occurred and was then reclassified
1,484/1,871 (79.3)
9,110/10,390 (87.7)
as “bleeding.” Prior knowledge suggested that the risk
Mean SD Median (IQR) Range, min, max Region*
bleeding. To evaluate the association between various bleeding classifications and mortality, hazard ratios (HRs) of mortality and 95% confidence intervals (CIs)
addition to the baseline characteristics (as listed in Table 1) and randomized treatment. The time-varying aspect of bleeding was 2-fold: the effect of bleeding and the status of bleeding for a subject, both of which
Cardiovascular risk factors
Renal inefficiency CrCl, ml/min* <30 30–60 $60
Continued on the next page
was examined at each time point since randomization, where everyone was first classified as “no
for mortality following a bleeding event differed in the short and long term; therefore, a piecewise hazard
events committee review. Bleeding definitions are
function was built representing periods within day 30,
provided in Online Table 1 (3). BARC grade 5 is fatal
day 31 to 1 year, and 1 year to 2 years post-bleeding.
bleeding and was not included in the analyses of the
Wald chi-square tests were carried out to examine
relationship with all-cause mortality. Subjects with
whether the HRs were consistent across these pe-
BARC grade 5 were analyzed according to the bleeding
riods. In subjects who had more than 1 bleed during
events before the fatal bleeding event.
follow-up, the subsequent bleeds were included in
The TRACER protocol required that all enrolled
the analyses and analyzed in the same way as the
patients return for study visits at 30 days; at 4, 8, and
initial one. Goodness-of-fit tests of -2 log likelihood
12 months; and then every 6 months thereafter. Pa-
were used to evaluate the improved model perfor-
tients who prematurely discontinued treatment were
mance comparing models with and without bleeding.
followed by telephone at the same intervals. During
These analyses were carried out for bleeding events
follow-up visits, patients underwent a complete
according to BARC, TIMI, and GUSTO classifications.
clinical evaluation. The TRACER trial was part of an investigational
new
drug
application;
therefore,
All statistical tests were 2-sided with a significance level of 0.05; p values are not adjusted for multiple
Vranckx et al.
JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2135–44
Clinical Validation of BARC Criteria in ACS Patients
comparisons. SAS software, version 9.2 (SAS Institute, Cary, North Carolina) was used for statistical analyses.
T A B L E 1 Continued
BARC Grades 2–4 (n ¼ 1,975)
RESULTS
BARC Grades 0–1 (n ¼ 10,969)
Cardiovascular disease history Prior myocardial infarction
579/1,974 (29.3)
3,212/10,964 (29.3)
in 37 countries. Approximately 9 of 10 patients
Prior percutaneous coronary intervention*
451/1,975 (22.8)
2,639/10,959 (24.1)
(n ¼ 11,399; 88%) underwent coronary angiography;
Prior CABG
278/1,975 (14.1)
1,265/10,964 (11.5)
7,075 (54%) patients received a coronary stent; and
Stroke*
115/1,975 (5.8)
438/10,964 (4.0)
1,312 (10%) patients were treated with CABG. The cu-
Peripheral arterial disease
173/1,975 (8.8)
763/10,962 (7.0)
mulative incidence of a BARC bleed of grade 2 or
Positive troponin or CK-MB
A total of 12,944 patients were enrolled at 818 sites
higher from randomization to last follow-up was 15.3% (n ¼ 1,975); 3.7% (n ¼ 484) of patients had a TIMI major or minor bleed and 4.0% (n ¼ 514) of patients had a bleed according to GUSTO severe or moderate
1,852/1,965 (94.2) 10,198/10,892 (93.6)
Electrocardiogram findings ST-segment depression ST-segment elevation Symmetric T-wave inversions
652/1,975 (33.0)
3,547/10,969 (32.3)
99/1,975 (5.0)
637/10,969 (5.8)
425/1,975 (21.5)
2,488/10,969 (22.7)
TIMI risk score‡
criteria. The cumulative incidence of bleeding ac-
0–2
8/1,975 (0.4)
59/10,969 (0.5)
cording to BARC criteria is shown in Online Figure 1.
