Editorial
Torrent of Troponin
Harvey D. White, DSc
How do we interpret these results? First the findings of this
study are important with contemporary troponin elevation
being related to 3-month cardiovascular mortality. However
the cut point for the TnT value, which barely reached statistical significance, is so high that it is associated with so few
events that it renders it nonuseful for either clinical or trial purposes and it will vary with the characteristics of the patients in
the study. The study also raises the question whether CK-MB
should be abandoned given that it was not related to cardiovascular death.
Patients with postprocedural TnT elevation had more complex coronary artery disease and were more likely to have
multivessel PCI or intervention on a saphenous vein graft.
This raises the intriguing possibility that a normal baseline
TnT is not really obtained with the relatively insensitive contemporary TnT assay. Similarly, postprocedural thrombolysis
in myocardial infarction (MI) flow <3 was more common in
patients with elevated TnT levels.
“The River Eddy Whirls”
—The Lady of Shalott, Lord Alfred Tennyson (1842)
I
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n this issue of Circulation: Cardiovascular Interventions,
Herrmann et al1 report data from a contemporary registry
from the Mayo clinic. The study examined the relationship
between the magnitude of periprocedural myonecrosis with
percutaneous coronary intervention (PCI), measured simultaneously with contemporary troponin T (TnT) and creatine
kinase-myocardial band (CK-MB), with 3-month postprocedural survival and determine whether there was a threshold
value for TnT at which prognosis was significantly affected.
Importantly they only included patients with normal baseline
biomarker levels.
Article see p 533
Of the 5268 patients (43%), 1142 (22%) patients after PCI
developed TnT or CK-MB elevation >1× upper limit of normal (ULN). Post PCI elevations tended to be small; the peak
level was 0.05 ng/mL (median; interquartile range, 0.02–0.15)
for TnT and 10.8 ng/mL (median; interquartile range, 7.3–
19.5) for CK-MB. This should be no surprise to the field and
highlights the critical role of making sure that the baseline
TnT value is normal before the procedure.2
Three-month mortality was 0.9% in patients with and 0.4%
in those without any level of postprocedural TnT elevation
(P=0.01). The optimal TnT cutoff value for 3-month mortality
prediction was 0.25 mg/mL, that is, 25× ULN, but this level
was found in only 7% of patients. In respect of prognostic bioequivalence, a cutoff value of 25× ULN for TnT and 5× ULN
for CK-MB provided similar information.
In a multivariate model that adjusted for the Mayo Clinic
risk scores, postprocedural TnT elevation remained associated with 3-month all-cause death (hazard ratio [HR] per doubling of TnT, 1.24 [1.08–1.43]; P=0.003) and cardiovascular
death (HR per doubling of TnT, 1.26 [1.04–1.54]; P=0.02).
Although any level of elevation of CK-MB was associated
with higher 3-month mortality, independent of the Mayo risk
score, there was no significant correlation with cardiovascular
mortality (HR per doubling, 1.30 [1.05–1.60]; P=0.069).
Potential Limitations of the Study
There are several important limitations of the study. The
numbers of events are small, for patients with TnT elevation
there were only 9 cardiac deaths. Relying on such a small
number of events is likely to be misleading. The authors
focus on total mortality and this is germane in studies where
a large number of deaths cannot be ascribed to cardiovascular causes. Here, we really want to determine whether
periprocedural elevation of biomarkers are related to cardiovascular morbidity/mortality and not to some other cause
such as cancer or pulmonary disease, which would be related
to baseline elevation of troponins and not to a complication
of PCI such as loss of a coronary artery side branch. Appropriately all deaths without known cause were considered cardiovascular for the purposes of the present analysis. Despite,
>50% of deaths were because of noncardiac causes (11/20)
and many others were unlikely to be related to a complication of PCI but were related to high-risk characteristics such
as refractory ventricular tachycardia. Also in a recent study,
procedural complications accounted for only 8.2% of postPCI in-hospital deaths and most deaths were attributed to
pre-existing or unrelated postprocedural disease processes.3
It might not be surprising that in a tertiary referral hospital such as the Mayo Clinic, multiple interventions may be
done on a variety of critically or terminally ill individuals with
elevated troponins whose longevity may be limited. Including
such patients in one sense may be reasonable since when
critical illness is present, elevations of TnT identify patients
at high risk. Despite this logic, criticisms related to patient
selection may blunt the importance of the principles involved
which are whether elevations of TnT post PCI are of clinical
cardiovascular importance.
