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High-Sensitivity Troponin T and Mortality After Elective Percutaneous Coronary Intervention
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 68, NO. 21, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.08.059
High-Sensitivity Troponin T and Mortality After Elective Percutaneous Coronary Intervention Gjin Ndrepepa, MD,a Roisin Colleran, MB, BCH,a Siegmund Braun, MD,b Salvatore Cassese, MD,a Julia Hieber, MD,a Massimiliano Fusaro, MD,a Sebastian Kufner, MD,a Ilka Ott, MD,a Robert A. Byrne, MB, BCH, PHD,a Oliver Husser, MD,a Christian Hengstenberg, MD,a Karl-Ludwig Laugwitz, MD,c,d Heribert Schunkert, MD,a,d Adnan Kastrati, MDa,d
ABSTRACT BACKGROUND The prognostic value of high-sensitivity troponin T (hs-TnT) elevation after elective percutaneous coronary intervention (PCI) in patients with or without raised baseline hs-TnT levels is unclear. OBJECTIVES The goal of this study was to assess whether the prognostic value of post-procedural hs-TnT level after elective PCI depends on the baseline hs-TnT level. METHODS This study included 5,626 patients undergoing elective PCI who had baseline and peak post-procedural hs-TnT measurements available. The primary outcome was 3-year mortality (with risk estimates calculated per SD increase of the log hs-TnT scale). RESULTS Patients were divided into 4 groups: nonelevated baseline and post-procedural hs-TnT levels (hs-TnT #0.014 mg/l; n ¼ 742); nonelevated baseline but elevated post-procedural hs-TnT levels (peak post-procedural hs-TnT >0.014 mg/l; n ¼ 2,721); elevated baseline hs-TnT levels (hs-TnT >0.014 mg/l) with no further rise post-procedure (n ¼ 516); and elevated baseline hs-TnT levels with a further rise post-procedure (n ¼ 1,647). A total of 265 deaths occurred: 6 (1.6%) in patients with nonelevated baseline and post-procedural hs-TnT levels; 54 (3.8%) in patients with nonelevated baseline but elevated post-procedural hs-TnT levels; 50 (16.0%) in patients with elevated baseline hs-TnT levels with no further rise post-procedure; and 155 (18.2%) in patients with elevated baseline hs-TnT levels with a further rise post-procedure (p < 0.001). After adjustment, baseline hs-TnT levels (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: 1.09 to 1.38; p < 0.001) but not peak post-procedural hs-TnT levels (HR: 1.04; 95% CI: 0.85 to 1.28; p ¼ 0.679) were associated with an increased risk of mortality. Peak post-procedural hs-TnT findings were not associated with mortality in patients with nonelevated (HR: 0.93; 95% CI: 0.69 to 1.25; p ¼ 0.653) or elevated (HR: 1.24; 95% CI: 0.91 to 1.69; p ¼ 0.165) baseline hs-TnT levels. CONCLUSIONS In patients with coronary artery disease undergoing elective PCI, an increase in post-procedural hs-TnT level did not offer prognostic information beyond that provided by the baseline level of the biomarker. (J Am Coll Cardiol 2016;68:2259–68) © 2016 by the American College of Cardiology Foundation.
C
ardiac troponins are the most commonly
myocardial damage occurring spontaneously or after
used biomarkers for the diagnosis of myo-
percutaneous
cardial damage. High-sensitivity troponin
Although elevation of cardiac troponin levels after
T (hs-TnT) assays enable the detection of even minor
elective PCI is common (3–5), the clinical significance
coronary
intervention
Listen to this manuscript’s audio summary by JACC Editor-in-Chief
From the aDepartment of Adult Cardiology, Deutsches Herzzentrum München, Technische Universität, Munich, Germany; bDe-
Dr. Valentin Fuster.
partment of Laboratory Medicine, Deutsches Herzzentrum München, Technische Universität, Munich, Germany; c1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany; and dDZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Dr. Byrne has received lecture fees from B. Braun Melsungen, Biotronik, and Boston Scientific; and research grants to the institution from Boston Scientific and HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 21, 2016; revised manuscript received August 5, 2016, accepted August 31, 2016.
(PCI)
(1,2).
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JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
Troponin and Mortality After Elective PCI
ABBREVIATIONS
of this finding remains unclear. A rise in hs-
DIAGNOSTIC
AND ACRONYMS
TnT level above the 99th percentile upper
stable angina, defined as chest pain that had
reference limit (URL) after elective PCI was
not changed in intensity, character, frequency, or
recently reported in up to 80% of patients
threshold over the preceding 2 months, underwent
who had baseline hs-TnT levels within
elective PCI if significant stenoses ($70% lumen
normal limits (6). Raised levels of baseline
obstruction) were documented on diagnostic coro-
circulating troponin in patients with stable
nary angiography. Patients undergoing PCI in the
coronary
setting of a scheduled examination after stent im-
CAD = coronary artery disease CI = confidence interval HR = hazard ratio hs-TnT = high-sensitivity troponin T
PCI = percutaneous coronary
artery
disease
(CAD)
are
also
TIMI = Thrombolysis In
PCI. Patients
with
the stented coronary segment or a significant stenosis
SEE PAGE 2269
in a nonstented segment was documented on coro-
Myocardial Infarction
Several previous studies have shown that
URL = upper reference limit
AND
plantation underwent PCI if a significant restenosis in
commonly found (7).
intervention
CRITERIA
baseline, but not post-procedural, troponin
nary angiography. Personnel blinded to patient clinical
or
follow-up
data
performed
angiographic
elevation was associated with a poor outcome after
analysis in the core laboratory using an automated
PCI (7,8). Thus, elevated baseline troponin is a great
edge detection system (CMS, Medis Medical Imaging
confounder that may modulate the association be-
Systems, Neuen, the Netherlands).
tween post-procedural troponin rise and outcome
Cardiovascular risk factors, including diabetes,
after PCI. Notably, whether the prognostic value of
arterial
post-procedural troponin is dependent on the base-
current smoking, were defined according to accepted
hypertension,
hypercholesterolemia,
and
line troponin level remains unknown. Moreover, the
criteria. Epicardial blood flow pre- and post-PCI was
magnitude of change and factors predisposing to
graded by using the Thrombolysis In Myocardial
elevated post-procedural levels after elective PCI in
Infarction (TIMI) group angiographic criteria. Left
patients with or without elevated baseline troponin
ventricular ejection fraction was calculated by using
are unclear.
the area–length method on left ventricular angiog-
The aim of the present study was 2-fold: first, to investigate whether the prognostic value of post-
raphy. Body mass index was calculated by using patient weight and height measured during the index
procedural hs-TnT level after elective PCI depends
hospitalization, and glomerular filtration rate was
on the baseline hs-TnT level; and second, to deter-
calculated according to the Cockcroft-Gault formula.
mine the factors that predispose to post-procedural
Coronary angiography and PCI were performed
hs-TnT elevation in patients with and without
according to standard practices. Before PCI, patients
elevated baseline hs-TnT levels.
received aspirin (325 to 500 mg) and clopidogrel (loading dose of 600 mg) and anticoagulation therapy
PATIENTS AND METHODS
in the form of unfractionated heparin or bivalirudin. After PCI, patients received clopidogrel 150 mg/day
STUDY PATIENTS. The present study was a retro-
until hospital discharge, followed by 75 mg/day for at
spective analysis of 5,626 patients with stable CAD
least 1 month after bare-metal stent implantation or
who underwent elective PCI in our hospitals between
at least 6 months after drug-eluting stent implanta-
October 2009 and January 2015, with the last day of
tion, in addition to aspirin 200 mg/day indefinitely.
follow-up at the end of May 2016. The indication for
Other
the index intervention was stable CAD (if significant
angiotensin-converting enzyme inhibitors, or beta-
coronary stenosis was found on diagnostic angiog-
blockers) were prescribed at the discretion of the
drugs
(comprising
predominantly
statins,
raphy in patients presenting with symptoms) or
treating physician.
restenosis diagnosed in the setting of scheduled
BIOCHEMICAL MEASUREMENTS. Blood samples were
angiography after previous stent implantation. All
collected in tubes containing a lithium-heparin anti-
patients had baseline (pre-procedural) and peak
coagulant. Blood samples for hs-TnT measurements
post-procedural hs-TnT measurements available for
were obtained before the procedure (on admission), 6 h
analysis. Each patient was included in the analysis
after PCI, and on a daily basis thereafter during the
only once (i.e., at his or her first PCI procedure).
hospital stay (usually 48 h). Two or more post-
Patients with acute coronary syndromes, acute in-
procedural hs-TnT measurements were performed in
fections, pregnancy, advanced impairment of renal
98.7% of patients. The peak level was defined as the
function (serum creatinine $2.0 mg/dl), or a known
highest
malignancy were excluded. The study was per-
Troponin T was measured by a high-sensitivity assay
formed
in a cobas e 411 immunoanalyzer using electro-
Helsinki.
in
accordance
with
the
Declaration
of
post-procedural
hs-TnT
concentration.
chemiluminescence technology (Roche Diagnostics,
Ndrepepa et al.
