Coronary Heart Disease

Biomarkers in Relation to the Effects of Ticagrelor in

Comparison With Clopidogrel in Non–ST-Elevation Acute
Coronary Syndrome Patients Managed With or Without
In-Hospital Revascularization
A Substudy From the Prospective Randomized Platelet Inhibition and
Patient Outcomes (PLATO) Trial
Lars Wallentin, MD, PhD; Daniel Lindholm, MD; Agneta Siegbahn, MD, PhD;
Lisa Wernroth, MSc; Richard C. Becker, MD; Christopher P. Cannon, MD;
Jan H. Cornel, MD, PhD; Anders Himmelmann, MD, PhD; Evangelos Giannitsis, MD;
Robert A. Harrington, MD; Claes Held, MD, PhD; Steen Husted, MD, DSc;
Hugo A. Katus, MD; Kenneth W. Mahaffey, MD; Ph. Gabriel Steg, MD;
Downloaded from http://circ.ahajournals.org/ by guest on September 2, 2017

Robert F. Storey, MD, DM; Stefan K. James, MD, PhD, for the PLATO study group

Background—Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients
with non–ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-
sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation
factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with
or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial.
Methods and Results—Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline
blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without
revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels.
Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular
death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively.
NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor
versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS
and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there
was no difference between ticagrelor and clopidogrel in the noninvasive group
Conclusions—Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke
in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively.
Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed
patients, but no apparent benefit was seen at normal hs-TnT.
Clinical Trial Registration—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.  
(Circulation. 2014;129:293-303.)
Key Words: acute coronary syndrome ◼ biological markers ◼ blood platelets ◼ myocardial infarction ◼ troponin

Received June 21, 2013; accepted September 9, 2013.

From the Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., D.L., L.W.,
C.H., S.K.J.); Department of Medical Sciences, Clinical Chemistry and Uppsala Clinical Research Center Uppsala University, Uppsala, Sweden (A.S.);
Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, Academic Health Center, Cincinnati, OH (R.C.B.); Department of
Medicine, Stanford University, Stanford, CA (R.A.H., K.W.M.); TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston,
MA (C.P.C.); Department of Cardiology, Medisch Centrum Alkmaar, Alkmaar, Netherlands (J.H.C.); AstraZeneca Research and Development, Mölndal,
Sweden (A.H.); Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany (E.G., H.A.K.); Medical Department, Hospital Unit West,
Herning/Holstbro, Denmark (S.H.); INSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE,
Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France; NHLI Imperial College, ICMS, Royal Brompton Hospital,
London, UK (P.G.S.); and Department of Cardiovascular Science, University of Sheffield, Sheffield, UK (R.F.S.).
Guest Editor for this article was Eric R. Bates, MD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
113.004420/-/DC1.
Correspondence to Lars Wallentin, MD, PhD, Uppsala Clinical Research Center, Dag Hammarskjölds väg 14B, Box 6363, 751 85 Uppsala University
Hospital, Uppsala, Sweden. E-mail Lars.Wallentin@ucr.uu.se
© 2013 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.004420