3–4
928/1,975 (47.0)
5,770/10,969 (52.6)
Baseline demographic characteristics for patients with (BARC 2, 3, or 4) or without (BARC 0 or 1) bleeding are reported in Table 1. Patients with actionable bleeding were older, more frequently from North America, more likely to be current smokers, and have reduced renal function, higher Killip class,
5–7
1,039/1,975 (52.6) 5,140/10,969 (46.9)
Baseline hemoglobin, g/dl* N Mean SD Median (IQR) Range, min, max
1,967
10,902
13.7 1.7
14.0 1.6
13.9 (12.7–14.9)
14.1 (13.0–15.1)
6.0, 20.0
4.3, 20.8
Killip class*§
and a history of prior stroke. Use of glycoprotein IIb/IIIa
I
inhibitors at baseline was also more common in pa-
II
95/1,970 (4.8)
399/10,862 (3.7)
tients with BARC actionable bleeding.
III–IV
42/1,970 (2.1)
88/10,862 (0.8)
Use or intent to use glycoprotein IIb/IIIa at randomization*
476/1,975 (24.1)
2,234/10,969 (20.4)
Use or intent to use direct thrombin inhibitor at randomization
345/1,975 (17.5)
1,811/10,969 (16.5)
1,734/1,975 (87.8)
9,573/10,969 (87.3)
1,120/1,917 (58.4)
6,403/10,598 (60.4)
BLEEDING EVENTS AND MORTALITY. In the 12,944
patients analyzed, there were 652 (5.0%) deaths at 2 years, with 196 (1.5%) deaths occurring within the first 30 days after randomization. The cumulative mortality rates post-bleeding by BARC, TIMI, and GUSTO categories are shown in the Central Illustration.
1,833/1,970 (93.0) 10,375/10,862 (95.5)
Randomization/stratification factors
Antiplatelet at randomization Thienopyridine at baseline* Aspirin dose at baseline, mg
The crude mortality rates were comparable among
#100
patients with BARC grade 3, GUSTO moderate or se-
100–300
vere, and TIMI minor or major bleeding (Table 2).
$300
The association between BARC bleeding and mortality was significant in the 30 days following bleeding and at 1 year post-bleeding (Table 3). In the interval beyond 1 year from bleeding, the hazard decreased and was no longer significant. The hazard of mortality increased progressively with higher non-CABG BARC grades (p for trend <0.0001 within 30 days and be-
135/1,917 (7.0)
914/10,598 (8.6)
662/1,917 (34.5)
3,281/10,598 (31.0)
Values are n/N (%) unless otherwise indicated. *p < 0.05 according to the multivariate Cox modeling of BARC bleeding $2 vs. <2 controlling for randomized treatment and the baseline covariates. †Race or ethnic group was reported by investigators after interviews with patients. ‡The TIMI risk score ranges from 0 to 7, with higher scores indicating greater risk. §According to the Killip classification, class II indicates cardiac S3 or rales on #50% of the lung fields, class III indicates rales on >50% of the lung fields, and class IV indicates signs of cardiogenic shock. BARC ¼ Bleeding Academic Research Consortium; BMI ¼ body mass index; CABG ¼ coronary artery bypass graft; CK-MB ¼ creatinine kinase-myocardial band; CrCl ¼ creatinine clearance; IQR ¼ interquartile range; SD ¼ standard deviation; TIMI ¼ Thrombolysis In Myocardial Infarction.
tween 30 days and 1 year) (Table 2). BARC grade 4 (bleeding following CABG), as a separate grade,
increase in the hazard was observed with BARC
contained a more than 10-fold increase in hazard up to
grades 3 or 4, TIMI major or minor, and GUSTO
30 days but not beyond. The inclusion of BARC
moderate or severe bleeding.
bleeding in a multivariable model predicting mortality significantly improved the goodness of fit (Table 4).