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Green Lane Cardiovascular Service, Auckland City Hospital,
Auckland, New Zealand.
Correspondence to Harvey D. White, DSc, Green Lane Cardiovascular
Service, Auckland City Hospital, Private Bag 92024, Auckland, New
Zealand. E-mail [email protected]
(Circ Cardiovasc Interv. 2014;7:435-438.)
© 2014 American Heart Association, Inc.
Circ Cardiovasc Interv is available at
http://circinterventions.ahajournals.org
DOI: 10.1161/CIRCINTERVENTIONS.114.001751
435
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The contemporary TnT is egregiously insensitive in detecting some baseline elevations and unfortunately high-sensitive
TnT was not available, which is better at detecting baseline
elevations. The study used a cut point for TnT of <0.01 ng/
mL, which is a strength of the study because it makes sure
that at least the 99th percentile upper reference limit (URL)
value is used at baseline. Only a prior Mayo study has done
this in the past.4 To not do this, renders less importance to
the prognostic impact of baseline samples. The frequency of
marked elevations is small when the baseline value is at the
99th percentile value. Most of the prognostic information is
in the baseline value2 and with higher sensitivity assays, the
results seen in this study may disappear and patients with
postprocedural elevation of troponins will likely be those with
worse coronary artery disease. It is known that elevated troponin values are associated with worse coronary anatomy in
patients with acute coronary syndromes and those with stable
coronary artery disease5 as well. And there are data to suggest
that the more extensive the coronary artery disease, the greater
the extent of the high-sensitive troponin elevations.6
When data indicating the potent prognostic value of elevated
high-sensitivity troponin values found in the Heart Outcomes
Prevention Evaluation study (HOPE)7 and Prevention of
Events with Angiotensin Converting Enzyme Inhibition
(PEACE)8 trials are added, it maybe that with better baseline
measurements, that even the significance of these marked elevations will be obviated. It is unfortunate high-sensitive troponin measurements were not available in this study.
Comparison With the Society for
Cardiovascular Angiography and
Interventions Definition
The threshold level found in the current study is lower than
the clinically relevant level defined as an event associated with
a worsened prognosis set by the Society for Cardiovascular
Angiography and Interventions definition of periprocedural
MI.9 This requires isolated elevation ≥10× for CK-MB using
the local laboratory ULN without sex-specific differences or
troponin ≥70× ULN. And if there are new Q waves or new left
bundle-branch block, the CK-MB level required is ≥5× ULN
and for troponin is ≥35× ULN.
Biomarker increases should not be used in isolation as they
may increase with successful procedures and optimal stent
deployment10 and if the baseline TnT is not elevated, there will
be few large biomarker elevations (eg, troponin ≥70× URL). If
so, there will be few periprocedural MIs identified and opportunity may be lost to improve patient outcomes.
The attempt to make a close correlation between diagnosis
and prognosis defy the reality that is present clinically. It is
clear that a substantial amount of cardiac injury may be well
tolerated in many patients with normal cardiac function who
undergo successful PCI. A similar amount of injury may be
less tolerated when there is poor ventricular function and less
than ideally successful procedures. Thus, attempts to find a
magic number where diagnosis and prognosis are similar are
unlikely to be fruitful and even if successful, this value would
vary depending on the TnT assay use. In addition, the concept
that any given diagnosis must have prognostic importance
maybe flawed. Clearly having cardiac injury is not a good
thing and most often it has prognostic importance in the right
clinical situation. However, in the absence of the development
of additional disease and assuming a good result has been
obtained, it is unclear that this search is one that will be productive, especially if one adheres to the concept that one needs
a normal baseline value as has been documented previously.2
In several studies the increase of troponin related to 3×
URL of CK-MB ranged from 20 to 60× URL reflecting the
heterogeneity of the assays involved. In the small gadolinium-enhanced Myocardial Injury following Coronary Artery
Surgery versus Angioplasty (MICASA) study, categorization
of a type 4a MI associated with a 3× elevation of CK-MB5
required a troponin elevation of >40× 99th percentile.11 In
the Evaluation of Drug Eluting Stents and Ischemic Events
(EVENT) registry,12 troponin levels had to be elevated 20×
ULN to be equivalent to the 1-year mortality (5.8%) associated with 3× elevation of CK-MB. In the Early Glycoprotein
IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute
Coronary Syndrome (EARLY ACS) and Superior Yield of
the New Strategy of Enoxaparin, Revascularization and
Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trials there was
a significant increase in 1-year mortality with an increase
of 10× URL of troponin (HR, 1.07; 95% confidence interval, 1.02–1.11; P=0.004).13 An elevation of troponin >60×
ULN had a similar adjusted 1-year mortality risk (5%) as 3×
CK-MB elevation. Thus, the concept that a given threshold
can be defined to cover all assays as suggested by the Society
for Cardiovascular Angiography and Interventions criteria is
unlikely to be correct.