293
 294  Circulation  January 21, 2014
D espite guideline recommendations of invasive treat-
ment,1,2 a substantial proportion of patients with non–ST-
elevation acute coronary syndrome (NSTE-ACS) and elevated
troponin is managed without early invasive procedures,3–5
using the invasive approach only in the case of remaining
signs or symptoms of ischemia.6,7 To select the most appro-
priate strategy, both clinical risk scores and the use of bio-
markers have been advocated. Over the past decades, elevated
levels of troponin,8–10 N-terminal probrain natriuretic peptide
(NT-proBNP),11,12 and growth differentiation factor-15 (GDF-
15)13–15 have been associated with worse outcome and benefit
of an early invasive strategy. Elevated levels of troponin have
also been found to identify those with larger benefit from anti-
thrombotic treatment, eg, glycoprotein IIb/IIIa inhibitors,16
and low-molecular-weight heparins.17 Currently, troponin is
the only biomarker recommended to be included among the
factors used for decision support in the treatment guidelines.1,2
Editorial see p 278
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Clinical Perspective on p 303
The Platelet Inhibition and Patient Outcomes (PLATO) trial
recently showed that the oral P2Y12-inhibitor ticagrelor, in
comparison with clopidogrel, reduced the incidence of cardio-
vascular (CV) death, myocardial infarction (MI), and stroke in
18 624 patients with NSTE-ACS or ST-elevation ACS during
6 to 12 months of treatment.3 The study included a biomarker
substudy where a prespecified objective was to evaluate if entry
levels of a specific biomarker might identify patient groups
with different effects of ticagrelor compared with clopidogrel.
In the present study, we investigated the prognostic impor-
tance of high-sensitivity troponin T (hs-TnT), NT-proBNP,
and GDF-15 in relation to randomized treatment (ticagrelor in
comparison with clopidogrel) managed with or without revas-
cularization in the NSTE-ACS subgroup of the PLATO trial.
Methods
Details of the design, patients, and outcome definitions, and results
for the overall PLATO study have been published.3,5 The PLATO trial
enrolled in total 18 624 patients presenting with ACS from 43 coun-
tries between October 2006 and July 2008. The present study focused
on the 9962 patients who fulfilled the criteria for NSTE-ACS and
also at randomization provided blood samples for biomarker analy-
ses. NSTE-ACS was defined as the absence of ST-segment elevation
or new left bundle-branch block; and at least 2 of the following 3 were
required for eligibility: (1) ST-segment depression or transient eleva-
tion ≥ 1 mm in ≥2 contiguous leads, (2) positive biomarker of myo-
cardial necrosis, (3) and 1 additional risk factor.5 The most important
exclusion criteria included contraindication to clopidogrel, fibrino-
lytic therapy within 24 hours, need for oral anticoagulation therapy,
need for dialysis, and clinically important anemia or thrombocytope-
nia. The trial was approved by ethical review boards and adhered to
the ethical principles of the Declaration of Helsinki. All patients gave
a written informed consent.
Study Medication
Patients were randomly assigned to treatment with ticagrelor or clopi-
dogrel. Ticagrelor was given with a loading dose of 180 mg followed
by 90 mg twice daily. Patients randomly assigned to clopidogrel who
had not received an open-label loading dose and had not been taking
clopidogrel for at least 5 days before randomization received a 300-
mg loading dose of clopidogrel study drug followed by 75 mg daily.
Others continued on a maintenance dose of 75 mg of clopidogrel
daily. All patients received acetylsalicylic acid unless intolerant. The
randomized treatment continued from a minimum of 6 to a maximum
of 12 months with a median duration of study treatment of 9.1 months
in the overall population.
Definition of Invasive or Noninvasive Treatment
At the time of randomization, patients were designated as planned
for initial invasive or initial conservative management by the treat-
ing physician within the interactive voice randomization system.
However, this initial decision was not binding and frequently
changed during hospital stay. For this analysis, we therefore clas-
sified the patients as in-hospital invasive if percutaneous coronary
intervention (PCI) or coronary artery bypass grafting (CABG) was
performed during the initial hospital stay, and otherwise as in-hos-
pital noninvasive.
Outcome Events
The primary outcome variable was time to first occurrence of any
event from the composite of CV death, MI, or stroke. Other outcome
variables included CV death and MI, the individual components of
the primary composite, and total death. The MI events were also clas-
sified post hoc according to the universal MI definition from 200718
before the revised definition published in 201219 as either (1) all MI
not associated with PCI, CABG, stent thrombosis, or death; (2) MI
associated with death (type 3); (3) MI associated with PCI (type 4a);
(4) MI associated with stent thrombosis (type 4b); or (5) MI asso-
ciated with CABG (type 5). In these analyses the separate types of
MI were stratified into spontaneous (nonprocedure-related) MI and
directly procedure-related (type 4a or type 5) MI. The reason for the
latter approach was the difference in long-term clinical consequences
between spontaneous and periprocedural events,20 the need to include
nonclassifiable “silent” MI, and the influence of admission levels
of hs-TnT on the possibility to diagnose periprocedural events. All
events were centrally adjudicated and classified by an independent
adjudication committee using previously published definitions.3,5
Biomarkers – Sampling and Methods
Blood samples were obtained via a direct venous puncture from
patients providing informed consent for the biomarker substudy at
randomization. This was at a median of 15 hours (Q1–Q3 8–21 hours)
after the index event, or 10 hours (Q1–Q3 3–17 hours) after admis-
sion. Plasma was frozen in aliquots and stored at –70°C until analyzed
centrally at the Uppsala Clinical Research Center laboratory. Hs-TnT
(lot number 153 401), NT-proBNP, and GDF-15 were determined
with sandwich immunoassays on the Cobas Analytics e601 and c501
Immunoanalyzer (Roche Diagnostics) according to the instructions
of the manufacturer. The Elecsys GDF-15 precommercial assay
(Roche Diagnostics) is composed of a monoclonal mouse antibody
for capture and a monoclonal mouse antibody fragment (F(ab′)2) for
detection, and uses a sandwich assay format. Detection is based on an
electrochemiluminescence immunoassay, using a ruthenium(II) com-
plex label.6 The precommercial assay correlates closely with a pre-
viously established immunoradiometric assay method21 (r=0.9801,
regression Passing/Bablok: slope, 1.049; intercept, −136 ng/L). The
assay is reported to have an interassay coefficient of variation of 2.3%
at 100 ng/L and 1.8% at 17 200 ng/L. The intra-assay coefficient of
variation was 0.8% at 1100 ng/L and 0.9% at 18 600 ng/L. The lower
detection limit was <10 ng/L (information by Roche Diagnostics).
Statistical Analysis
Baseline characteristics were summarized by using frequencies
for categorical variables and medians with interquartile intervals
for continuous variables. For test of differences among groups, the
χ2 test or Fisher exact test was used for categorical variables, and
the Wilcoxon rank sum test was used for continuous variables. The
tested cutoff levels of the biomarkers for discriminative purposes
were based on previous studies (hs-TnT, 14.0 ng/L; NT-proBNP,
400 and 1000 ng/L; and GDF-15, 1200 and 1800 ng/L).13,14,22–24 Also,
quartiles of the distribution in the current material were investigated
as sensitivity analyses.
 Wallentin et al   Biomarkers and Ticagrelor in Non–ST-elevation ACS   295