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Troponin and Mortality After Elective PCI
T A B L E 1 Baseline Data
hs-TnT Elevated at Baseline (n ¼ 2,163)
Age, yrs
hs-TnT Not Elevated at Baseline (n ¼ 3,463)
Further Elevation Post-PCI (n ¼ 1,647)
No Further Elevation Post-PCI (n ¼ 516)
p Value
Elevation Post-PCI (n ¼ 2,721)
No Elevation Post-PCI (n ¼ 742)
p Value
75.0 [68.5–81.1]
72.7 [66.7–78.8]
<0.001
69.3 [61.6–74.4]
66.1 [58.3–72.2]
<0.001
Female
332 (20.2)
105 (20.3)
0.925
619 (22.7)
197 (26.6)
Diabetes
624 (37.9)
206 (39.9)
0.407
712 (26.2)
238 (32.1)
0.001
245 (14.9)
87 (16.9)
0.275
180 (6.6)
64 (8.6)
0.058
27.0 [24.3–30.0]
27.5 [24.7–30.4]
0.130
27.3 [24.8–30.1]
27.6 [25.2–30.5]
0.018
1,226 (74.4)
354 (68.6)
0.009
2,089 (76.8)
527 (71.0)
0.001
78 (15.1)
0.218
388 (14.3)
129 (17.4)
0.034
On insulin therapy Body mass index, kg/m2 History of arterial hypertension Current smoker
214 (13.0)
Hypercholesterolemia
0.030
1,256 (76.3)
387 (75.0)
0.559
2,218 (81.5)
581 (78.3)
0.049
History of myocardial infarction
583 (35.4)
172 (33.3)
0.391
819 (30.1)
248 (33.4)
0.082
History of coronary artery bypass grafting
266 (16.2)
70 (13.6)
0.157
317 (11.7)
82 (11.1)
0.651
Baseline hs-TnT, mg/l
0.022 [0.020–0.040]
0.030 [0.020–0.067]
<0.001
0.010 [0.010–0.010]
0.010 [0.009–0.010]
<0.001
Peak post-procedural hs-TnT, mg/l
0.079 [0.040–0.171]
0.030 [0.020–0.060]
<0.001
0.040 [0.020–0.090]
0.010 [0.010–0.010]
<0.001
Glomerular filtration rate, ml/min
59.5 [43.5–79.1]
63.6 [47.3–84.6]
82.0 [64.7–102.8]
87.1 [70.8–107.4]
<0.001
140 (8.5)
61 (11.8)
0.010
No. of stenosed coronary arteries
0.068
1
0.002 434 (16.0)
144 (19.4)
2
370 (22.5)
117 (22.7)
698 (25.7)
218 (29.4)
3
1,137 (69.0)
338 (65.5)
1,589 (58.3)
380 (51.2)
1,507 (91.5)
455 (88.2)
0.023
2,287 (84.0)
598 (80.6)
0.025
785 (47.7)
167 (32.4)
<0.001
1,291 (47.4)
203 (27.4)
<0.001
60.0 [52.0–62.0]
60.0 [52.0–62.0]
0.400
Multivessel disease Multilesion intervention Left ventricular ejection fraction, %*
52.0 [40.0–60.0]
53.0 [43.8–60.0]
0.200
Statin
1,487 (90.6)
463 (89.9)
0.631
2,552 (93.9)
687 (92.7)
0.229
Beta-blocker
1,407 (85.7)
447 (86.8)
0.547
2,386 (87.9)
652 (88.0)
0.956
ACE inhibitor
1,090 (66.6)
352 (68.8)
0.363
1,845 (67.9)
498 (67.2)
0.728
Therapy on discharge
Values are median [25th to 75th percentile] or n (%). *Available in 3,799 patients. ACE ¼ angiotensin-converting enzyme; hs-TnT ¼ high-sensitivity troponin T; PCI ¼ percutaneous coronary intervention.
Risch-Rotkreuz, Switzerland). The limit of blank for
patient clinical or laboratory data performed follow-
this assay (the concentration below which analyte-free
up and adjudication of events.
samples
are
found
with
95%
probability)
is #0.003 m g/l. The functional sensitivity (the lowest
STATISTICAL ANALYSIS. Data are presented as me-
analyte concentration that can be reproducibly
dians with 25th to 75th percentiles, proportions (%), or
measured with a coefficient of variation #10%)
Kaplan-Meier estimates (%). The distribution of
is #0.013 m g/l. The 99th percentile URL is 0.014 m g/l.
continuous data was tested by using the 1-sample
Baseline and peak post-procedural hs-TnT values were
Kolmogorov-Smirnov test. Because all continuous
used for analysis. Creatinine was measured with a ki-
data exhibited a non-Gaussian distribution pattern,
netic colorimetric assay using the compensated Jaffe
the Kruskal-Wallis rank sum test was used for inter-
method. Laboratory personnel unaware of patient
group comparisons. Categorical data were compared
clinical or follow-up data measured other biochemical
by using the chi-square test. The correlates of
parameters using standard laboratory methods.
increased hs-TnT after PCI were assessed by using the multiple linear regression model. All variables in
OUTCOME AND FOLLOW-UP. The primary outcome
Tables 1 and 2, except for left ventricular ejection
measure was all-cause mortality up to 3 years after
fraction (due to incomplete data) and therapy at
PCI. Follow-up was performed by telephone inter-
discharge, were entered into the model. Due to the
view at 1, 6, and 12 months after PCI in the first year
skewed distribution of the hs-TnT levels, baseline and
and yearly thereafter. Data on mortality were ob-
post-procedural hs-TnT measurements were entered
tained from hospital charts, death certificates, tele-
into the model after logarithmic transformation.
phone contact with relatives of the patient or family
Survival analysis was performed by using the
physicians, insurance companies, or the registration
Kaplan-Meier method, and differences in survival
of address office. Medical personnel unaware of
rates were assessed according to the univariable Cox
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Troponin and Mortality After Elective PCI
T A B L E 2 Procedural Data (Lesion-Based Analysis)
hs-TnT Elevated at Baseline (n ¼ 3,500) Further Elevation Post-PCI (n ¼ 2,764)
hs-TnT Not Elevated at Baseline (n ¼ 5,654)
No Further Elevation Post-PCI (n ¼ 736)
Pre-procedural TIMI flow grade*
p Value
Elevated Post-PCI (n ¼ 4,665)
Not Elevated Post-PCI (n ¼ 989)
166 (3.6)
36 (3.6) 24 (2.4)
0.749
0
127 (4.6)
35 (4.8)
0.470
1
58 (2.1)
12 (1.6)
94 (2.0)
2
149 (5.4)
45 (6.1)
274 (5.9)
47 (4.8)
3
2,424 (87.9)
644 (87.5)
4,126 (88.5)
882 (89.2)
114 (4.1)
31 (4.1)
192 (4.1)
36 (3.6)
Vessel treated
<0.001
0.384
Left main coronary artery Left anterior descending coronary artery
1,116 (40.4)
311 (42.3)
1,986 (42.6)
426 (43.1)
Left circumflex artery
669 (24.2)
152 (20.7)
1,121 (24.0)
193 (19.5)
Right coronary artery
796 (28.8)
218 (29.6)
1,300 (27.9)
314 (31.7)
69 (2.5)
24 (3.3)
Bypass graft
p Value
66 (1.4)
20 (2.1)
2,103 (76.1)
516 (70.1)
<0.001
3,422 (73.4)
629 (63.6)
<0.001
Bifurcation lesion
923 (33.8)
211 (28.7)
0.008
1,649 (35.5)
286 (29.0)
<0.001
Restenotic lesion
262 (9.5)
77 (10.5)
0.423
445 (9.5)
124 (12.5)
0.004
0.200
3.00 [2.99–3.50]
3.00 [2.75–3.50]
0.010
Complex lesion (AHA B2/C class)
Balloon diameter, mm
3.00 [3.00–3.50]
3.00 [2.75–3.50]
Maximal balloon pressure, atm
15.0 [12.8–17.0]
14.0 [12.0–16.0]
0.008
15.0 [12.0–17.0]
14.0 [12.0–16.0]
<0.001
Total stented length, mm
24.0 [18.0–35.0]
23.0 [18.0–30.8]
0.002
23.0 [18.0–33.0]
23.0 [18.0–28.0]
<0.001
Post-procedural TIMI flow grade†
0.672
0
7 (0.2)
3 (0.4)
0.927 8 (0.2)
1 (0.1)
1
10 (0.4)
1 (0.1)
3 (0.1)
1 (0.1)
2
44 (1.6)
13 (1.8)
85 (1.8)
17 (1.7)
3
2,699 (97.8)
716 (97.7)
4,563 (97.9)
970 (98.1)
Values are n (%) of lesions or median [25th to 75th percentiles]. *Available for 3,494 lesions in patients with elevated baseline troponin levels and 5,649 lesions in patients with baseline troponin levels within normal limits. †Available for 3,493 lesions in patients with elevated baseline troponin levels and 5,648 lesions in patients with baseline troponin levels within normal limits. AHA ¼ American Heart Association; TIMI ¼ Thrombolysis In Myocardial Infarction; other abbreviations as in Table 1.
proportional hazards model. Independent correlates
the cutoff, patients were divided into a group
of all-cause mortality were assessed by using the
with baseline hs-TnT level within normal limits
multivariable Cox proportional hazards model. All
(hs-TnT #0.014 mg/l [n ¼ 3,463]) and a group with
variables in Tables 1 and 2 were tested in the uni-
elevated baseline hs-TnT level (hs-TnT >0.014 m g/l
variable analysis, and those exhibiting a significant
[n ¼ 2,163]). Using the peak post-procedural hs-TnT
association with mortality were entered into the
level, patients with normal baseline hs-TnT were
model to assess factors associated with mortality. The
divided into a group with elevated post-procedural
baseline and post-procedural hs-TnT measurements
hs-TnT level (hs-TnT >0.014 mg/l [n ¼ 2,721]) and
were entered into the model after logarithmic trans-
another group with normal post-procedural hs-TnT
formation.
equation
level (hs-TnT #0.014 m g/l [n ¼ 742]). Patients with
method was applied in all analyses (including multi-
elevated baseline hs-TnT levels were also divided
variable analyses) that involved lesion characteristics
into 2 groups: 1 with a further post-procedural rise in
to account for clustering of the data in the same pa-
hs-TnT (peak post-procedural hs-TnT level higher
tient. Statistical analysis was performed by using the
than baseline hs-TnT level [n ¼ 1,647]) and another
R
for
group with no further rise in post-procedural hs-TnT
Statistical Computing, Vienna, Austria). A 2-sided
(peak post-procedural hs-TnT equal to or lower than
p value <0.05 was considered to indicate statistical
the baseline hs-TnT level [n ¼ 516]). Baseline data are
2.15.1
The
generalized
Statistical
Package
estimating
(R
Foundation
significance.
RESULTS
shown in Table 1, and procedural characteristics are displayed in Table 2. CORRELATES OF POST-PROCEDURAL HS-TnT. Baseline
PATIENT CLASSIFICATION AND BASELINE DATA. Over-
and peak post-PCI hs-TnT levels in the whole group
all, the study included 5,626 patients. Using the
of patients are shown in the Central Illustration. In
99th percentile URL of baseline hs-TnT (0.014 m g/l) as
patients with nonelevated baseline hs-TnT levels,
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
2263
Troponin and Mortality After Elective PCI
C E N T R A L IL LU ST R A T I O N Troponin and Mortality After Elective PCI: Baseline and Post-Procedural hs-TnT Levels
Ndrepepa, G. et al. J Am Coll Cardiol. 2016;68(21):2259–68.