Elevation of CK-MB post PCI has been associated with
2-year mortality but not TnT elevations.14 The Randomized,
Two-Arm, Non-Inferiority Study Comparing EndeavorResolute Stent With Abbot Xience-V Stent (RESOLUTE-AC)
studies showed no relation of 3× elevation of CK-MB with
2-year cardiovascular mortality15 However in a study of
23 604 patients from Korea, 5× URL increase in CK-MB
was associated with an increase in mortality at 2.9 years
(HR, 1.33; 95% confidence interval, 1.03–1.71).16 Also in the
Therapeutic Outcomes by Optimizing Platelet Inhibition with
Prasugrel (TRITON), cardiovascular mortality was increased
at 180 days if CK-MB rose 3× (2 samples) or 5× (1 sample)
URL (adjusted HR, 2.4; 95% confidence interval, 1.6–3.7).17
Third Universal Definition of MI
In the universal definitions of MI, the diagnosis of MI is based
on pathophysiology, that is, myocyte necrosis in the setting of
ischemia and there is no requirement for the diagnosis of MI
to be related to mortality. The 2007 universal definition of a
periprocedural MI (type 4a MI) had been controversial with
data challenging the idea that type 4a MIs are prognostically
important. The 2007 universal definition required increases
of cardiac biomarkers >3× 99th percentile URL with troponin preferred.18 Because myocardial injury occurs commonly after PCI,19 the definition resulted in large numbers
of patients being defined as having had a procedure-related
MI, with ≈15% of patients undergoing PCI having an MI,19
with higher rates in patients undergoing complex procedures.
Some of this was because of the fact that many studies did
not adhere to the need for a normal baseline or defined that
White Torrent of Troponin 437
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with some other criteria other than the 99th percentile URL.19
Therefore, the universal definition has not been embraced
enthusiastically by the interventional community either in
clinical practice or in trials.
In the 2012 universal definition, the biomarker cut point
level was raised to an elevation of TnT values >5× 99th
percentile URL and associated ischemic features or angiographic complications were added.20 The definition states
that troponins should be measured before PCI to assess
whether the baseline is stable.20 If the baseline is not stable
or values are not falling, increasing biomarker values cannot
be interpreted as being related to PCI. Several studies have
shown that only elevation of pre-PCI biomarkers and not
post-PCI levels affects survival.2,4,21 If biomarker values are
not elevated >5× 99th percentile URL, then the term myocardial injury should be used.
The increase from 3× to 5× 99th percentile from the 2007
definition was chosen arbitrarily, given the increasing sensitivity of troponin assays and also the fact that many less sensitive assays are still in use. It was to improve the specificity
of the diagnosis of post-PCI MI that the 2012 universal definition of MI that in addition either (1) symptoms suggestive
of myocardial ischemia, (2) new ischemic ECG changes, (3)
angiographic findings consistent with a procedural complication with loss of a major artery or side branch, embolization, or (4) imaging demonstration of new loss of viable
myocardium or new regional wall motion abnormality are
required. It is unfortunate that their use was not included in
the current study.