Table.  Baseline Characteristics and Biomarkers

In-Hospital Invasive Noninvasive
Ticagrelor Clopidogrel Ticagrelor Clopidogrel
Group of Characteristics Characteristic n=2697 n=2660 P Value* n=2302 n=2287 P Value*
Demographics Age, y, median (Q1–Q3) 63 (55–70) 63 (55–71) 0.7117 65 (57–73) 65 (57–74) 0.8811
Age ≥75 y 395 (14.6) 424 (15.9) 0.1882 459 (19.9) 504 (22.0) 0.0809
Female 660 (24.5) 685 (25.8) 0.2800 912 (39.6) 900 (39.4) 0.8544
Weight, kg median (Q1–Q3) 80 (71–91) 80 (70–90) 0.3839 79 (69–89) 77 (68–88) 0.1114
Risk factor Habitual smoker 924 (34.3) 890 (33.5) 0.5353 517 (22.5) 573 (25.1) 0.0388
Hypertension 1765 (65.4) 1747 (65.7) 0.8572 1745 (75.8) 1701 (74.4) 0.2638
Dyslipidemia 1427 (52.9) 1479 (55.6) 0.0498 1178 (51.2) 1116 (48.8) 0.1076
Diabetes mellitus 710 (26.3) 686 (25.8) 0.6549 750 (32.6) 665 (29.1) 0.0102
Medical history Angina pectoris 1256 (46.6) 1261 (47.4) 0.5400 1366 (59.3) 1319 (57.7) 0.2521
Myocardial infarction 586 (21.7) 573 (21.5) 0.8684 688 (29.9) 697 (30.5) 0.6636
Congestive heart failure 102 (3.8) 106 (4.0) 0.7006 262 (11.4) 292 (12.8) 0.1495
PCI 487 (18.1) 467 (17.6) 0.6320 350 (15.2) 345 (15.1) 0.9105
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CABG 194 (7.2) 197 (7.4) 0.7646 196 (8.5) 225 (9.8) 0.1203
TIA 85 (3.2) 75 (2.8) 0.4752 88 (3.8) 99 (4.3) 0.3860
Nonhemorrhagic stroke 85 (3.2) 94 (3.5) 0.4364 142 (6.2) 123 (5.4) 0.2511
Peripheral arterial disease 173 (6.4) 176 (6.6) 0.7645 192 (8.3) 182 (8.0) 0.6358
Chronic renal disease 112 (4.2) 99 (3.7) 0.4175 131 (5.7) 148 (6.5) 0.2685
Risk indicators ST-segment depression ≥1 mm 1468 (54.4) 1447 (54.4) 0.9810 1397 (60.7) 1449 (63.4) 0.0622
non-STEMI TIMI NSTE-ACS risk score >4 1304 (48.4) 1258 (47.3) 0.4388 834 (36.2) 854 (37.3) 0.4347
Antithrombotic treatment Aspirin 2638 (97.8) 2592 (97.4) 0.3750 2214 (96.2) 2199 (96.2) 0.9760
in hospital
Other medication in β-Blockade 2379 (88.2) 2357 (88.6) 0.6476 1921 (83.4) 1889 (82.6) 0.4616
hospital ACE inhibitor or ARB 2242 (83.1) 2190 (82.3) 0.4394 1849 (80.3) 1820 (79.6) 0.5500
Statin 2616 (97.0) 2580 (97.0) 0.9928 2045 (88.8) 2035 (89.0) 0.8423
Ca-inhibitor 604 (22.4) 638 (24.0) 0.1680 616 (26.8) 609 (26.6) 0.9275
Diuretic 947 (35.1) 921 (34.6) 0.7073 1020 (44.3) 960 (42.0) 0.1135
Proton pump inhibitor 1377 (51.1) 1330 (50.0) 0.4392 817 (35.5) 793 (34.7) 0.5695
Invasive procedures All PCI 2379 (88.2) 2330 (87.6) 0.4900 204 (8.9) 229 (10.0) 0.1822
All CABG 392 (14.5) 400 (15.0) 0.6041 217 (9.4) 211 (9.2) 0.8153
GDF-15, 3 groups <1200 ng/L 839 (31.1) 876 (32.9) 0.1758 552 (24.0) 522 (22.8) 0.6440
1200–1800 ng/L 913 (33.9) 912 (34.3) 721 (31.3) 732 (32.0)
>1800 ng/L 945 (35.0) 872 (32.8) 1029 (44.7) 1033 (45.2)
NT-proBNP, 3 groups <400 ng/L 1096 (40.6) 1094 (41.1) 0.0492 869 (37.7) 873 (38.2) 0.9369
400–1000 ng/L 801 (29.7) 716 (26.9) 557 (24.2) 555 (24.3)
>1000 ng/L 800 (29.7) 850 (32.0) 876 (38.1) 859 (37.6)
hs-TnT, 2 groups <14 ng/L 181 (6.7) 165 (6.2) 0.4493 517 (22.5) 496 (21.7) 0.5290
≥14 ng/L 2516 (93.3) 2495 (93.8) 1785 (77.5) 1791 (78.3)
hs-TnT, 4 groups <14 ng/L 181 (6.7) 165 (6.2) 0.8947 517 (22.5) 496 (21.7) 0.5252
14–134 ng/L 792 (29.4) 780 (29.3) 654 (28.4) 629 (27.5)
135–494 ng/L 888 (32.9) 886 (33.3) 528 (22.9) 566 (24.7)
>495 ng/L 836 (31.0) 829 (31.2) 603 (26.2) 596 (26.1)
Values are proportion (%) or median (interquartile range). ACE indicates angiotensin-converting-enzyme; ARB, angiotensin II receptor blockers; CABG, coronary artery
bypass grafting; GDF-15, growth differentiation factor-15; hs-TnT, high-sensitivity troponin T; NSTE-ACS, non–ST-elevation acute coronary syndrome; NT-proBNP,
N-terminal pro-brain natriuretic peptide; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack; and TIMI,
Thrombolysis in Myocardial Infarction.
*P values from χ2/Fisher exact test (categorical variables) or Wilcoxon rank-sum test (continuous variables).