The graph in the left upper corner shows the distribution of paired baseline and peak post-procedural high-sensitivity troponin T (hs-TnT) values in each patient. The graph in the right upper corner shows the median and 25th to 75th percentiles of baseline (0.01 mg/l [0.01 to 0.02 mg/l]) and peak post-procedural (0.04 mg/l [0.02 to 0.10 mg/l]) hs-TnT levels. The median and 25th percentile values of baseline hs-TnT level are the same (0.01 mg/l). The lower graph shows the cumulative distribution curves of the baseline (blue line) and post-procedural (orange line) hs-TnT concentration. PCI ¼ percutaneous coronary intervention.
the mean baseline and post-procedural hs-TnT values
0.020 [0.010 to 0.060] m g/l), and 0.131 m g/l (median:
were 0.0095 m g/l and 0.098 m g/l. In patients with
0.023 [0.004 to 0.080] mg/l) in those with elevated
elevated baseline hs-TnT levels, mean baseline and
baseline hs-TnT levels. The multiple linear regression
mg/l
model with the generalized estimating equation
mg/l. The mean change in hs-TnT
method was used to assess independent correlates of
(peak post-procedural value baseline value) was
peak post-procedural hs-TnT in patients with and
0.088 m g/l in patients with nonelevated baseline
without elevated baseline hs-TnT levels (2 separate
hs-TnT levels (median [25th to 75th percentiles]:
models). Independent correlates of post-procedural
post-procedural and
0.244
hs-TnT
values
were
0.113
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Troponin and Mortality After Elective PCI
T A B L E 3 Independent Correlates of Post-Procedural hs-TnT Concentration Obtained
From the Multiple Linear Regression Model
hs-TnT are shown in Table 3. The elevated baseline hsTnT level and increased CAD severity and/or procedure complexity were independently associated with
Patients With hs-TnT Elevated at Baseline (n ¼ 2,163)
Diabetes Multivessel disease
Patients With hs-TnT Not Elevated at Baseline (n ¼ 3,463)
Coefficient*
p Value
Coefficient
p Value
–0.111785651
0.022
0.281562811
<0.001
0.287904096
–0.191225601
<0.001
elevated hs-TnT levels after PCI. Notably, restenotic lesions were associated with reduced odds of an elevation in hs-TnT after PCI in patients from both groups.
<0.001
POST-PROCEDURAL HS-TnT AND MORTALITY. Overall,
–
–
0.125431940
0.019
there were 265 deaths during the follow-up period:
0.654213201
<0.001
0.832773399
<0.001
6 deaths (1.6%) in patients with normal baseline and
Previous myocardial infarction
–0.128152726
0.011
–
–
post-procedural hs-TnT levels; 54 deaths (3.8%) in
Restenotic lesion
–0.189879905
<0.001
–0.238671558
<0.001
patients with normal baseline and raised post-
ACC/AHA B2/C class lesion
0.147118526
<0.001
0.178565892
<0.001
Multivessel disease
0.281562811
<0.001
–
–
0.006
–
–
Arterial hypertension Baseline troponin
Glomerular filtration rate
–0.002781484
Body mass index
–
Bifurcation lesion
0.087846055
Left anterior descending artery intervention Maximal balloon pressure Post-procedural TIMI flow Total stented length
0.159625100 – –0.291569192 0.008934003
– 0.044 <0.001 –
procedural hs-TnT levels; 50 deaths (16.0%) in patients with raised baseline levels but no further elevation in post-procedural hs-TnT; and 155 deaths
–0.013267508
0.037
0.142993244
<0.001
(18.2%)
among
<0.001
hs-TnT
levels
0.171036095 0.016835049
<0.001
0.003
–0.334634960
0.005
<0.001
0.009691764
<0.001
*Coefficients denote the change in log post-procedural high-sensitivity troponin T (hs-TnT) per unit change in the independent variable. The negative sign before the coefficients shows the inverse correlation between the independent variable and the post-procedural troponin concentration.
patients and
with
further
elevated elevation
baseline in
post-
procedural hs-TnT (overall log-rank test p < 0.001) (Figure 1). In patients with normal baseline hs-TnT levels, elevated post-procedural hs-TnT measurements were associated with increased risk of mortality compared with patients with a post-procedural hs-TnT level within normal limits (univariable hazard ratio [HR]: 2.38; 95% confidence interval [CI]: 1.03 to
ACC ¼ American College of Cardiology; other abbreviations as in Tables 1 and 2.
5.54; p ¼ 0.043). In patients with elevated baseline
F I G U R E 1 Kaplan-Meier Curves Showing Probability of 3-Year Mortality for Patient Subgroups According to Baseline and Post-Procedural
High-Sensitivity Troponin T Levels
Probability of Mortality (%)
30.0 25.0 HR=2.38 [1.03-5.54]; P=0.043 18.2%
20.0 15.0
16.0% 10.0 5.0
HR=1.09 [0.79-1.51]; P=0.575 3.8%
0.0
1.6% 0
1
Troponin groups/patients at risk Raised at baseline/further raised after PCI Raised at baseline/not raised after PCI Not raised at baseline/raised after PCI Not raised at baseline/not raised after PCI
2
3
529 198 1142 309
248 106 588 144
Years 1647 516 2721 742
912 325 1832 484
The curves are hierarchically ordered according to the order of the numbers of patients at risk. Percentages show the Kaplan-Meier estimates of mortality. Numbers in brackets denote 95% confidence intervals. HR ¼ hazard ratio; PCI ¼ percutaneous coronary intervention.
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
hs-TnT levels, further elevation in post-procedural
T A B L E 4 Results of Multivariable Cox Proportional Hazards Model Applied to
hs-TnT was not associated with increased risk of
Assess Predictors of All-Cause Mortality With Baseline and Post-Procedural
mortality compared with patients with no further
hs-TnT Entered Into the Model
elevation in post-procedural hs-TnT (univariable HR: 1.09; 95% CI: 0.79 to 1.51; p ¼ 0.575). In the univariable analysis, age (p < 0.001), female sex (p ¼ 0.002), diabetes (p ¼ 0.009), arterial hyper-
HR (95% CI)
p Value
Peak post-procedural hs-TnT (for 1-SD increase in logarithmic scale of hs-TnT)
1.04 (0.85–1.28)
0.679
Baseline hs-TnT (for 1-SD increase in logarithmic scale of hs-TnT)
1.22 (1.09–1.38)
<0.001 <0.001
tension (p < 0.001), body mass index (p ¼ 0.019),
Age (for 10-yr increase)
1.92 (1.31–2.81)
hypercholesterolemia (p ¼ 0.005), multivessel dis-
Female
0.57 (0.34–0.91)
0.028
ease (p < 0.001), previous coronary artery bypass
Diabetes
1.09 (0.72–1.65)
0.693
surgery (p < 0.001), baseline hs-TnT level (p < 0.001),
Arterial hypertension
0.54 (0.37–0.79)
0.002
peak post-procedural hs-TnT level (p < 0.001),
Body mass index (for 5 kg/m2 increase)
1.22 (0.96–1.55)
0.112
glomerular filtration rate (p < 0.001), left ventricular
Hypercholesterolemia
0.73 (0.48–1.12)
0.149
ejection
fraction
(p
2265
Troponin and Mortality After Elective PCI
<
0.001),
vessel
treated
(p ¼ 0.004), restenotic lesions (p < 0.001), baseline
Multivessel disease
1.26 (0.63–2.53)
0.505
Previous coronary artery bypass surgery
1.03 (0.64–1.65)
0.897
TIMI flow grade (p ¼ 0.014), balloon diameter
GFR (for 30 ml/min decrease)
1.69 (1.14–2.51)
0.008
LVEF (for 10% decrease)
1.41 (1.23–1.62)
<0.001
(p ¼ 0.003), maximal balloon pressure (p ¼ 0.007),
Vessel treated
1.54 (0.92–2.59)
and post-procedural TIMI flow grade (p ¼ 0.042) were
Restenotic lesions
1.32 (0.87–1.99)
0.187
independently associated with mortality risk. All of
Baseline TIMI flow grade (for 1 grade decrease)
1.26 (0.98–1.64)
0.076
Balloon diameter (for 0.5-mm increase)
1.05 (0.94–1.17)
0.387
Maximal balloon pressure (5 atm increase)
1.16 (0.96–1.39)
0.120
these variables, except for post-procedural TIMI flow (due to strong correlation with post-procedural hsTnT), were entered into the Cox proportional hazards model with the generalized estimating equation
0.102
CI ¼ confidence interval; GFR ¼ glomerular filtration rate; HR ¼ hazard ratio; LVEF ¼ left ventricular ejection fraction; other abbreviations as in Tables 1 and 2.
method. When the post-procedural hs-TnT-mortality association was tested in the model in the entire group of patients and adjusted for the factors associated with mortality risk listed previously (excluding baseline hs-TnT), there was a trend for an association between post-procedural hs-TnT level and the risk of mortality (adjusted HR: 1.22; 95% CI: 0.98 to 1.41; p ¼ 0.082 for each SD increase in the logarithmic scale of post-procedural hs-TnT). When baseline hs-TnT level was entered into the model, the baseline hsTnT level (HR: 1.22; 95% CI: 1.09 to 1.38; p < 0.001), but not peak post-procedural hs-TnT level (HR: 1.04; 95% CI: 0.85 to 1.28; p ¼ 0.679), was associated with increased risk of mortality (both risk estimates calculated per SD increase in the logarithmic scale of hs-TnT) (Table 4). The association between peak post-
>70 the 99th percentile URL cutoff, compared with post-procedural hs-TnT #70 the 99th percentile URL, was associated with increased risk of mortality in patients with elevated baseline hs-TnT level (45.1% vs. 17.1%; univariable HR: 4.20; 95% CI: 1.98 to 8.44; p < 0.001) but not in those with nonelevated levels of the biomarker (5.3% vs. 3.3%; HR: 1.42; 95% CI: 0.03 to 8.72; p ¼ 0.772). In patients with elevated baseline hs-TnT, the association between the >70 the 99th percentile URL cutoff and mortality was tested in the multivariable Cox model, with hs-TnT entered as a categorical variable (dichotomized at the 70 the 99th percentile cutoff). The analysis showed a trend toward an independent association between hs-TnT
procedural hs-TnT and mortality was not significant in the group with normal baseline hs-TnT level (HR:
T A B L E 5 Mortality According to Different Cutoffs of Post-Procedural hs-TnT
0.93; 95% CI: 0.69 to 1.25; p ¼ 0.653) or in the group with elevated baseline hs-TnT level (HR: 1.24; 95% CI:
Elevated Baseline hs-TnT (n ¼ 2,163)
0.91 to 1.69; p ¼ 0.165), with both risk estimates
Patients (%) Mortality (%)* Patients (%) Mortality (%)*
calculated per SD increase in the logarithmic scale of peak post-procedural hs-TnT.