The timing of a BARC 2, 3, or 4 bleed (during the index stay, including bleeding events related to
TIMI major or minor bleeding and GUSTO moderate
instrumentation or trauma; within 7 days of discharge;
or severe bleeding were also significantly associated
and beyond 7 days after discharge) did not affect the
with
mortality
(Tables
to
relationship with mortality (Online Figure 2). Finally,
BARC bleeding, the relationship with mortality was
transfusion was not independently associated with
significant up to 1 year after bleeding, but not there-
mortality and did not confer additional prognostic
after. In comparing the 3 scales, a similar degree of
value on top of BARC criteria (Online Table 3).
3
and
4).
Similar
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Clinical Validation of BARC Criteria in ACS Patients
T A B L E 2 Cumulative Mortality After Bleeding
30 Days Post-Bleeding
Crude Rate
1 Yr Post-Bleeding
Kaplan-Meier Estimated Rate
Crude Rate
Kaplan-Meier Estimated Rate
2 Yrs Post-Bleeding
Crude Rate
Kaplan-Meier Estimated Rate
BARC Grade 1
17/1,584 (1.1)
1.1 (0.6–1.6)
59/1,584 (3.7)
4.2 (3.2–5.2)
73/1,584 (4.6)
6.1 (4.6–7.6)
Grade 2
19/1,320 (1.4)
1.5 (0.9–2.1)
71/1,320 (5.4)
6 (4.6–7.4)
83/1,320 (6.3)
8.2 (6.3–10.1)
Grade 3a
15/344 (4.4)
4.4 (2.2–6.6)
43/344 (12.5)
14.2 (10.2–18.2)
52/344 (15.1)
19.8 (14.6–25)
Grade 3b
30/250 (12.0)
12.2 (8.1–16.3)
50/250 (20.0)
21.3 (16–26.6)
51/250 (20.4)
22.5 (16.8–28.2)
Grade 3c
23/68 (33.8)
33.9 (22.6–45.2)
30/68 (44.1)
48.4 (35–61.8)
30/68 (44.1)
48.4 (35–61.8)
Grade 4
14/155 (9.0)
9.1 (4.6–13.6)
22/155 (14.2)
14.5 (8.9–20.1)
22/155 (14.2)
14.5 (8.9–20.1)
Grades 2–4
80/1,975 (4.1)
4.1 (3.2–5.0)
180/1,975 (9.1)
9.9 (8.5–11.3)
200/1,975 (10.1)
12.3 (10.6–14)
Grades 3, 4
74/773 (9.6)
9.7 (7.6–11.8)
133/773 (17.2)
18.5 (15.6–21.4)
143/773 (18.5)
21.4 (18.1-24.7)
54/280 (19.3)
19.4 (14.8–24)
76/280 (27.1)
28.3 (22.8–33.8)
78/280 (27.9)
30.0 (24.2–35.8)
76/783 (9.7)
9.8 (7.7–11.9)
134/783 (17.1)
18.3 (15.5–21.1)
146/783 (18.6)
21.4 (18.2–24.6)
Major
56/406 (13.8)
13.9 (10.5–17.3)
84/406 (20.7)
21.7 (17.6–25.8)
85/406 (20.9)
22.4 (18–26.8)
Major or minor
64/625 (10.2)
10.3 (7.9–12.7)
106/625 (17.0)
18.1 (14.9–21.3)
111/625 (17.8)
20.0 (16.5–23.5)
GUSTO Severe Moderate or severe TIMI
Values are n/N (%) or % (IQR). GUSTO ¼ Global Use of Strategies to Open Occluded Coronary Arteries; other abbreviations as in Table 1.