The treatment effects in relation to the levels of the biomarkers Biomarkers and their interaction with the randomized treatment
were evaluated with a Cox proportional hazards model within the were entered as dependent variables by using dummy variables. In
in-hospital invasive and noninvasive treatment groups, respectively. all models, age, sex, diabetes mellitus, smoking status, hypertension,
 296  Circulation  January 21, 2014

congestive heart failure, peripheral arterial disease, previous MI, pre-
vious PCI, previous CABG, ST depression in ECG at entry, and the
declaration of planned invasive or noninvasive treatment at random-
ization were included. The results from the models were presented as
estimated hazard ratios, with 95% confidence intervals, of the treat-
ment effect of ticagrelor using clopidogrel as reference. The treatment
hazard ratios were reported for each level of the biomarker, regardless
of the significance of interaction. The proportional hazards assump-
tion, with respect to the cardiac biomarkers, was assessed by visual
inspection of log-cumulative hazard plots. Kaplan-Meier curves were
estimated for the time to event for each cutoff range of the biomarker
and the log-rank test was calculated. All analyses were performed by
using SAS version 9.2. A P value of 0.05 was used as a critical value
determining statistical significance, and there were no adjustments
for multiple comparisons.
invasively and noninvasively managed patients, with the
exception that there were somewhat more smokers in the clop-
idogrel group in the in-hospital noninvasive arm. As expected,
there were differences in characteristics in relation to the in-
hospital invasive or noninvasive treatment. Patients treated
invasively were more often male and habitual smokers, and
reported less hypertension, diabetes mellitus, previous angina
pectoris, MI, heart failure and stroke, but more often previous
PCI. At entry, the invasively managed patients less often had
ST-segment depression but more often had troponin elevation
and higher Thrombolysis in Myocardial Infarction NSTE-
ACS risk score.

Results Biomarkers and Effects of Ticagrelor in the

In the PLATO trial, 9946 patients had an entry diagnosis of
NSTE-ACS and provided plasma samples for analyses of all
biomarkers, allowing inclusion in the present study. Baseline
characteristics by randomized treatment and management
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In-Hospital Noninvasive Group
In patients managed without revascularization, hs-TnT levels
were significantly related to the rate of the primary composite
end point of CV death, MI, and stroke (log-rank P<0.001),

strategy are shown in the Table. The randomized treat- driven by associations both with CV death and spontaneous
ment groups were balanced within the respective in-hospital MI (Figures 1 and 2) corresponding mainly to type 1 to 3 MI

Figure 1. Efficacy of ticagrelor relative clopidogrel on CV death, MI, and stroke in relation to predefined levels of biomarkers at baseline
in the in-hospital noninvasive group. Cox proportional hazards model with biomarker level, treatment, interaction between treatment
and biomarker level and established risk factors as covariates. Established risk factors in the model are sex, diabetes mellitus, smoking
status, hypertension, congestive heart failure, peripheral arterial disease, previous MI, previous PCI, previous CABG, ST-depression in
ECG at entry, and the declaration of planned invasive or noninvasive treatment at randomization. CABG indicates coronary artery bypass
grafting; CI, confidence interval; CV, cardiovascular; GDF-15, growth differentiation factor-15; HR, hazard ratio; hs-TnT, high-sensitivity
troponin T; MI, myocardial infarction; NT-proBNP, N-terminal pro-brain natriuretic peptide; and PCI, percutaneous coronary intervention.
 Wallentin et al   Biomarkers and Ticagrelor in Non–ST-elevation ACS   297
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Figure 2. Kaplan-Meier estimates of cumulative event rates of CV death and spontaneous MI in ticagrelor and clopidogrel assigned
patients in the in-hospital noninvasive and in-hospital invasive groups in relation to the predefined levels of hs-TnT (A), GDF-15 (B),
and NT-proBNP (C) in patients with NSTE-ACS. Numbers at risk printed in black represent clopidogrel, and numbers in red represent
ticagrelor. CV indicates cardiovascular; GDF-15, growth differentiation factor-15; hs-TnT, high-sensitivity troponin T; MI, myocardial
infarction; NSTE-ACS, non–ST-elevation acute coronary syndrome; and NT-proBNP, N-terminal pro-brain natriuretic peptide.

(Table I in the online-only Data Supplement). Ticagrelor ver-
sus clopidogrel reduced the composite of CV death, MI, and
stroke with a larger effect in the patients in the upper tertiles
of positive hs-TnT levels, ie, those with a higher risk, whereas
there was a lack of effect in those with negative hs-TnT
(<14 ng/L) (interaction P=0.042) (Figure 1). As shown in
Figure 3, the treatment effect of ticagrelor in the noninvasive
cohort with hs-TnT ≥14 ng/L was dominated by a reduc-
tion in CV mortality. In the same cohort, there also appeared
numeric reductions in all types of MI, with the exception of
 298  Circulation  January 21, 2014
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Figure 3. Efficacy of ticagrelor relative to clopidogrel in relation to predefined levels of hs-TnT at baseline in the in-hospital noninvasive
group. Cox proportional hazards model with biomarker level, treatment, interaction between treatment and biomarker level and established
risk factors as covariates. Established risk factors in the model are sex, diabetes mellitus, smoking status, hypertension, congestive heart
failure, peripheral arterial disease, previous MI, previous PCI, previous CABG, ST-depression in ECG at entry, and the declaration of planned
invasive or noninvasive treatment at randomization. CI indicates confidence interval, CV, cardiovascular; HR, hazard ratio; hs-TnT, high-
sensitivity troponin T; and MI, myocardial infarction.