Baseline hs-TnT Within Normal Limits (n ¼ 3,463)
Not increased (vs. baseline)
516 (23.9)
50 (16.0)
742 (21.4)
6 (1.6)
1 to 3 99th percentile URL
595 (27.5)
45 (17.0)
1,475 (42.6)
26 (3.4) 12 (5.4)
MORTALITY ACCORDING TO VARIOUS CUTOFFS OF
>3 to 5 99th percentile URL
362 (16.8)
35 (17.1)
453 (13.1)
>5 to 10 99th percentile URL
295 (13.6)
28 (20.8)
380 (11.0)
7 (2.7)
POST-PROCEDURAL HS-TnT. The association between
>10 to 35 99th percentile URL
286 (13.2)
28 (17.2)
310 (8.9)
7 (4.6)
post-procedural hs-TnT level and mortality was
>35 to 70 99th percentile URL
65 (3.0)
6 (15.5)
62 (1.8)
1 (1.8)
assessed over several multiples of 99th percentile URL
>70 99th percentile URL
44 (2.0)
13 (45.1)
41 (1.2)
1 (5.3)
cutoffs in patients with and without elevations in baseline hs-TnT. The results of this analysis are shown in Table 5. Notably, the hs-TnT elevation
*Numbers in parentheses in the mortality columns represent Kaplan-Meier estimates of mortality. hs-TnT ¼ high-sensitivity troponin T; URL ¼ upper reference limit.
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Troponin and Mortality After Elective PCI
>70 the 99th percentile URL and mortality
the risk of subsequent mortality up to 3 years after PCI.
(p ¼ 0.093), and a trend toward an interaction between
A PCI-related hs-TnT elevation 6 times the URL in pa-
post-procedural hs-TnT >70 the 99th percentile URL
tients with normal baseline hs-TnT and >9 times the
and baseline level of the biomarker with regard to the
URL in patients with elevated baseline levels of the
prediction of mortality (p for interaction ¼ 0.073).
biomarker was not associated with increased mortality risk. The striking separation of the Kaplan-Meier
DISCUSSION
curves for mortality (showing mortality differences predominantly secondary to baseline hs-TnT levels),
The main findings of this study can be summarized as
in addition to the results of the multivariable analysis,
follows: 1) in patients with CAD undergoing elective
lend further support to this finding. Miller et al. (8) also
PCI, a procedure-related hs-TnT rise occurred in the
showed that long-term prognosis was most often
majority of patients (77.6%); 2) post-procedural
related to the baseline troponin level, rather than to
hs-TnT
elevation
was
not
associated
with
an
the biomarker response to PCI. However, the study by
increased risk of mortality for up to 3 years, regard-
Miller et al. differs from the present study in that it
less of the pre-procedural hs-TnT level; 3) the pre-
included not only patients with stable CAD but also
procedural hs-TnT elevation was independently
those with acute coronary syndromes, a conventional
associated with an increased risk of mortality; and 4)
troponin assay was used, and fewer deaths were re-
pre-procedural hs-TnT level and angiographic char-
ported. Notwithstanding these differences, the cur-
acteristics underlying procedure complexity were
rent study corroborates the findings of Miller et al. in a
independent correlates of elevated post-procedural
large series of patients with stable CAD by using a
hs-TnT level in patients both with and without
contemporary high-sensitivity cardiac troponin assay.
elevated baseline levels of the biomarker.
Furthermore, by finding a trend toward an interaction
Circulating troponin after PCI consists of 2 frac-
between the post-procedural hs-TnT >70 the 99th
tions: a pre-procedural or baseline fraction and a
percentile URL and baseline hs-TnT level regarding
fraction
prediction of mortality, the present study may offer
that
reflects
PCI-related
troponin
rise.
Continuous microscopic loss of cardiomyocytes dur-
support to the definition of clinically relevant
ing normal life (9) and cardiomyocyte renewal (10) are
myocardial infarction after coronary revascularization
2 processes that contribute to physiological baseline
in the Consensus Document of the Society for Cardio-
concentrations
vascular Angiography and Interventions (16).
of
circulating
troponin.
Multiple
additional factors can increase levels of circulating
Although factors responsible for baseline hs-TnT
cardiac troponin in clinical scenarios other than acute
elevation help to explain the increased mortality
coronary syndromes (11). Prasad et al. (7) showed that
risk in patients with elevated baseline levels of the
37%
have
biomarker, the relationship between factors associ-
elevated pre-procedural troponin levels. The elevated
ated with troponin rise post-PCI and mortality is less
circulating troponin level in these patients may be
clear. Procedure-related factors or complications
explained by a less favorable cardiovascular and
increasing the risk of myocardial damage via distal
metabolic risk profile (11), more extensive CAD (12), or
embolization, side-branch occlusion, or suboptimal
clinically silent complicated atherosclerotic plaques
myocardial flow are proven risk factors for post-
(13). It is proposed that elevated baseline circulating
procedural troponin rise (3,17,18). The present study
troponin level in patients with stable CAD may be
also found that increased procedural complexity was
caused by cardiometabolic risk–related stress on the
associated with elevated hs-TnT levels after PCI,
myocardium (14,15) or by cycles of silent atheroscle-
regardless of the baseline hs-TnT level. However, if
rotic plaque rupture and sealing, leading to repeated
the troponin response to PCI was assessed by using
myocardial ischemia (13). Both of these conditions are
less sensitive troponin assays, as was the case in
associated with increased cardiovascular risk, and
multiple
they may explain the association between elevated
myocardial damage would be needed to result in a
baseline hs-TnT and mortality.
procedure-related troponin rise. The currently used
of
patients
undergoing
elective
PCI
previous
studies,
relatively
extensive
The principal finding of the present study was that
high-sensitivity troponin assays, including that used
post-procedural hs-TnT elevation was not associated
in the present study, allow detection of troponin
with an increased risk of mortality, regardless of
release from minuscule damage of myocardial tissue.
baseline hs-TnT level. Although elevated baseline hs-
Thus, it is plausible that post-procedural elevation of
TnT in itself was strongly associated with an
the magnitude observed in the present study may
increased risk of mortality, it had no impact on the
reflect subtle PCI-related myocardial damage that is
association between the PCI-related rise in hs-TnT and
too small (or transient) to have clinical sequelae.
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
Troponin and Mortality After Elective PCI
A study by Lim et al. (19) found that only a small
as others regarding post-procedural troponin mea-
minority (5 of 26 patients) fulfilling troponin criteria
surements. We are aware of the possibility that the
for PCI-related (type 4a) myocardial infarction had
precise peak value of post-procedural troponin may
evidence of peri-procedural necrosis on cardiac
have been missed in a number of patients. This would
magnetic resonance imaging. The investigators sug-
have required multiple measurements in a short time
gest that current troponins are oversensitive for the
interval. Finally, these data are from the hs-TnT assay
diagnosis of PCI-related myocardial injury. In the
and may not be extrapolated to assess the perfor-
present study, despite post-procedural hs-TnT ele-
mance of other conventional or high-sensitivity
vations in the majority of patients and identification
troponin assays. In the present study, a 0.014-mg/l
of several indexes of procedural complexity as pre-
cutoff was used to define the hs-TnT elevation, which
post-
differs from the 0.03-m g/l cutoff we used previously
procedural TIMI flow (grade 3) was restored in >97%
to detect troponin elevations with conventional
of patients. Thus, a combination of factors (including
troponin assays.
disposing
factors
for
this
rise,
optimal
the use of a high-sensitivity troponin assay) capable of detecting troponin elevation caused by subtle PCIrelated myocardial damage, adjustment for baseline hs-TnT level, and the capacity of current-day PCI to achieve optimal revascularization, even in the setting of high procedural complexity, may have attenuated the association of post-procedural troponin rise with mortality. The inverse association between restenotic lesions and post-procedural hs-TnT may offer evidence for the role of distal embolization in the elevation of post-procedural hs-TnT level. Intervention in restenotic lesions, which have a higher fibrotic/atherosclerotic content ratio compared with native atherosclerotic plaques, may be associated with less distal embolization, myocardial injury, and troponin elevation due to this factor.
CONCLUSIONS In patients with CAD undergoing elective PCI, postprocedural hs-TnT elevation was not associated with an increased risk of mortality for up to 3 years in patients with or without elevated baseline levels of the biomarker. Although there was a strong and independent association between baseline hs-TnT and mortality, the PCI-related elevation in hs-TnT did not offer prognostic information beyond that provided by baseline hs-TnT levels. REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Gjin
Ndrepepa,
Deutsches
Herzzentrum,
Laza-
rettstrasse 36, 80636 München, Germany. E-mail: [email protected].
STUDY LIMITATIONS. First, serial testing of hs-TnT
levels before PCI was not performed, resulting in a
PERSPECTIVES
lack of data on biomarker stability at baseline. If hsTnT levels are unstable before PCI, the ability to discriminate between a spontaneous and procedurerelated hs-TnT elevation is limited. This scenario is particularly relevant in the case of patients presenting with acute coronary syndromes. Nonetheless, all patients included in the present study had clinically stable CAD at the time of the index PCI. Moreover, given that the proportion of patients with hs-TnT elevation post-PCI seems to differ little between the groups with or without elevated baseline hs-TnT levels, we believe that PCI was responsible for the biomarker increase in the vast majority of patients in both groups. The collection of blood samples after the
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with CAD undergoing elective PCI, the baseline level of hs-TnT was strongly and independently associated with 3-year mortality, whereas post-procedural hs-TnT elevations did not provide additional prognostic information beyond the baseline hs-TnT level. TRANSLATIONAL OUTLOOK: Further studies in larger numbers of patients are needed to determine whether certain thresholds of post-procedural hs-TnT elevation carry independent prognostic value in patients with particular patterns of CAD undergoing PCI.
PCI follows the common practice in our center as well
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cardiac troponin: from theory to clinical practice. Rev Esp Cardiol (Engl Ed) 2013;66: 687–91.
effect on long-term survival of increased troponin I following uncomplicated elective percutaneous coronary intervention. Clin Cardiol 2010;33:E40–4.
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4. De Labriolle A, Lemesle G, Bonello L, et al. Prognostic significance of small troponin I rise after a successful elective percutaneous coronary intervention of a native artery. Am J Cardiol 2009; 103:639–45. 5. Cavallini C, Savonitto S, Ardissino D. Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study: reply. Eur Heart J 2005; 26:2206–7. 6. Ndrepepa G, Braun S, Cassese S, et al. Prognostic value of high-sensitivity troponin T after percutaneous coronary intervention in patients with stable coronary artery disease. Rev Esp Cardiol (Engl Ed) 2016;69:746–53. 7. Prasad A, Rihal CS, Lennon RJ, et al. Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and postintervention troponin T
9. Olivetti G, Giordano G, Corradi D, et al. Gender differences and aging—effects on the human heart. J Am Coll Cardiol 1995;26:1068–79. 10. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science 2009;324:98–102. 11. Ndrepepa G, Braun S, Mehilli J, et al. Prognostic value of sensitive troponin T in patients with stable and unstable angina and undetectable conventional troponin. Am Heart J 2011;161:68–75. 12. Ndrepepa G, Braun S, Schulz S, et al. Highsensitivity troponin T level and angiographic severity of coronary artery disease. Am J Cardiol 2011;108:639–43. 13. Korosoglou G, Lehrke S, Mueller D, et al. Determinants of troponin release in patients with stable coronary artery disease: insights from CT angiography characteristics of atherosclerotic plaque. Heart 2011;97:823–31.
levels in 5487 patients. Circ Cardiovasc Interv 2008;1:10–9.