COMPARISON OF BLEEDING DEFINITIONS. In the dis-
classification of severity is necessary. The BARC
tribution of bleeding using BARC, TIMI major/minor,
consensus document proposed a hierarchical grading
and GUSTO moderate/severe criteria (Table 5), only
system to classify bleeding events in cardiovascular
one-half of BARC 3 bleeds were concomitantly
investigations (3), but validation (especially on its
captured in both the TIMI minor or major and GUSTO
prognostic implication) is required. We studied the
moderate or severe categories. Of the remaining BARC
impact of bleeding classified with the BARC scale on
3 bleeds, approximately 30% were captured as GUSTO
mortality in a cohort of patients with NSTE-ACS
moderate or severe only (but not TIMI major or minor)
treated according to current clinical practice and
and approximately 20% were captured as TIMI major
enrolled in the TRACER trial. We concluded that
or minor only (but not GUSTO moderate or severe).
bleeds classified as BARC grades 2, 3, or 4 were
There were 159 bleeds that were not classified by
independently associated with an increased risk of
BARC criteria. Those were CABG-related bleeds that
mortality. Blood transfusion for bleeding was not an
were classified as GUSTO moderate or severe but did
independent predictor for mortality after full adjust-
not meet the BARC CABG definition. In fact, trans-
ment for all available variables and bleeding. There
fusion and hemodynamic instability, key elements of
was a gradual increase in the risk of mortality up to
the GUSTO criteria, are not part of the BARC 4 criteria.
1 year following a bleeding event with an increasing
To understand the additive predictive value of
BARC-graded severity of bleeding.
bleeding grades on mortality, we first created a
The strengths of our analysis relied on the
multivariable model to predict 1-year mortality using
extended follow-up, the well-described and contem-
baseline characteristics and then added various
porary NSTE-ACS patient population, and the pro-
bleeding classifications to assess to what degree the
spective collection and blinded adjudication of
inclusion of bleeding scales in the mortality model
bleeding events. TRACER patients were largely
would improve the prediction capability of the
included with positive biomarkers and then treated
model. The inclusion of BARC 2, 3, or 4 and of BARC
with a variety of strategies according to modern
3 or 4 criteria to the baseline model significantly
standards of care and physicians’ choices. More than
increased the predictive value of the model (Table 4),
90% of patients in TRACER had positive troponin,
to a similar degree as TIMI minor or major bleeding
90% underwent diagnostic angiography, and nearly
and GUSTO moderate or severe bleeding.
60% underwent PCI. One of 10 patients had CABG
DISCUSSION
during the index hospitalization.
Bleeds are not equal and do not carry the same
bleeding scales used for the main safety analysis and
hazard for mortality over time; therefore, accurate
reporting in the TRACER trial. The TIMI definition
The TIMI and GUSTO criteria were the prespecified
Vranckx et al.
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Clinical Validation of BARC Criteria in ACS Patients
T A B L E 3 Association of Bleeding and Mortality
HR (95% CI)* p Value
p Value for Testing Same HR
30 Days Post-Bleeding