Conclusions
Herrmann et al1 report data from a large carefully collected registry of patients undergoing PCI. A prognostically important
level was defined for post-PCI TnT elevation with a threshold
of 25× ULN for TnT, which occurred in 7% of patients in the
study. This was the optimal cutoff value to identify patients at
increased risk for cardiovascular death within 3 months after
PCI, although this risk is largely conferred by adverse baseline
and procedural characteristics. It seems rational that the cut
point for troponin should be much higher than for CK-MB but
it is unlikely that these criteria with the present assay can be
applied to any other assay in clinical use, including the highsensitivity TnT assay.
The number of events in this study is extremely small (9
cardiac deaths and 11 noncardiac deaths), probably because
of the excellent procedures performed, perhaps lower risk
patients, and high rates of evidence-based medicine. It likely
reflects reality, that is, post-PCI values of TnT are not often
associated with increases in mortality. Indeed, it is likely that
more sensitive baseline values might have obviated even these
modest findings still further. Elevation of troponin levels is
often not related to the procedure and therefore coupling a rise
in troponins with complications of PCI may obscure the causality of adverse outcomes. Larger studies with ascertainment
of complications of PCI to improve the specificity of the diagnosis and with focus on cardiovascular deaths with different
high-sensitivity troponin assays are required to inform us further about whether there are any troponin thresholds that contain prognostic information after PCI and if so to define the
mechanisms. At present, it seems that the baseline value which
is indicative of the extent and severity of the coronary artery
disease, even in this study, has much more import. Perhaps
these patients may benefit from more aggressive therapy such
as high dose statins. Even if some post-PCI threshold can be
defined, it is not at all clear that insisting that prognostic and
diagnostic criteria be the same in general and applicable to all
TnT assays will be a reasonable strategy.
Disclosures
Dr White has received research grants from Sanofi Aventis, Eli Lilly,
Medicines Company, National Institutes of Health, Pfizer, Roche,
Johnson&Johnson, Schering Plough, Merck, Sharpe & Dohme, Astra
Zeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development,
and Bristol-Myers Squibb and is on Advisory boards for Merck,
Sharpe & Dohme, Roche, and Regado Bioscience.
References
1. Herrmann J, Lennon RJ, Jaffe AS, Holmes DR Jr, Rihal CS, Prasad A.
Defining the optimal cardiac troponin T threshold for predicting death
caused by periprocedural myocardial infarction after percutaneous coronary intervention. Circ Cardiovasc Interv. 2014;7:533–542.
2. Miller WL, Garratt KN, Burritt MF, Lennon RJ, Reeder GS, Jaffe AS.
Baseline troponin level: key to understanding the importance of post-PCI
troponin elevations. Eur Heart J. 2006;27:1061–1069.
3. Valle JA, Smith DE, Booher AM, Menees DS, Gurm HS. Cause and circumstance of in-hospital mortality among patients undergoing contemporary percutaneous coronary intervention: a root-cause analysis. Circ
Cardiovasc Qual Outcomes. 2012;5:229–235.
4. Prasad A, Rihal CS, Lennon RJ, Singh M, Jaffe AS, Holmes DR Jr.
Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and postintervention troponin T levels in 5487 patients. Circ Cardiovasc Interv.
2008;1:10–19.
5. Korosoglou G, Lehrke S, Mueller D, Hosch W, Kauczor HU, Humpert
PM, Giannitsis E, Katus HA. Determinants of troponin release in patients
with stable coronary artery disease: insights from CT angiography characteristics of atherosclerotic plaque. Heart. 2011;97:823–831.
6.Laufer EM, Mingels AM, Winkens MH, Joosen IA, Schellings MW,
Leiner T, Wildberger JE, Narula J, Van Dieijen-Visser MP, Hofstra L. The
extent of coronary atherosclerosis is associated with increasing circulating
levels of high sensitive cardiac troponin T. Arterioscler Thromb Vasc Biol.
2010;30:1269–1275.
7. Kavasak PA XL, Yusuf S, McQueen MJ. High-sensitivity cardiac troponin
I measurement for risk stratification in a stable high-risk population. Clin
Chem. 2011;57:1146–53.
8.Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM,
Jablonski KA, Tjora S, Domanski MJ, Gersh BJ, Rouleau JL, Pfeffer MA,
Braunwald E; Prevention of Events with Angiotensin Converting Enzyme
Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med. 2009;361:2538–2547.