14. Unger RH. Lipotoxic diseases. Annu Rev Med
8. Miller WL, Garratt KN, Burritt MF, et al. Baseline troponin level: key to understanding the importance of post-PCI troponin elevations. Eur Heart J 2006;27:1061–9.
15. Hessel MH, Michielsen EC, Atsma DE, et al. Release kinetics of intact and degraded troponin I and T after irreversible cell damage. Exp Mol Pathol 2008;85:90–5.
16. Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). Catheter Cardiovasc Interv 2014;83:27–36. 17. Ricciardi MJ, Davidson CJ, Gubernikoff G, et al. Troponin I elevation and cardiac events after percutaneous coronary intervention. Am Heart J 2003;145:522–8. 18. Lansky AJ, Stone GW. Periprocedural myocardial infarction prevalence, prognosis, and prevention. Circ Cardiovasc Interv 2010;3: 602–10. 19. Lim CC, van Gaal WJ, Testa L, et al. With the “universal definition,” measurement of creatine kinase-myocardial band rather than troponin allows more accurate diagnosis of periprocedural necrosis and infarction after coronary intervention. J Am Coll Cardiol 2011;57:653–61.
2002;53:319–36. KEY WORDS angina, biomarkers, coronary artery disease, coronary stenosis, prognosis, risk factors, stable
VOL. 68, NO. 21, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.08.059
High-Sensitivity Troponin T and Mortality After Elective Percutaneous Coronary Intervention Gjin Ndrepepa, MD,a Roisin Colleran, MB, BCH,a Siegmund Braun, MD,b Salvatore Cassese, MD,a Julia Hieber, MD,a Massimiliano Fusaro, MD,a Sebastian Kufner, MD,a Ilka Ott, MD,a Robert A. Byrne, MB, BCH, PHD,a Oliver Husser, MD,a Christian Hengstenberg, MD,a Karl-Ludwig Laugwitz, MD,c,d Heribert Schunkert, MD,a,d Adnan Kastrati, MDa,d
ABSTRACT BACKGROUND The prognostic value of high-sensitivity troponin T (hs-TnT) elevation after elective percutaneous coronary intervention (PCI) in patients with or without raised baseline hs-TnT levels is unclear. OBJECTIVES The goal of this study was to assess whether the prognostic value of post-procedural hs-TnT level after elective PCI depends on the baseline hs-TnT level. METHODS This study included 5,626 patients undergoing elective PCI who had baseline and peak post-procedural hs-TnT measurements available. The primary outcome was 3-year mortality (with risk estimates calculated per SD increase of the log hs-TnT scale). RESULTS Patients were divided into 4 groups: nonelevated baseline and post-procedural hs-TnT levels (hs-TnT #0.014 mg/l; n ¼ 742); nonelevated baseline but elevated post-procedural hs-TnT levels (peak post-procedural hs-TnT >0.014 mg/l; n ¼ 2,721); elevated baseline hs-TnT levels (hs-TnT >0.014 mg/l) with no further rise post-procedure (n ¼ 516); and elevated baseline hs-TnT levels with a further rise post-procedure (n ¼ 1,647). A total of 265 deaths occurred: 6 (1.6%) in patients with nonelevated baseline and post-procedural hs-TnT levels; 54 (3.8%) in patients with nonelevated baseline but elevated post-procedural hs-TnT levels; 50 (16.0%) in patients with elevated baseline hs-TnT levels with no further rise post-procedure; and 155 (18.2%) in patients with elevated baseline hs-TnT levels with a further rise post-procedure (p < 0.001). After adjustment, baseline hs-TnT levels (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: 1.09 to 1.38; p < 0.001) but not peak post-procedural hs-TnT levels (HR: 1.04; 95% CI: 0.85 to 1.28; p ¼ 0.679) were associated with an increased risk of mortality. Peak post-procedural hs-TnT findings were not associated with mortality in patients with nonelevated (HR: 0.93; 95% CI: 0.69 to 1.25; p ¼ 0.653) or elevated (HR: 1.24; 95% CI: 0.91 to 1.69; p ¼ 0.165) baseline hs-TnT levels. CONCLUSIONS In patients with coronary artery disease undergoing elective PCI, an increase in post-procedural hs-TnT level did not offer prognostic information beyond that provided by the baseline level of the biomarker. (J Am Coll Cardiol 2016;68:2259–68) © 2016 by the American College of Cardiology Foundation.
C
ardiac troponins are the most commonly
myocardial damage occurring spontaneously or after
used biomarkers for the diagnosis of myo-
percutaneous
cardial damage. High-sensitivity troponin
Although elevation of cardiac troponin levels after
T (hs-TnT) assays enable the detection of even minor
elective PCI is common (3–5), the clinical significance
coronary
intervention
Listen to this manuscript’s audio summary by JACC Editor-in-Chief
From the aDepartment of Adult Cardiology, Deutsches Herzzentrum München, Technische Universität, Munich, Germany; bDe-
Dr. Valentin Fuster.
partment of Laboratory Medicine, Deutsches Herzzentrum München, Technische Universität, Munich, Germany; c1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany; and dDZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Dr. Byrne has received lecture fees from B. Braun Melsungen, Biotronik, and Boston Scientific; and research grants to the institution from Boston Scientific and HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 21, 2016; revised manuscript received August 5, 2016, accepted August 31, 2016.
(PCI)
(1,2).
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Troponin and Mortality After Elective PCI
ABBREVIATIONS
of this finding remains unclear. A rise in hs-
DIAGNOSTIC
AND ACRONYMS
TnT level above the 99th percentile upper
stable angina, defined as chest pain that had
reference limit (URL) after elective PCI was
not changed in intensity, character, frequency, or
recently reported in up to 80% of patients
threshold over the preceding 2 months, underwent
who had baseline hs-TnT levels within
elective PCI if significant stenoses ($70% lumen
normal limits (6). Raised levels of baseline
obstruction) were documented on diagnostic coro-
circulating troponin in patients with stable
nary angiography. Patients undergoing PCI in the
coronary
setting of a scheduled examination after stent im-
CAD = coronary artery disease CI = confidence interval HR = hazard ratio hs-TnT = high-sensitivity troponin T
PCI = percutaneous coronary
artery
disease
(CAD)
are
also
TIMI = Thrombolysis In
PCI. Patients
with
the stented coronary segment or a significant stenosis
SEE PAGE 2269
in a nonstented segment was documented on coro-
Myocardial Infarction
Several previous studies have shown that
URL = upper reference limit
AND
plantation underwent PCI if a significant restenosis in
commonly found (7).
intervention
CRITERIA
baseline, but not post-procedural, troponin
nary angiography. Personnel blinded to patient clinical
or
follow-up
data
performed
angiographic
elevation was associated with a poor outcome after
analysis in the core laboratory using an automated
PCI (7,8). Thus, elevated baseline troponin is a great
edge detection system (CMS, Medis Medical Imaging
confounder that may modulate the association be-
Systems, Neuen, the Netherlands).
tween post-procedural troponin rise and outcome
Cardiovascular risk factors, including diabetes,
after PCI. Notably, whether the prognostic value of
arterial
post-procedural troponin is dependent on the base-
current smoking, were defined according to accepted
hypertension,
hypercholesterolemia,
and
line troponin level remains unknown. Moreover, the
criteria. Epicardial blood flow pre- and post-PCI was
magnitude of change and factors predisposing to
graded by using the Thrombolysis In Myocardial
elevated post-procedural levels after elective PCI in
Infarction (TIMI) group angiographic criteria. Left
patients with or without elevated baseline troponin
ventricular ejection fraction was calculated by using
are unclear.
the area–length method on left ventricular angiog-
The aim of the present study was 2-fold: first, to investigate whether the prognostic value of post-
raphy. Body mass index was calculated by using patient weight and height measured during the index
procedural hs-TnT level after elective PCI depends
hospitalization, and glomerular filtration rate was
on the baseline hs-TnT level; and second, to deter-
calculated according to the Cockcroft-Gault formula.
mine the factors that predispose to post-procedural
Coronary angiography and PCI were performed
hs-TnT elevation in patients with and without
according to standard practices. Before PCI, patients
elevated baseline hs-TnT levels.
received aspirin (325 to 500 mg) and clopidogrel (loading dose of 600 mg) and anticoagulation therapy
PATIENTS AND METHODS
in the form of unfractionated heparin or bivalirudin. After PCI, patients received clopidogrel 150 mg/day
STUDY PATIENTS. The present study was a retro-
until hospital discharge, followed by 75 mg/day for at
spective analysis of 5,626 patients with stable CAD
least 1 month after bare-metal stent implantation or
who underwent elective PCI in our hospitals between
at least 6 months after drug-eluting stent implanta-
October 2009 and January 2015, with the last day of
tion, in addition to aspirin 200 mg/day indefinitely.
follow-up at the end of May 2016. The indication for
Other
the index intervention was stable CAD (if significant
angiotensin-converting enzyme inhibitors, or beta-
coronary stenosis was found on diagnostic angiog-
blockers) were prescribed at the discretion of the
drugs
(comprising
predominantly
statins,
raphy in patients presenting with symptoms) or
treating physician.
restenosis diagnosed in the setting of scheduled
BIOCHEMICAL MEASUREMENTS. Blood samples were
angiography after previous stent implantation. All
collected in tubes containing a lithium-heparin anti-
patients had baseline (pre-procedural) and peak
coagulant. Blood samples for hs-TnT measurements
post-procedural hs-TnT measurements available for
were obtained before the procedure (on admission), 6 h
analysis. Each patient was included in the analysis
after PCI, and on a daily basis thereafter during the
only once (i.e., at his or her first PCI procedure).
hospital stay (usually 48 h). Two or more post-
Patients with acute coronary syndromes, acute in-
procedural hs-TnT measurements were performed in
fections, pregnancy, advanced impairment of renal
98.7% of patients. The peak level was defined as the
function (serum creatinine $2.0 mg/dl), or a known
highest
malignancy were excluded. The study was per-
Troponin T was measured by a high-sensitivity assay
formed
in a cobas e 411 immunoanalyzer using electro-
Helsinki.
in
accordance
with
the
Declaration
of
post-procedural
hs-TnT
concentration.