31 Days–1 Yr Post-Bleeding
1–2 Years Post-Bleeding
Grades 2–4 vs. <2
7.35 (5.59–9.68) <0.0001
2.56 (2.02–3.25) <0.0001
1.24 (0.75–2.04) 0.4043
<0.0001
<0.0001
<0.0001
Grades 3, 4 vs. <3
14.25 (10.72–18.94) <0.0001
3.36 (2.51–4.51) <0.0001
1.64 (0.86–3.14) 0.1340
<0.0001
0.0446
<0.0001
Grade 1
1.74 (1.06–2.86) 0.0282
1.06 (0.75–1.49) 0.7377
1.13 (0.65–1.97) 0.6683
0.1010
0.8454
0.2751
Grade 2
2.23 (1.38–3.61) 0.0011
1.70 (1.25–2.32) 0.0008
1.00 (0.52–1.90) 0.9950
0.3431
0.1379
0.1582
Grade 3a
4.54 (2.68–7.70) <0.0001
2.61 (1.75–3.89) <0.0001
3.10 (1.56–6.16) 0.0012
0.0948
0.6611
0.5749
Grade 3b
11.60 (7.47–18.03) <0.0001
3.26 (2.03–5.23) <0.0001
0.56 (0.08–4.06) 0.5697
<0.0001
0.0893
<0.0001
0.000 0.9902
<0.0001
0.9882
0.0021
<0.0001
0.9598
0.0003
Bleeding Categories
Day 30, 1 Yr 1 Yr, 2 Yrs Day 30, 1 Yr, 2 Yrs
BARC
Compared with grade 0
Grade 3c Grade 4
58.07 (34.39–98.04) 10.75 (5.04–22.94) <0.0001 <0.0001 10.05 (5.41–18.69) <0.0001
1.11 (0.45–2.71) 0.8204
0.000 0.9601
<0.0001
<0.0001
0.0357
Major or minor vs. not major/minor
16.30 (12.08–21.99) <0.0001
3.25 (2.31–4.56) <0.0001
0.99 (4.41–2.44) ¼0.9897
<0.0001
0.0248
<0.0001
Major vs. not major
22.65 (16.49–31.09) <0.0001
3.08 (2.02–468) <0.0001
0.31 (0.04–2.22) 0.2426
<0.0001
0.0248
<0.0001
2.72 (1.52–4.87) 0.0007
1.37 (0.86–2.19) 0.1808
0.39 (0.10–1.60) 0.1908
0.0638
0.0943
0.0219
Minor
7.29 (2.95–18.00) <0.0001
1.89 (0.69–5.18) 0.2139
0.000 0.9527
0.0479
0.9498
0.1410
Major
22.43 (13.54–37.15) <0.0001
6.16 (3.55–10.69) <0.0001
1.34 (0.19–9.67) ¼0.7720
0.0005
0.1437
0.0002
Moderate or severe vs. not moderate/severe
14.20 (0.69–18.88) <0.0001
3.09 (2.30–4.16) <0.0001
1.75 (0.96–3.18) 0.0658
<0.0001
0.8970
<0.0001
Severe vs. not severe
29.25 (21.07–40.62) <0.0001
4.12 (2.61–6.50) <0.0001
0.96 (0.24–3.88) 0.9494
<0.0001
0.0501
<0.0001
Mild
0.95 (0.46–2.00) 0.9003
0.74 (0.44–1.26) 0.2697
0.72 (0.26–1.96) 0.5201
0.5821
0.9585
0.8422
Moderate
7.43 (4.01–13.76) <0.0001
3.70 (2.22–6.19) <0.0001
0.00 (0.00–0.00) 0.9505
0.0790
0.9446
0.2132
28.45 (16.88–47.93) <0.0001
6.74 (3.54–12.82) <0.0001
1.70 (0.24–12.24) 0.5999
0.0005
0.1918
0.0002
Test of trend across grades 1, 2, 3a–3c TIMI
Compared with no TIMI bleeding Needing medical attention
GUSTO
Compared with no GUSTO bleeding
Severe
*HR is estimated by Cox regression model of all-cause mortality with bleeding class as a time-varying factor and with different HR estimated at 30 days, 1 yr, and 2 yrs postbleeding, adjusted for baseline covariates and randomized treatment. Baseline covariates are: demographics (age, sex, race, region, body weight, BMI), cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, smoking), renal inefficiency, cardiovascular disease history (prior myocardial infarction, percutaneous coronary intervention, CABG, stroke, peripheral arterial disease), features on presentation (heart rate, blood pressure, ST-segment deviation, Killip class), and treatment received (glycoprotein IIb/IIIa inhibitor, aspirin dose, and thienopyridine use). BARC grade 5 is fatal bleeding. Subjects with BARC grade 5 bleeding were analyzed on the basis of bleeding assessments before the fatal event. CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.
integrates mainly laboratory-based data, whereas the
the TIMI and GUSTO scales (5). The hazard of death
GUSTO definition is largely clinically based (10,11).