type 5 (CABG-related) MI (Table I in the online-only Data
Supplement). There were no consistent relations between hs-
TnT and the risk of major non–CABG-related bleeding in the
in-hospital noninvasive cohort (Figure I in the online-only
Data Supplement).
Increasing levels of NT-proBNP and GDF-15 were associ-
ated with increasing risk for CV death, MI, and stroke based
on relations to both CV death and spontaneous MI (Figures 1
and 2; log-rank P<0.001). There was no significant interaction
between the relative reduction of these events with ticagre-
lor in comparison with clopidogrel and the levels of these
markers. Increasing levels of NT-proBNP and GDF-15 were
associated with increasing risk of major non–CABG-related
bleeding, but there was no significant interaction between the
biomarker levels and treatment (Figure I in the online-only
Data Supplement).
Biomarkers and Effects of Ticagrelor in the
In-Hospital Invasive Group
In the in-hospital revascularization group, the level of hs-TnT
showed no relationship with the rate of the primary composite
end point (Figure 4), the composite of CV death/spontaneous
MI (Figure 2), CV death alone, spontaneous MI alone, or any
of the different types of MI (Table II in the online-only Data
Supplement). Ticagrelor substantially reduced the rate of the
primary composite and its individual components in the in-
hospital invasive cohort (Figure 5). Numerically there was a
larger relative reduction in patients with elevated than normal
hs-TnT levels, although not significant in the interaction anal-
ysis (Figures 4 and 5). There was no association between the
hs-TnT level and the risk of major non-CABG bleeding and
no interaction with the effect of ticagrelor in comparison with
clopidogrel (Figure II in the online-only Data Supplement).
 Wallentin et al   Biomarkers and Ticagrelor in Non–ST-elevation ACS   299
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Figure 4. Efficacy of ticagrelor relative to clopidogrel on CV death, MI, and stroke in relation to predefined levels of biomarkers at baseline
in the in-hospital invasive group. CI indicates confidence interval; CV, cardiovascular; GDF-15, growth differentiation factor-15; HR,
hazard ratio; hs-TnT, high-sensitivity troponin T; MI, myocardial infarction; and NT-proBNP, N-terminal pro-brain natriuretic peptide.

The levels of NT-proBNP and GDF-15 were significantly
related to the rate of CV death, MI, and stroke (log-rank
P<0.001) based on relations to both CV death and spontaneous
MI in the in-hospital invasive group (Figures 2 and 4). There
was no significant interaction between the reduction of these
events with ticagrelor in comparison with clopidogrel and the
levels of these markers (Figure 4).The relative reduction of these
events with ticagrelor in comparison with clopidogrel in the in-
hospital invasive group was consistent regardless of the levels
of these markers. As in the noninvasive group, the absolute
reduction of events with ticagrelor treatment was considerably
larger in patients with higher NT-proBNP or GDF-15 levels, ie,
in those with highest risk (Figures 2 and 4). Concerning major
non–CABG-related bleeding, there was a significant relation-
ship to the levels of NT-proBNP and GDF-15 with higher rates
of bleeding at higher levels. The increase in bleeding events
with ticagrelor in comparison with clopidogrel in the invasive
group was accordingly larger at higher levels of these biomark-
ers (Figure II in the online-only Data Supplement).
Discussion
In the present study of patients with NSTE-ACS managed
without in-hospital revascularization, we verified the strong
association between baseline level of hs-TnT and the risk of
subsequent CV death and mainly spontaneous MI (type 1–3).
There was no relation between the hs-TnT level and these out-
comes in patients who underwent in-hospital revasculariza-
tion. Among patients without in-hospital revascularization, the
benefit of ticagrelor seemed confined to those with elevated
hs-TnT, whereas in patients with in-hospital revascularization
there was no significant interaction with the hs-TnT level at
entry. This study also verified NT-proBNP and GDF-15 as
strong predictors of subsequent CV death and spontaneous
MI, regardless of in-hospital revascularization procedures. In
addition, patients with higher levels of NT-proBNP or GDF-
15 had larger absolute benefits from ticagrelor because of their
association with higher risks of subsequent events and lack
of interaction with treatment effect. These biomarkers might
thus help to tailor treatment with potent P2Y12 inhibitors in
NSTE-ACS, eg, by selecting more intense treatment for tro-
ponin-positive patients at intermediate to high risk, regardless
of invasive management strategy, and downprioritizing its use
in noninvasively managed patients with normal hs-TnT levels.
The finding that more intense platelet inhibition with
ticagrelor (in comparison with clopidogrel) is effective
mainly in troponin-positive patients is in accordance with
 300  Circulation  January 21, 2014
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Figure 5. Efficacy of ticagrelor relative to clopidogrel in relation to predefined levels of hs-TnT at baseline in the in-hospital invasive group.
Cox proportional hazards model with biomarker level, treatment, interaction between treatment and biomarker level and established
risk factors as covariates. Established risk factors in the model are sex, diabetes mellitus, smoking status, hypertension, congestive
heart failure, peripheral arterial disease, previous MI, previous PCI, previous CABG, ST-depression in ECG at entry, and the declaration
of planned invasive or noninvasive treatment at randomization. CI indicates confidence interval; CV, cardiovascular; HR, hazard ratio;
hs-TnT, high-sensitivity troponin T; and MI, myocardial infarction.