9. Moussa ID, Klein LW, Shah B, Mehran R, Mack MJ, Brilakis ES, Reilly JP,
Zoghbi G, Holper E, Stone GW. 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). J Am Coll Cardiol. 2013;62:1563–1570.
10.Iakovou I, Mintz GS, Dangas G, Abizaid A, Mehran R, Kobayashi Y,
Lansky AJ, Aymong ED, Nikolsky E, Stone GW, Moses JW, Leon MB.
Increased CK-MB release is a “trade-off” for optimal stent implantation:
an intravascular ultrasound study. J Am Coll Cardiol. 2003;42:1900–1905.
11. Lim CC, van Gaal WJ, Testa L, Cuculi F, Arnold JR, Karamitsos T, Francis
JM, Petersen SE, Digby JE, Westaby S, Antoniades C, Kharbanda RK,
Burrell LM, Neubauer S, Banning AP. 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;57:653–661.
12.Novack V, Pencina M, Cohen DJ, Kleiman NS, Yen CH, Saucedo JF,
Berger PB, Cutlip DE. Troponin criteria for myocardial infarction after
percutaneous coronary intervention. Arch Intern Med. 2012;172:502–508.
13. Tricoci P, Leonardi S, White J, White HD, Armstrong PW, Montalescot
G, Giugliano RP, Gibson CM, Van de Werf F, Califf RM, Harrington RA,
438 Circ Cardiovasc Interv August 2014
Downloaded from http://circinterventions.ahajournals.org/ by guest on June 18, 2017
Braunwald E, Mahaffey KW, Newby LK. Cardiac troponin after percutaneous coronary intervention and 1-year mortality in non-ST-segment elevation acute coronary syndrome using systematic evaluation of biomarker
trends. J Am Coll Cardiol. 2013;62:242–251.
14.Cavallini C, Savonitto S, Violini R, Arraiz G, Plebani M, Olivari Z,
Rubartelli P, Battaglia S, Niccoli L, Steffenino G, Ardissino D; Italian
‘Atherosclerosis, Thorombosis, and Vascular Biology’ and ‘Society for
Invasive Cardiology-GISE’ Investigators. 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.
Eur Heart J. 2005;26:1494–1498.
15. Vranckx P, Farooq V, Garg S, Van Es GA, Silber S, Windecker S, Stone
GW, Serruys PW. Different cardiac biomarkers to detect peri-procedural
myocardial infarction in contemporary coronary stent trials: impact on
outcome reporting. Heart. 2012;98:1424–1430.
16. Park DW, Kim YH, Yun SC, Ahn JM, Lee JY, Kim WJ, Kang SJ, Lee SW,
Lee CW, Park SW, Park SJ. Frequency, causes, predictors, and clinical significance of peri-procedural myocardial infarction following percutaneous
coronary intervention. Eur Heart J. 2013;34:1662–1669.
17. Bonaca MP, Wiviott SD, Braunwald E, Murphy SA, Ruff CT, Antman
EM, Morrow DA. American College of Cardiology/American Heart
Association/European Society of Cardiology/World Heart Federation
universal definition of myocardial infarction classification system and the
risk of cardiovascular death: observations from the TRITON-TIMI 38 trial
(Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction
38). Circulation. 2012;125:577–583.
18. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task
Force for the Redefinition of Myocardial Infarction. Universal definition
of myocardial infarction. Eur Heart J. 2007;28:2525–2538.
19. Jaffe AS, Apple FS, Lindahl B, Mueller C, Katus HA. Why all the struggle
about CK-MB and PCI? Eur Heart J. 2012;33:1046–1048.
20. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD;
for the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task
Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Eur Heart J. 2012;33:2551–2567.
21. Prasad A, Gersh BJ, Bertrand ME, Lincoff AM, Moses JW, Ohman EM,
White HD, Pocock SJ, McLaurin BT, Cox DA, Lansky AJ, Mehran R,
Stone GW. Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the
ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy)
trial. J Am Coll Cardiol. 2009;54:477–486.
Key Words: Editorials ◼ myocardial infarction ◼ troponin
Torrent of Troponin
Harvey D. White
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Circ Cardiovasc Interv. 2014;7:435-438
doi: 10.1161/CIRCINTERVENTIONS.114.001751
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