associated with BARC grade 3 criteria was similar in
For this analysis, all bleeding events were reclassified
magnitude compared with TIMI (major or minor) and
according to the BARC hierarchical bleeding scale
GUSTO (moderate or severe) bleeding criteria. How-
(grade 2, 3, or 4) using data prospectively collected as
ever, our analysis demonstrated that BARC classifica-
part of the clinical event committee adjudication for
tion is potentially able to capture a larger proportion
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Clinical Validation of BARC Criteria in ACS Patients
that the impact of bleeding on the risk of death is
T A B L E 4 Mortality Models: Improvement in Goodness of Fit*
Change in -2log Likelihood vs. Baseline Model†
Covariates
increased only for a certain period after the event (13). Degrees of Freedom
p Value
Baseline þ BARC
The vast majority of bleeding events occurred early after randomization. However, in the current analysis we could not demonstrate a differential hazard for
$2
10,326–10,136 ¼ 190
3
<0.0001
$3
10,326–10,054 ¼ 272
3
<0.0001
mortality by BARC-graded bleeding occurring during
Baseline þ TIMI major
10,326–10,100 ¼ 226
3
<0.0010
the index stay, including the majority of instru-
Baseline þ TIMI major or minor
10,326–10,096 ¼ 230
3
<0.0001
mented and traumatic bleeds, and after discharge.
Baseline þ GUSTO severe
10,326–10,090 ¼ 236
3
<0.0001
Interestingly, in TRACER, even BARC 1 bleeds—
Baseline þ GUSTO moderate or severe
10,326–10,074 ¼ 252
3
<0.0001
recently shown to be associated with decreased shortand
long-term
quality
of
life
(14)—carried
an
increased hazard of death up to 30 days.
*After including bleeding classifications. †Bigger changes indicate more improved fit.
Finally, this analysis provides a first validation of
Abbreviations as in Tables 1 and 2.
BARC 4 grade (CABG-related) bleeding in a large of clinically significant bleeding than either the GUSTO
cohort of patients with ACS (1,312 patients underwent
or TIMI scales. We showed that TIMI major or minor
CABG during the index hospitalization). We observed
criteria only capture about 70% of bleeds meeting
that BARC 4–defined CABG-related bleeding carried a
BARC 3 criteria, whereas GUSTO moderate or severe
high 30-day HR, similar to BARC 3b grade, but leveled
criteria capture approximately 80% of BARC 3
off thereafter.
bleeding. The similar prognostic significance of the 3
Our findings complement the results from TRITON-
scales, but with a more inclusive set of criteria in the
TIMI 38 (Trial to Assess Improvement in Therapeutic
BARC scale, may make BARC a more desirable bleeding
Outcomes by Optimizing Platelet Inhibition with
scale given the possibility to capture more bleeding.
Prasugrel–Thrombolysis In Myocardial Infarction 38)
Not surprisingly, BARC 3C (intracranial) bleeding
and PRODIGY (Prolonging Dual Antiplatelet Treat-
events were associated with the worst prognosis.
ment After Grading Stent-Induced Intimal Hyperpla-
Blood transfusion for bleeding was not an indepen-
sia) (5,15). In both trials, which were confined to
dent predictor for mortality after full adjustment for
patients presenting with ACS undergoing an early
baseline variables, treatment regimen, and BARC-
invasive treatment strategy, the impact of bleeding
graded bleeding.
on mortality was restricted to more serious bleeding
The increase in mortality was significant up to 1
events. Focusing on the time dependency of this
year after a BARC actionable bleeding, whereas the
relationship, the associated HR was similar for
relationship between bleeding and mortality became
bleeding events occurring during the index hospital-
weaker and nonsignificant beyond 1 year from the
ization—clustering the instrumented bleeds—or post-
bleed. The reason for this finding is not entirely clear,
discharge. This finding points to the detrimental
but it is possible that patients at a higher risk of
nature of a major bleed per se, regardless of the
mortality have a fatal outcome relatively early after a
timing of the index procedure or randomization. The
bleed so those who survive beyond 1 year represent a
decline in the hazard for mortality late after a first
lower risk group. On the other hand, it may also be
serious non-CABG bleeding event is biologically
T A B L E 5 Distribution of All Bleeding Events*
TIMI Major/Minor and GUSTO Severe/Moderate
TIMI Major/Minor but not GUSTO Severe/Moderate
GUSTO Severe/Moderate but not TIMI Major/Minor
Other TIMI and GUSTO Categories
Total
159 (3.21)
64 (1.29)
223 (4.50)
Not classified by BARC
0 (0.00)
0 (0.00)
BARC 1
0 (0.00)
0 (0.00)
0 (0.00)
2,183 (44.09)
2,183 (44.09)
BARC 2
0 (0.00)
0 (0.00)
0 (0.00)
1,591 (32.13)
1,591 (32.13)
BARC 3a
103 (2.08)
120 (2.42)
155 (3.13)
0 (0.00)
378 (7.63)
BARC 3b
206 (4.16)
19 (0.38)
40 (0.81)
0 (0.00)
265 (5.35)
72 (1.45)
0 (0.00)
0 (0.00)
23 (0.46)
95 (1.92)
7 (0.14)
0 (0.00)
0 (0.00)
166 (3.35)
BARC 3c BARC 4 BARC 5 Total
159 (3.21) 0 (0.00) 540 (10.91)
Values are n (%). *By BARC, TIMI, and GUSTO bleeding definitions. Abbreviations as in Tables 1 and 2.