similar findings concerning glycoprotein IIb/IIIa inhibitors
and low-molecular-weight heparins.16,17 The usefulness of
NT-proBNP and GDF-15 as indicators of the overall long-
term cardiovascular and bleeding risk is in accordance with
previous experiences with these markers.11,12,14,15 Although the
absolute benefits with both ticagrelor and invasive treatment
were larger at higher risk, further work is needed to appro-
priately evaluate the usefulness of adding these biomarkers to
currently established risk scores for decision support.
In contrast to many previous studies, we separately analyzed
the relations between the baseline biomarkers, study treatment,
and the occurrence of spontaneous or procedure-related events.
The relations between biomarkers and outcomes were caused
by relations to spontaneous events, ie, CV death and spontane-
ous (mainly type 1–3) MI. None of the biomarkers had any
positive relation with procedure-related (type 4a or type 5) MI.
However, it should be observed that procedure-related events
are only possible to diagnose in patients with normal or stable
troponin levels before coronary procedures.18 Some studies
have shown a relation of procedure-related MI to long-term
outcome,25,26 whereas others have shown no or only a weak
relation.20,27–29 The reduction of both procedural and spontane-
ous events by ticagrelor versus clopidogrel in the invasively
managed patients may be the main explanation for the lack of
significant interaction between hs-TnT and effect of ticagrelor
in the in-hospital invasive in contrast to the in-hospital nonin-
vasive group where very few procedural events occurred.
The blood samples for this study were obtained at an aver-
age 15 hours after the index event, and therefore reflect the
occurrence of any elevation of high-sensitivity troponin,
although not necessarily the maximal level in the acute stage.
In the present study, a normal level of hs-TnT was the only
 Wallentin et al   Biomarkers and Ticagrelor in Non–ST-elevation ACS   301
variable indicating a lack of benefit of ticagrelor in compari-
son with clopidogrel in NSTE-ACS patients managed with-
out revascularization while in-hospital for the index event.
However, more importantly, the study showed that elevation
of hs-TnT is associated with a raised risk of CV death and
spontaneous MI and a substantial benefit of ticagrelor in com-
parison with clopidogrel treatment in noninvasively as well as
invasively managed patients.
Over the past years, NT-proBNP has appeared as one of the
best prognostic markers for outcomes in NSTE-ACS, with an
increased rate of subsequent events at elevated levels in both
noninvasively and invasively managed patients.11,12,22 However,
NT-proBNP levels has not been shown to significantly interact
with the outcome of an early invasive strategy.11,30 This trial
verified that a higher NT-proBNP level was related to a raised
risk of future events both in invasively and noninvasively man-
aged patients with NSTE-ACS, but without any interaction
with the benefits of ticagrelor in comparison with clopidogrel.
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Accordingly, a higher NT-proBNP level indicated an increased
risk of CV death and spontaneous MI and thereby predicted a
greater absolute benefit from ticagrelor treatment.
In recent years, GDF-15 also has appeared as a very consis-
tent marker of adverse long-term outcome in NSTE-ACS.13,14
In previous studies of patients with NSTE-ACS, GDF-15 has
been found not only to predict future events, but also to con-
tribute to the identification of high-risk patients with a benefit
of an early invasive strategy.13 In the present trial, we verified
the usefulness of the previously established cutoff levels for
GDF-15 for risk stratification in NSTE-ACS. The GDF-15
level was related to an increased risk of CV death and sponta-
neous MI, both in the invasively and noninvasively managed
patients, but without any interaction with the effect of ticagre-
lor versus clopidogrel treatment. Thus, a higher GDF-15 level
was shown to contribute to the prediction of an increased risk
of CV death and spontaneous MI, and thereby to the predic-
tion of a larger absolute benefit from ticagrelor treatment.
Although multiple clinical findings and levels of several
biomarkers are related to outcome in patients with NSTE-
ACS, only a limited number of variables contribute meaning-
ful information on the effects of specific treatments.31–34 In the
present study, we found that a normal level of hs-TnT identi-
fied patients with limited or no benefit of more intense platelet
inhibition, especially in patients managed with a noninvasive
treatment approach. The other biomarkers, NT-proBNP and
GDF-15, did not show any directional interaction with the
effects of ticagrelor treatment, but they contributed informa-
tion on the magnitude of benefit by a successful intervention
such as ticagrelor regardless of invasive or noninvasive man-
agement. The complementary contributions from these bio-
markers seem logical, with troponin indicating acute plaque
instability, thrombus formation, and myocardial damage;
NT-proBNP indicating both acute and chronic myocardial
stretch and overload; and GDF-15 indicating a chronic condi-
tion of cellular stress and need of cellular repair.
Limitations
The stratification of the material according to in-hospital revas-
cularization was a postrandomization clinical decision that, in
some instances, might have been influenced by events already
occurring before the procedures. However, most differences
in the primary outcome events occurred after the procedures,
which strengthens the results. In addition, similar results were
obtained if the analyses were stratified based on the intended
use of an early invasive or noninvasive treatment, as declared
by the investigator at randomization (data not shown). The
number of patients with normal hs-TnT was small, especially
in the in-hospital invasive treatment group, which leads to
uncertainty concerning the results in this subgroup. Therefore,
the usefulness of different treatments in NSTE-ACS patients
with normal hs-TnT needs further exploration.
Conclusions
Hs-TnT, GDF-15, and NT-proBNP are powerful predictors of
cardiovascular events in NSTE-ACS managed noninvasively,
and NT-proBNP and GDF-15 are also powerful predictors in
those managed invasively. Elevated hs-TnT predicts substantial
benefit of ticagrelor over clopidogrel, whereas event rates are
low and benefits limited, if any, in those with normal hs-TnT.
The magnitude of benefit of ticagrelor is related to the degree
of elevation of GDF-15 and NT-proBNP, and their use might
help tailor treatment with ticagrelor to the appropriate patients.
Acknowledgments
Ulla Nässander Schikan, PhD, at Uppsala Clinical Research Center,
Uppsala, Sweden, provided editorial assistance.