chemiluminescence technology (Roche Diagnostics,
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
2261
Troponin and Mortality After Elective PCI
T A B L E 1 Baseline Data
hs-TnT Elevated at Baseline (n ¼ 2,163)
Age, yrs
hs-TnT Not Elevated at Baseline (n ¼ 3,463)
Further Elevation Post-PCI (n ¼ 1,647)
No Further Elevation Post-PCI (n ¼ 516)
p Value
Elevation Post-PCI (n ¼ 2,721)
No Elevation Post-PCI (n ¼ 742)
p Value
75.0 [68.5–81.1]
72.7 [66.7–78.8]
<0.001
69.3 [61.6–74.4]
66.1 [58.3–72.2]
<0.001
Female
332 (20.2)
105 (20.3)
0.925
619 (22.7)
197 (26.6)
Diabetes
624 (37.9)
206 (39.9)
0.407
712 (26.2)
238 (32.1)
0.001
245 (14.9)
87 (16.9)
0.275
180 (6.6)
64 (8.6)
0.058
27.0 [24.3–30.0]
27.5 [24.7–30.4]
0.130
27.3 [24.8–30.1]
27.6 [25.2–30.5]
0.018
1,226 (74.4)
354 (68.6)
0.009
2,089 (76.8)
527 (71.0)
0.001
78 (15.1)
0.218
388 (14.3)
129 (17.4)
0.034
On insulin therapy Body mass index, kg/m2 History of arterial hypertension Current smoker
214 (13.0)
Hypercholesterolemia
0.030
1,256 (76.3)
387 (75.0)
0.559
2,218 (81.5)
581 (78.3)
0.049
History of myocardial infarction
583 (35.4)
172 (33.3)
0.391
819 (30.1)
248 (33.4)
0.082
History of coronary artery bypass grafting
266 (16.2)
70 (13.6)
0.157
317 (11.7)
82 (11.1)
0.651
Baseline hs-TnT, mg/l
0.022 [0.020–0.040]
0.030 [0.020–0.067]
<0.001
0.010 [0.010–0.010]
0.010 [0.009–0.010]
<0.001
Peak post-procedural hs-TnT, mg/l
0.079 [0.040–0.171]
0.030 [0.020–0.060]
<0.001
0.040 [0.020–0.090]
0.010 [0.010–0.010]
<0.001
Glomerular filtration rate, ml/min
59.5 [43.5–79.1]
63.6 [47.3–84.6]
82.0 [64.7–102.8]
87.1 [70.8–107.4]
<0.001
140 (8.5)
61 (11.8)
0.010
No. of stenosed coronary arteries
0.068
1
0.002 434 (16.0)
144 (19.4)
2
370 (22.5)
117 (22.7)
698 (25.7)
218 (29.4)
3
1,137 (69.0)
338 (65.5)
1,589 (58.3)
380 (51.2)
1,507 (91.5)
455 (88.2)
0.023
2,287 (84.0)
598 (80.6)
0.025
785 (47.7)
167 (32.4)
<0.001
1,291 (47.4)
203 (27.4)
<0.001
60.0 [52.0–62.0]
60.0 [52.0–62.0]
0.400
Multivessel disease Multilesion intervention Left ventricular ejection fraction, %*
52.0 [40.0–60.0]
53.0 [43.8–60.0]
0.200
Statin
1,487 (90.6)
463 (89.9)
0.631
2,552 (93.9)
687 (92.7)
0.229
Beta-blocker
1,407 (85.7)
447 (86.8)
0.547
2,386 (87.9)
652 (88.0)
0.956
ACE inhibitor
1,090 (66.6)
352 (68.8)
0.363
1,845 (67.9)
498 (67.2)
0.728
Therapy on discharge
Values are median [25th to 75th percentile] or n (%). *Available in 3,799 patients. ACE ¼ angiotensin-converting enzyme; hs-TnT ¼ high-sensitivity troponin T; PCI ¼ percutaneous coronary intervention.
Risch-Rotkreuz, Switzerland). The limit of blank for
patient clinical or laboratory data performed follow-
this assay (the concentration below which analyte-free
up and adjudication of events.
samples
are
found
with
95%
probability)
is #0.003 m g/l. The functional sensitivity (the lowest
STATISTICAL ANALYSIS. Data are presented as me-
analyte concentration that can be reproducibly
dians with 25th to 75th percentiles, proportions (%), or
measured with a coefficient of variation #10%)
Kaplan-Meier estimates (%). The distribution of
is #0.013 m g/l. The 99th percentile URL is 0.014 m g/l.
continuous data was tested by using the 1-sample
Baseline and peak post-procedural hs-TnT values were
Kolmogorov-Smirnov test. Because all continuous
used for analysis. Creatinine was measured with a ki-
data exhibited a non-Gaussian distribution pattern,
netic colorimetric assay using the compensated Jaffe
the Kruskal-Wallis rank sum test was used for inter-
method. Laboratory personnel unaware of patient
group comparisons. Categorical data were compared
clinical or follow-up data measured other biochemical
by using the chi-square test. The correlates of
parameters using standard laboratory methods.
increased hs-TnT after PCI were assessed by using the multiple linear regression model. All variables in
OUTCOME AND FOLLOW-UP. The primary outcome
Tables 1 and 2, except for left ventricular ejection
measure was all-cause mortality up to 3 years after
fraction (due to incomplete data) and therapy at
PCI. Follow-up was performed by telephone inter-
discharge, were entered into the model. Due to the
view at 1, 6, and 12 months after PCI in the first year
skewed distribution of the hs-TnT levels, baseline and
and yearly thereafter. Data on mortality were ob-
post-procedural hs-TnT measurements were entered
tained from hospital charts, death certificates, tele-
into the model after logarithmic transformation.
phone contact with relatives of the patient or family
Survival analysis was performed by using the
physicians, insurance companies, or the registration
Kaplan-Meier method, and differences in survival
of address office. Medical personnel unaware of
rates were assessed according to the univariable Cox
2262
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Troponin and Mortality After Elective PCI
T A B L E 2 Procedural Data (Lesion-Based Analysis)
hs-TnT Elevated at Baseline (n ¼ 3,500) Further Elevation Post-PCI (n ¼ 2,764)
hs-TnT Not Elevated at Baseline (n ¼ 5,654)
No Further Elevation Post-PCI (n ¼ 736)
Pre-procedural TIMI flow grade*
p Value
Elevated Post-PCI (n ¼ 4,665)
Not Elevated Post-PCI (n ¼ 989)
166 (3.6)
36 (3.6) 24 (2.4)
0.749
0
127 (4.6)
35 (4.8)
0.470
1
58 (2.1)
12 (1.6)
94 (2.0)
2
149 (5.4)
45 (6.1)
274 (5.9)
47 (4.8)
3
2,424 (87.9)
644 (87.5)
4,126 (88.5)
882 (89.2)
114 (4.1)
31 (4.1)
192 (4.1)
36 (3.6)
Vessel treated
<0.001
0.384
Left main coronary artery Left anterior descending coronary artery
1,116 (40.4)
311 (42.3)
1,986 (42.6)
426 (43.1)
Left circumflex artery
669 (24.2)
152 (20.7)
1,121 (24.0)
193 (19.5)
Right coronary artery
796 (28.8)
218 (29.6)
1,300 (27.9)
314 (31.7)
69 (2.5)
24 (3.3)
Bypass graft
p Value
66 (1.4)
20 (2.1)
2,103 (76.1)
516 (70.1)
<0.001
3,422 (73.4)
629 (63.6)
<0.001
Bifurcation lesion
923 (33.8)
211 (28.7)
0.008
1,649 (35.5)
286 (29.0)
<0.001
Restenotic lesion
262 (9.5)
77 (10.5)
0.423
445 (9.5)
124 (12.5)
0.004
0.200
3.00 [2.99–3.50]
3.00 [2.75–3.50]
0.010
Complex lesion (AHA B2/C class)
Balloon diameter, mm
3.00 [3.00–3.50]
3.00 [2.75–3.50]
Maximal balloon pressure, atm
15.0 [12.8–17.0]
14.0 [12.0–16.0]
0.008
15.0 [12.0–17.0]
14.0 [12.0–16.0]
<0.001
Total stented length, mm
24.0 [18.0–35.0]
23.0 [18.0–30.8]
0.002
23.0 [18.0–33.0]
23.0 [18.0–28.0]
<0.001
Post-procedural TIMI flow grade†
0.672
0
7 (0.2)
3 (0.4)
0.927 8 (0.2)
1 (0.1)
1
10 (0.4)
1 (0.1)
3 (0.1)
1 (0.1)
2
44 (1.6)
13 (1.8)
85 (1.8)
17 (1.7)
3
2,699 (97.8)
716 (97.7)
4,563 (97.9)
970 (98.1)
Values are n (%) of lesions or median [25th to 75th percentiles]. *Available for 3,494 lesions in patients with elevated baseline troponin levels and 5,649 lesions in patients with baseline troponin levels within normal limits. †Available for 3,493 lesions in patients with elevated baseline troponin levels and 5,648 lesions in patients with baseline troponin levels within normal limits. AHA ¼ American Heart Association; TIMI ¼ Thrombolysis In Myocardial Infarction; other abbreviations as in Table 1.
proportional hazards model. Independent correlates
the cutoff, patients were divided into a group
of all-cause mortality were assessed by using the
with baseline hs-TnT level within normal limits
multivariable Cox proportional hazards model. All
(hs-TnT #0.014 mg/l [n ¼ 3,463]) and a group with
variables in Tables 1 and 2 were tested in the uni-
elevated baseline hs-TnT level (hs-TnT >0.014 m g/l
variable analysis, and those exhibiting a significant
[n ¼ 2,163]). Using the peak post-procedural hs-TnT
association with mortality were entered into the
level, patients with normal baseline hs-TnT were
model to assess factors associated with mortality. The
divided into a group with elevated post-procedural
baseline and post-procedural hs-TnT measurements
hs-TnT level (hs-TnT >0.014 mg/l [n ¼ 2,721]) and
were entered into the model after logarithmic trans-
another group with normal post-procedural hs-TnT
formation.
equation
level (hs-TnT #0.014 m g/l [n ¼ 742]). Patients with
method was applied in all analyses (including multi-
elevated baseline hs-TnT levels were also divided
variable analyses) that involved lesion characteristics
into 2 groups: 1 with a further post-procedural rise in
to account for clustering of the data in the same pa-
hs-TnT (peak post-procedural hs-TnT level higher
tient. Statistical analysis was performed by using the
than baseline hs-TnT level [n ¼ 1,647]) and another
R
for
group with no further rise in post-procedural hs-TnT
Statistical Computing, Vienna, Austria). A 2-sided
(peak post-procedural hs-TnT equal to or lower than
p value <0.05 was considered to indicate statistical
the baseline hs-TnT level [n ¼ 516]). Baseline data are
2.15.1
The
generalized
Statistical
Package
estimating
(R
Foundation
significance.