0 (0.00) 146 (2.95)
0 (0.00) 354 (7.15)
50 (1.01)
50 (1.01)
3,911 (78.99)
4,951 (100.00)
Vranckx et al.
JACC VOL. 67, NO. 18, 2016 MAY 10, 2016:2135–44
Clinical Validation of BARC Criteria in ACS Patients
plausible and may explain the attenuation in the
the initial treatment strategy, BARC bleeding grades
hazard beyond 1 year in our analysis.
independently and incrementally predicted 1-year
In TRACER, we could not detect any additional risk
mortality. BARC grade 3 had a hazard of death similar
for 30-day or 1-year mortality with blood transfusion
to that provided by TIMI and GUSTO scales, but could
for bleeding beyond the BARC serious (grade 3 or 4)
capture more bleeding than TIMI major or minor or
events. Use of transfusion is highly variable, and local
GUSTO moderate or severe criteria only. These data
policy may differ across centers and providers, which
add to the clinical validity of the BARC classification
may explain this finding. Information on policy and
that, by integrating elements of both GUSTO and TIMI
guidance adopted in the use of blood transfusion was
scales, may be helpful to standardize bleeding
not collected.
endpoint definitions in clinical investigations and
STUDY LIMITATIONS. The most relevant limitation
may thus be used in addition to or in substitution of
of the present analysis is the different timing of
these 2 scales.
the adjudication of bleeding. More specifically, bleeding according to BARC criteria was derived
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
retrospectively, although it was on the basis of
Pierluigi Tricoci, Duke Clinical Research Institute,
prospectively collected data by a central adjudica-
Box 3850, 2400 Pratt Street, Durham, North Car-
tion committee.
olina 27705. E-mail: [email protected].
Although TRACER did not have significant exclusion criteria on the basis of the presumed risk of
PERSPECTIVES
bleeding, patients with active bleeding, hemorrhagic diathesis, or history of intracranial hemorrhage at any time were excluded. Patients with concomitant or foreseeable need for oral anticoagulation were not included in the trial. Even after adjustment, the possibility of residual confounding remains for the relationship between bleeding and mortality. For the outcome analysis, models were adjusted for baseline variables but not for post-randomization factors, such as recurrent myocardial infarction or reinterventions during follow-up.
COMPETENCY IN PRACTICE-BASED LEARNING: In patients with non–ST-segment elevation acute coronary syndromes, bleeding is a composite endpoint associated with a risk of mortality over the course of the subsequent year. The Bleeding Academic Research Consortium criteria capture most overt bleeding events and therefore form a meaningful tool for assessment of the safety of antithrombotic therapy. TRANSLATIONAL OUTLOOK: Further studies are needed to develop methods for integrated assessment of both safety and
CONCLUSIONS
efficacy to reflect the net clinical benefit of antithrombotic in-
In this validation of the BARC hierarchical classifica-
terventions in randomized trials and clinical practice.
tion in patients with a recent NSTE-ACS, regardless of
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A PPE NDI X For supplemental tables and figures, please see the online version of this article.