Sources of Funding
The PLATO study was funded by AstraZeneca. Support for the anal-
ysis and interpretation of results and preparation of the manuscript
was provided through funds to the Uppsala Clinical Research Center
and Duke Clinical Research Institute as part of the Clinical Study
Agreement.
Disclosures
Dr Wallentin reports research grants from AstraZeneca, Merck
& Co, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer,
GlaxoSmithKline; being consultant for Abbott, Merck & Co,
Regado Biosciences, Athera Biotechnologies, Boehringer-Ingelheim,
AstraZeneca, GlaxoSmithKline, and Bristol-Myers Squibb/Pfizer;
lecture fees from AstraZeneca, Boehringer-Ingelheim, Bristol-
Myers Squibb/Pfizer, and GlaxoSmithKline; honoraria from
Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb/Pfizer,
and GlaxoSmithKline; travel support from AstraZeneca and Bristol-
Myers Squibb/Pfizer. Dr Lindholm reports institutional research
grant from AstraZeneca. Dr Siegbahn reports institutional research
grants from AstraZeneca, Boehringer-Ingelheim and Bristol-Mayer
Squibb. Dr Wernroth reports no conflict of interest. Dr Becker reports
scientific advisory fees from Merck, Portola, Boehringer-Ingelheim,
Bayer, and Daiichi-Sankyo. Dr Cannon reports research grants/
support from Accumetrics, AstraZeneca, CSL Behring, Essentialis,
GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; on advi-
sory boards for Alnylam, Bristol-Myers Squibb, Lipimedix, and
Pfizer (funds donated to charity); and holds equity in Automedics
Medical Systems. Dr Cornel reports advisory board fees from
Bristol-Myers Squibb, AstraZeneca, Eli Lilly/Daiichi Sankyo; and
consultancy fees from Merck and Servier. Dr Himmelmann reports
being an employee of AstraZeneca. Dr Giannitsis reports speaker
honoraria and advisory board honorarias from Roche Diagnostics
and AstraZeneca. Dr Harrington reports consulting/advisory board
fees from Bristol-Myers Squibb, Sanofi, Portola Pharmaceuticals,
Johnson & Johnson and Merck; grant support from Eli Lilly/
Daiichi Sankyo., Merck, Portola Pharmaceuticals, Sanofi, Johnson
& Johnson, Bristol-Myers Squibb, The Medicines Company and
 302  Circulation  January 21, 2014
AstraZeneca. Dr Held reports institutional research grants from
AstraZeneca, Merck, GlaxoSmithKline, Roche and Bristol-Myers
Squibb; being an advisory board member for AstraZeneca; honoraria
from AstraZeneca. Dr Husted reports being advisory board member
for AstraZeneca, Bristol-Myers Squibb, Pfizer, and Bayer; research
support from GlaxoSmithKline, and Pfizer. Dr Katus reports hono-
raria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Roche, and
Bayer; and holds a patent jointly with Roche and receives royalties for
this patent. Dr Mahaffey reports consulting fees from AstraZeneca,
Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly,
GlaxoSmithKline, Johnson & Johnson, Merck, Ortho/McNeill,
Sanofi-Aventis, and Schering-Plough (now Merck); grant support
from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi
Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck,
Novartis, Portola Pharmaceutical, Pozen, Regado, Sanofi-Aventis,
Schering-Plough (now Merck), and The Medicines Company. Dr
Steg reports research grants from NYU School of Medicine, Sanofi,
and Servier; consultancy fees/honoraria from Amarin, Astellas,
AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb,
Daiichi/sankyo, Eisai, GlaxoSmithKline, Lilly, Medtronic, MSD,
Novartis, Otsuka, Pfizer, Roche, Sanofi, Servier, The Medicines
Company, and Vivus; and has equity ownership in Aterovax. Dr Storey
Downloaded from http://circ.ahajournals.org/ by guest on September 2, 2017
reports research grants from AstraZeneca, Eli Lilly/Daiichi Sankyo,
and Merck; research support from Accumetrics; honoraria from
AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, Iroko, Accumetrics,
and Medscape; consultancy fees from AstraZeneca, Merck, Novartis,
Accumetrics, Sanofi-Aventis/Regeneron, and Bristol-Myers Squibb.
Dr James reports research grants from AstraZeneca, Eli Lilly, Bristol-
Myers Squibb, Terumo Inc, Medtronic, and Vascular Solutions;
honoraria from The Medicines Company, AstraZeneca, Eli Lilly,
Bristol-Myers Squibb, and IROKO; consultant/advisory board fees
from AstraZeneca, Eli Lilly, Merck, Medtronic, and Sanofi.
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Clinical Perspective
Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-eleva-
tion acute coronary syndrome. We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal
pro-brain natriuretic peptide, and growth differentiation factor-15 in relation to randomized treatment (ticagrelor versus clopi-
dogrel) and management strategy (with or without revascularization) in 9946 patients with non-ST-elevation acute coronary
syndrome in the PLATelet inhibition and patient Outcomes (PLATO) trial. During index hospitalization, 5357 were revascular-
ized, and 4589 were managed without revascularization. Increasing levels of hs-TnT were associated with increasing risk of
cardiovascular death, myocardial infarction, and stroke in medically managed patients, but not in those managed invasively.
N-terminal pro-brain natriuretic peptide and growth differentiation factor-15 levels were associated with the same events inde-
pendent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction,
and stroke in patients with non-ST-elevation acute coronary syndrome and hs-TnT ≥14.0 ng/L in both invasively and noninva-
sively managed patients. In patients with hs-TnT <14.0 ng/L there was no difference between ticagrelor and clopidogrel in the
noninvasive group. Thus, elevation of N-terminal pro-brain natriuretic peptide and growth differentiation factor-15 may be used
as general indicators of raised relative risk, which remain even if the risk associated with the acute coronary artery disease is
reduced by specific treatment with revascularization and ticagrelor. Determination of hs-TnT is useful because elevated levels
identify patients with an increased risk for adverse outcomes specifically related to acute coronary artery disease, which can be
reduced by revascularization and intense platelet inhibition with ticagrelor. Identification of patients with normal hs-TnT is also
useful, because these patients seem to have no important benefits from either of these specific treatments.
 Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in
Non−ST-Elevation Acute Coronary Syndrome Patients Managed With or Without
In-Hospital Revascularization: A Substudy From the Prospective Randomized Platelet
Inhibition and Patient Outcomes (PLATO) Trial
Lars Wallentin, Daniel Lindholm, Agneta Siegbahn, Lisa Wernroth, Richard C. Becker,
Christopher P. Cannon, Jan H. Cornel, Anders Himmelmann, Evangelos Giannitsis, Robert A.
Downloaded from http://circ.ahajournals.org/ by guest on September 2, 2017