RESULTS
shown in Table 1, and procedural characteristics are displayed in Table 2. CORRELATES OF POST-PROCEDURAL HS-TnT. Baseline
PATIENT CLASSIFICATION AND BASELINE DATA. Over-
and peak post-PCI hs-TnT levels in the whole group
all, the study included 5,626 patients. Using the
of patients are shown in the Central Illustration. In
99th percentile URL of baseline hs-TnT (0.014 m g/l) as
patients with nonelevated baseline hs-TnT levels,
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
2263
Troponin and Mortality After Elective PCI
C E N T R A L IL LU ST R A T I O N Troponin and Mortality After Elective PCI: Baseline and Post-Procedural hs-TnT Levels
Ndrepepa, G. et al. J Am Coll Cardiol. 2016;68(21):2259–68.
The graph in the left upper corner shows the distribution of paired baseline and peak post-procedural high-sensitivity troponin T (hs-TnT) values in each patient. The graph in the right upper corner shows the median and 25th to 75th percentiles of baseline (0.01 mg/l [0.01 to 0.02 mg/l]) and peak post-procedural (0.04 mg/l [0.02 to 0.10 mg/l]) hs-TnT levels. The median and 25th percentile values of baseline hs-TnT level are the same (0.01 mg/l). The lower graph shows the cumulative distribution curves of the baseline (blue line) and post-procedural (orange line) hs-TnT concentration. PCI ¼ percutaneous coronary intervention.
the mean baseline and post-procedural hs-TnT values
0.020 [0.010 to 0.060] m g/l), and 0.131 m g/l (median:
were 0.0095 m g/l and 0.098 m g/l. In patients with
0.023 [0.004 to 0.080] mg/l) in those with elevated
elevated baseline hs-TnT levels, mean baseline and
baseline hs-TnT levels. The multiple linear regression
mg/l
model with the generalized estimating equation
mg/l. The mean change in hs-TnT
method was used to assess independent correlates of
(peak post-procedural value baseline value) was
peak post-procedural hs-TnT in patients with and
0.088 m g/l in patients with nonelevated baseline
without elevated baseline hs-TnT levels (2 separate
hs-TnT levels (median [25th to 75th percentiles]:
models). Independent correlates of post-procedural
post-procedural and
0.244
hs-TnT
values
were
0.113
2264
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JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
Troponin and Mortality After Elective PCI
T A B L E 3 Independent Correlates of Post-Procedural hs-TnT Concentration Obtained
From the Multiple Linear Regression Model
hs-TnT are shown in Table 3. The elevated baseline hsTnT level and increased CAD severity and/or procedure complexity were independently associated with
Patients With hs-TnT Elevated at Baseline (n ¼ 2,163)
Diabetes Multivessel disease
Patients With hs-TnT Not Elevated at Baseline (n ¼ 3,463)
Coefficient*
p Value
Coefficient
p Value
–0.111785651
0.022
0.281562811
<0.001
0.287904096
–0.191225601
<0.001
elevated hs-TnT levels after PCI. Notably, restenotic lesions were associated with reduced odds of an elevation in hs-TnT after PCI in patients from both groups.
<0.001
POST-PROCEDURAL HS-TnT AND MORTALITY. Overall,
–
–
0.125431940
0.019
there were 265 deaths during the follow-up period:
0.654213201
<0.001
0.832773399
<0.001
6 deaths (1.6%) in patients with normal baseline and
Previous myocardial infarction
–0.128152726
0.011
–
–
post-procedural hs-TnT levels; 54 deaths (3.8%) in
Restenotic lesion
–0.189879905
<0.001
–0.238671558
<0.001
patients with normal baseline and raised post-
ACC/AHA B2/C class lesion
0.147118526
<0.001
0.178565892
<0.001
Multivessel disease
0.281562811
<0.001
–
–
0.006
–
–
Arterial hypertension Baseline troponin
Glomerular filtration rate
–0.002781484
Body mass index
–
Bifurcation lesion
0.087846055
Left anterior descending artery intervention Maximal balloon pressure Post-procedural TIMI flow Total stented length
0.159625100 – –0.291569192 0.008934003
– 0.044 <0.001 –
procedural hs-TnT levels; 50 deaths (16.0%) in patients with raised baseline levels but no further elevation in post-procedural hs-TnT; and 155 deaths
–0.013267508
0.037
0.142993244
<0.001
(18.2%)
among
<0.001
hs-TnT
levels
0.171036095 0.016835049
<0.001
0.003
–0.334634960
0.005
<0.001
0.009691764
<0.001
*Coefficients denote the change in log post-procedural high-sensitivity troponin T (hs-TnT) per unit change in the independent variable. The negative sign before the coefficients shows the inverse correlation between the independent variable and the post-procedural troponin concentration.
patients and
with
further
elevated elevation
baseline in
post-
procedural hs-TnT (overall log-rank test p < 0.001) (Figure 1). In patients with normal baseline hs-TnT levels, elevated post-procedural hs-TnT measurements were associated with increased risk of mortality compared with patients with a post-procedural hs-TnT level within normal limits (univariable hazard ratio [HR]: 2.38; 95% confidence interval [CI]: 1.03 to
ACC ¼ American College of Cardiology; other abbreviations as in Tables 1 and 2.
5.54; p ¼ 0.043). In patients with elevated baseline
F I G U R E 1 Kaplan-Meier Curves Showing Probability of 3-Year Mortality for Patient Subgroups According to Baseline and Post-Procedural
High-Sensitivity Troponin T Levels
Probability of Mortality (%)
30.0 25.0 HR=2.38 [1.03-5.54]; P=0.043 18.2%
20.0 15.0
16.0% 10.0 5.0
HR=1.09 [0.79-1.51]; P=0.575 3.8%
0.0
1.6% 0
1
Troponin groups/patients at risk Raised at baseline/further raised after PCI Raised at baseline/not raised after PCI Not raised at baseline/raised after PCI Not raised at baseline/not raised after PCI
2
3
529 198 1142 309
248 106 588 144
Years 1647 516 2721 742
912 325 1832 484
The curves are hierarchically ordered according to the order of the numbers of patients at risk. Percentages show the Kaplan-Meier estimates of mortality. Numbers in brackets denote 95% confidence intervals. HR ¼ hazard ratio; PCI ¼ percutaneous coronary intervention.
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
hs-TnT levels, further elevation in post-procedural
T A B L E 4 Results of Multivariable Cox Proportional Hazards Model Applied to
hs-TnT was not associated with increased risk of
Assess Predictors of All-Cause Mortality With Baseline and Post-Procedural
mortality compared with patients with no further
hs-TnT Entered Into the Model
elevation in post-procedural hs-TnT (univariable HR: 1.09; 95% CI: 0.79 to 1.51; p ¼ 0.575). In the univariable analysis, age (p < 0.001), female sex (p ¼ 0.002), diabetes (p ¼ 0.009), arterial hyper-
HR (95% CI)
p Value
Peak post-procedural hs-TnT (for 1-SD increase in logarithmic scale of hs-TnT)
1.04 (0.85–1.28)
0.679
Baseline hs-TnT (for 1-SD increase in logarithmic scale of hs-TnT)
1.22 (1.09–1.38)
<0.001 <0.001
tension (p < 0.001), body mass index (p ¼ 0.019),
Age (for 10-yr increase)
1.92 (1.31–2.81)
hypercholesterolemia (p ¼ 0.005), multivessel dis-
Female
0.57 (0.34–0.91)
0.028
ease (p < 0.001), previous coronary artery bypass
Diabetes
1.09 (0.72–1.65)
0.693
surgery (p < 0.001), baseline hs-TnT level (p < 0.001),
Arterial hypertension
0.54 (0.37–0.79)
0.002
peak post-procedural hs-TnT level (p < 0.001),
Body mass index (for 5 kg/m2 increase)
1.22 (0.96–1.55)
0.112
glomerular filtration rate (p < 0.001), left ventricular
Hypercholesterolemia
0.73 (0.48–1.12)
0.149
ejection
fraction
(p
2265
Troponin and Mortality After Elective PCI
<
0.001),
vessel
treated
(p ¼ 0.004), restenotic lesions (p < 0.001), baseline
Multivessel disease
1.26 (0.63–2.53)
0.505
Previous coronary artery bypass surgery
1.03 (0.64–1.65)
0.897
TIMI flow grade (p ¼ 0.014), balloon diameter
GFR (for 30 ml/min decrease)
1.69 (1.14–2.51)
0.008
LVEF (for 10% decrease)
1.41 (1.23–1.62)
<0.001
(p ¼ 0.003), maximal balloon pressure (p ¼ 0.007),
Vessel treated
1.54 (0.92–2.59)
and post-procedural TIMI flow grade (p ¼ 0.042) were
Restenotic lesions
1.32 (0.87–1.99)
0.187
independently associated with mortality risk. All of
Baseline TIMI flow grade (for 1 grade decrease)
1.26 (0.98–1.64)
0.076
Balloon diameter (for 0.5-mm increase)
1.05 (0.94–1.17)
0.387
Maximal balloon pressure (5 atm increase)
1.16 (0.96–1.39)
0.120
these variables, except for post-procedural TIMI flow (due to strong correlation with post-procedural hsTnT), were entered into the Cox proportional hazards model with the generalized estimating equation
0.102
CI ¼ confidence interval; GFR ¼ glomerular filtration rate; HR ¼ hazard ratio; LVEF ¼ left ventricular ejection fraction; other abbreviations as in Tables 1 and 2.
method. When the post-procedural hs-TnT-mortality association was tested in the model in the entire group of patients and adjusted for the factors associated with mortality risk listed previously (excluding baseline hs-TnT), there was a trend for an association between post-procedural hs-TnT level and the risk of mortality (adjusted HR: 1.22; 95% CI: 0.98 to 1.41; p ¼ 0.082 for each SD increase in the logarithmic scale of post-procedural hs-TnT). When baseline hs-TnT level was entered into the model, the baseline hsTnT level (HR: 1.22; 95% CI: 1.09 to 1.38; p < 0.001), but not peak post-procedural hs-TnT level (HR: 1.04; 95% CI: 0.85 to 1.28; p ¼ 0.679), was associated with increased risk of mortality (both risk estimates calculated per SD increase in the logarithmic scale of hs-TnT) (Table 4). The association between peak post-
>70 the 99th percentile URL cutoff, compared with post-procedural hs-TnT #70 the 99th percentile URL, was associated with increased risk of mortality in patients with elevated baseline hs-TnT level (45.1% vs. 17.1%; univariable HR: 4.20; 95% CI: 1.98 to 8.44; p < 0.001) but not in those with nonelevated levels of the biomarker (5.3% vs. 3.3%; HR: 1.42; 95% CI: 0.03 to 8.72; p ¼ 0.772). In patients with elevated baseline hs-TnT, the association between the >70 the 99th percentile URL cutoff and mortality was tested in the multivariable Cox model, with hs-TnT entered as a categorical variable (dichotomized at the 70 the 99th percentile cutoff). The analysis showed a trend toward an independent association between hs-TnT
procedural hs-TnT and mortality was not significant in the group with normal baseline hs-TnT level (HR:
T A B L E 5 Mortality According to Different Cutoffs of Post-Procedural hs-TnT
0.93; 95% CI: 0.69 to 1.25; p ¼ 0.653) or in the group with elevated baseline hs-TnT level (HR: 1.24; 95% CI:
Elevated Baseline hs-TnT (n ¼ 2,163)
0.91 to 1.69; p ¼ 0.165), with both risk estimates
Patients (%) Mortality (%)* Patients (%) Mortality (%)*
calculated per SD increase in the logarithmic scale of peak post-procedural hs-TnT.
Baseline hs-TnT Within Normal Limits (n ¼ 3,463)
Not increased (vs. baseline)
516 (23.9)
50 (16.0)
742 (21.4)
6 (1.6)
1 to 3 99th percentile URL
595 (27.5)
45 (17.0)
1,475 (42.6)
26 (3.4) 12 (5.4)
MORTALITY ACCORDING TO VARIOUS CUTOFFS OF
>3 to 5 99th percentile URL
362 (16.8)
35 (17.1)
453 (13.1)
>5 to 10 99th percentile URL
295 (13.6)
28 (20.8)
380 (11.0)
7 (2.7)
POST-PROCEDURAL HS-TnT. The association between
>10 to 35 99th percentile URL
286 (13.2)
28 (17.2)
310 (8.9)
7 (4.6)
post-procedural hs-TnT level and mortality was
>35 to 70 99th percentile URL
65 (3.0)
6 (15.5)
62 (1.8)
1 (1.8)
assessed over several multiples of 99th percentile URL
>70 99th percentile URL
44 (2.0)
13 (45.1)
41 (1.2)
1 (5.3)
cutoffs in patients with and without elevations in baseline hs-TnT. The results of this analysis are shown in Table 5. Notably, the hs-TnT elevation
*Numbers in parentheses in the mortality columns represent Kaplan-Meier estimates of mortality. hs-TnT ¼ high-sensitivity troponin T; URL ¼ upper reference limit.
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Troponin and Mortality After Elective PCI
>70 the 99th percentile URL and mortality
the risk of subsequent mortality up to 3 years after PCI.
(p ¼ 0.093), and a trend toward an interaction between
A PCI-related hs-TnT elevation 6 times the URL in pa-
post-procedural hs-TnT >70 the 99th percentile URL
tients with normal baseline hs-TnT and >9 times the
and baseline level of the biomarker with regard to the
URL in patients with elevated baseline levels of the
prediction of mortality (p for interaction ¼ 0.073).
biomarker was not associated with increased mortality risk. The striking separation of the Kaplan-Meier
DISCUSSION
curves for mortality (showing mortality differences predominantly secondary to baseline hs-TnT levels),
The main findings of this study can be summarized as
in addition to the results of the multivariable analysis,
follows: 1) in patients with CAD undergoing elective
lend further support to this finding. Miller et al. (8) also
PCI, a procedure-related hs-TnT rise occurred in the
showed that long-term prognosis was most often
majority of patients (77.6%); 2) post-procedural
related to the baseline troponin level, rather than to
hs-TnT
elevation
was
not
associated
with
an
the biomarker response to PCI. However, the study by
increased risk of mortality for up to 3 years, regard-
Miller et al. differs from the present study in that it
less of the pre-procedural hs-TnT level; 3) the pre-
included not only patients with stable CAD but also
procedural hs-TnT elevation was independently
those with acute coronary syndromes, a conventional
associated with an increased risk of mortality; and 4)
troponin assay was used, and fewer deaths were re-
pre-procedural hs-TnT level and angiographic char-
ported. Notwithstanding these differences, the cur-
acteristics underlying procedure complexity were
rent study corroborates the findings of Miller et al. in a
independent correlates of elevated post-procedural
large series of patients with stable CAD by using a
hs-TnT level in patients both with and without
contemporary high-sensitivity cardiac troponin assay.
elevated baseline levels of the biomarker.
Furthermore, by finding a trend toward an interaction
Circulating troponin after PCI consists of 2 frac-
between the post-procedural hs-TnT >70 the 99th
tions: a pre-procedural or baseline fraction and a
percentile URL and baseline hs-TnT level regarding
fraction
prediction of mortality, the present study may offer
that
reflects
PCI-related
troponin
rise.
Continuous microscopic loss of cardiomyocytes dur-
support to the definition of clinically relevant
ing normal life (9) and cardiomyocyte renewal (10) are
myocardial infarction after coronary revascularization
2 processes that contribute to physiological baseline
in the Consensus Document of the Society for Cardio-
concentrations
vascular Angiography and Interventions (16).
of
circulating
troponin.
Multiple
additional factors can increase levels of circulating
Although factors responsible for baseline hs-TnT
cardiac troponin in clinical scenarios other than acute
elevation help to explain the increased mortality
coronary syndromes (11). Prasad et al. (7) showed that
risk in patients with elevated baseline levels of the
37%
have
biomarker, the relationship between factors associ-
elevated pre-procedural troponin levels. The elevated
ated with troponin rise post-PCI and mortality is less
circulating troponin level in these patients may be
clear. Procedure-related factors or complications
explained by a less favorable cardiovascular and
increasing the risk of myocardial damage via distal
metabolic risk profile (11), more extensive CAD (12), or
embolization, side-branch occlusion, or suboptimal
clinically silent complicated atherosclerotic plaques
myocardial flow are proven risk factors for post-
(13). It is proposed that elevated baseline circulating
procedural troponin rise (3,17,18). The present study
troponin level in patients with stable CAD may be
also found that increased procedural complexity was
caused by cardiometabolic risk–related stress on the
associated with elevated hs-TnT levels after PCI,
myocardium (14,15) or by cycles of silent atheroscle-
regardless of the baseline hs-TnT level. However, if
rotic plaque rupture and sealing, leading to repeated
the troponin response to PCI was assessed by using
myocardial ischemia (13). Both of these conditions are
less sensitive troponin assays, as was the case in
associated with increased cardiovascular risk, and
multiple
they may explain the association between elevated
myocardial damage would be needed to result in a
baseline hs-TnT and mortality.
procedure-related troponin rise. The currently used
of
patients
undergoing
elective
PCI
previous
studies,
relatively
extensive
The principal finding of the present study was that
high-sensitivity troponin assays, including that used
post-procedural hs-TnT elevation was not associated
in the present study, allow detection of troponin
with an increased risk of mortality, regardless of
release from minuscule damage of myocardial tissue.
baseline hs-TnT level. Although elevated baseline hs-
Thus, it is plausible that post-procedural elevation of
TnT in itself was strongly associated with an
the magnitude observed in the present study may
increased risk of mortality, it had no impact on the
reflect subtle PCI-related myocardial damage that is
association between the PCI-related rise in hs-TnT and
too small (or transient) to have clinical sequelae.
Ndrepepa et al.
JACC VOL. 68, NO. 21, 2016 NOVEMBER 29, 2016:2259–68
Troponin and Mortality After Elective PCI
A study by Lim et al. (19) found that only a small
as others regarding post-procedural troponin mea-
minority (5 of 26 patients) fulfilling troponin criteria
surements. We are aware of the possibility that the
for PCI-related (type 4a) myocardial infarction had
precise peak value of post-procedural troponin may
evidence of peri-procedural necrosis on cardiac
have been missed in a number of patients. This would
magnetic resonance imaging. The investigators sug-
have required multiple measurements in a short time
gest that current troponins are oversensitive for the
interval. Finally, these data are from the hs-TnT assay
diagnosis of PCI-related myocardial injury. In the
and may not be extrapolated to assess the perfor-
present study, despite post-procedural hs-TnT ele-
mance of other conventional or high-sensitivity
vations in the majority of patients and identification
troponin assays. In the present study, a 0.014-mg/l
of several indexes of procedural complexity as pre-
cutoff was used to define the hs-TnT elevation, which
post-
differs from the 0.03-m g/l cutoff we used previously
procedural TIMI flow (grade 3) was restored in >97%
to detect troponin elevations with conventional
of patients. Thus, a combination of factors (including
troponin assays.
disposing
factors
for
this
rise,
optimal
the use of a high-sensitivity troponin assay) capable of detecting troponin elevation caused by subtle PCIrelated myocardial damage, adjustment for baseline hs-TnT level, and the capacity of current-day PCI to achieve optimal revascularization, even in the setting of high procedural complexity, may have attenuated the association of post-procedural troponin rise with mortality. The inverse association between restenotic lesions and post-procedural hs-TnT may offer evidence for the role of distal embolization in the elevation of post-procedural hs-TnT level. Intervention in restenotic lesions, which have a higher fibrotic/atherosclerotic content ratio compared with native atherosclerotic plaques, may be associated with less distal embolization, myocardial injury, and troponin elevation due to this factor.
CONCLUSIONS In patients with CAD undergoing elective PCI, postprocedural hs-TnT elevation was not associated with an increased risk of mortality for up to 3 years in patients with or without elevated baseline levels of the biomarker. Although there was a strong and independent association between baseline hs-TnT and mortality, the PCI-related elevation in hs-TnT did not offer prognostic information beyond that provided by baseline hs-TnT levels. REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Gjin
Ndrepepa,
Deutsches
Herzzentrum,
Laza-
rettstrasse 36, 80636 München, Germany. E-mail: [email protected].
STUDY LIMITATIONS. First, serial testing of hs-TnT
levels before PCI was not performed, resulting in a
PERSPECTIVES
lack of data on biomarker stability at baseline. If hsTnT levels are unstable before PCI, the ability to discriminate between a spontaneous and procedurerelated hs-TnT elevation is limited. This scenario is particularly relevant in the case of patients presenting with acute coronary syndromes. Nonetheless, all patients included in the present study had clinically stable CAD at the time of the index PCI. Moreover, given that the proportion of patients with hs-TnT elevation post-PCI seems to differ little between the groups with or without elevated baseline hs-TnT levels, we believe that PCI was responsible for the biomarker increase in the vast majority of patients in both groups. The collection of blood samples after the
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with CAD undergoing elective PCI, the baseline level of hs-TnT was strongly and independently associated with 3-year mortality, whereas post-procedural hs-TnT elevations did not provide additional prognostic information beyond the baseline hs-TnT level. TRANSLATIONAL OUTLOOK: Further studies in larger numbers of patients are needed to determine whether certain thresholds of post-procedural hs-TnT elevation carry independent prognostic value in patients with particular patterns of CAD undergoing PCI.
PCI follows the common practice in our center as well
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