Harrington, Claes Held, Steen Husted, Hugo A. Katus, Kenneth W. Mahaffey, Ph. Gabriel Steg,
Robert F. Storey and Stefan K. James
for the PLATO study group

Circulation. 2014;129:293-303; originally published online October 29, 2013;

doi: 10.1161/CIRCULATIONAHA.113.004420
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SUPPLEMENTAL MATERIAL

Supplemental Table 1. Hs troponin-T in relation to different types of myocardial infarction in the in-hospital non-invasive group

Hazard p-value for

Endpoint Hs-TnT ng/L Clopidogrel Ticagrelor ratio (95%) interaction
Spontaneous
<14 ng/L 7/496 (1.4%) 9/517 (1.7%) 1.26 (0.47-3.39) 0.5263
MI*
>=14 ng/L 129/1791 (7.2%) 118/1785 (6.6%) 0.91 (0.71-1.17) .

trend-test p=<.001 trend-test p=<.001 .

Type 1-2** <14 ng/L 7/496 (1.4%) 8/517 (1.5%) 1.12 (0.41-3.09) 0.6814

>=14 ng/L 119/1791 (6.6%) 108/1785 (6.1%) 0.90 (0.69-1.17) .

trend-test p=<.001 trend-test p=<.001 .

Type 3 <14 ng/L 0.9999

>=14 ng/L 8/1791 (0.4%) 7/1785 (0.4%) 0.87 (0.32-2.40) .

trend-test p=0.136 trend-test p=0.154 .

Type 4a <14 ng/L 0.9999

>=14 ng/L 5/1791 (0.3%) 4/1785 (0.2%) 0.80 (0.22-2.98) .

trend-test p=0.239 trend-test p=0.281 .

Type 4b <14 ng/L 1/517 (0.2%) 0.9932

>=14 ng/L 5/1791 (0.3%) 4/1785 (0.2%) 0.79 (0.21-2.95) .

trend-test p=0.239 trend-test p=0.895 .

Type 5 <14 ng/L 0.9998

>=14 ng/L 6/1791 (0.3%) 10/1785 (0.6%) 1.67 (0.61-4.60) .

trend-test p=0.197 trend-test p=0.088 .

* Spontaneous MI includes also silent MI, which are not possible to classify according to the Type 1 – 5 classification system.

** The separation of MI into different types allows several events to occur in the same patient.

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SupplementalTable 2. Hs troponin-T in relation to different types of myocardial infarction in the in-hospital invasive group

Hazard p-value for

Endpoint Hs-TnT ng/L Clopidogrel Ticagrelor ratio (95%) interaction
Spontaneous <14 ng/L 7/165 (4.2%) 5/181 (2.8%) 0.64 (0.20-2.00) 0.7379
MI*
>=14 ng/L 124/2495 (5.0%) 98/2516 (3.9%) 0.78 (0.60-1.01) .

trend-test p=0.676 trend-test p=0.443 .

Type 1-2** <14 ng/L 5/165 (3.0%) 4/181 (2.2%) 0.72 (0.19-2.67) 0.8617

>=14 ng/L 94/2495 (3.8%) 77/2516 (3.1%) 0.81 (0.60-1.09) .

trend-test p=0.628 trend-test p=0.517 .

Type 3 <14 ng/L 1/181 (0.6%) 0.9958

>=14 ng/L 1/2495 (0.0%) 1/2516 (0.0%) 0.99 (0.06-15.81) .

.
Type 4a <14 ng/L 8/165 (4.8%) 6/181 (3.3%) 0.68 (0.24-1.95) 0.7400

>=14 ng/L 79/2495 (3.2%) 45/2516 (1.8%) 0.56 (0.39-0.81) .

trend-test p=0.239 trend-test p=0.145 .

Type 4b <14 ng/L 2/165 (1.2%) 0.9790

>=14 ng/L 34/2495 (1.4%) 22/2516 (0.9%) 0.64 (0.37-1.09) .

trend-test p=0.871 trend-test p=0.207 .

Type 5 <14 ng/L 3/181 (1.7%) 0.9842

>=14 ng/L 12/2495 (0.5%) 20/2516 (0.8%) 1.65 (0.81-3.38) .

trend-test p=0.372 trend-test p=0.223 .

* Spontaneous MI includes also silent MI, which are not possible to classify according to the Type 1 – 5 classification system.

** The separation of MI into different types allows several events to occur in the same patient.

2
Supplemental Figure A1. Major non-CABG-related bleeding with ticagrelor relative clopidogrel in relation to predefined levels of
biomarkers at baseline in the in-hospital non-invasive group

Cox proportional hazards model with biomarker level, treatment, interaction between treatment and biomarker level and
established risk factors as covariates. Established risk factors in the model are gender, diabetes mellitus, smoking status,
hypertension, congestive heart failure, peripheral arterial disease, previous MI, previous PCI, previous CABG, ST-depression in
ECG at entry, and the declaration of planned invasive or non-invasive treatment at randomization. CI = confidence interval; HR =
hazard ratio

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Supplemental Figure A2. Major non-CABG-related bleeding with ticagrelor relative clopidogrel in relation to predefined levels of
biomarkers at baseline in the in-hospital invasive group

Cox proportional hazards model with biomarker level, treatment, interaction between treatment and biomarker level and
established risk factors as covariates. Established risk factors in the model are gender, diabetes mellitus, smoking status,
hypertension, congestive heart failure, peripheral arterial disease, previous MI, previous PCI, previous CABG, ST-depression in
ECG at entry, and the declaration of planned invasive or non-invasive treatment at randomization. CI = confidence interval; HR =
hazard ratio