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Prognostic significance of troponin level in 3121 patients presenting
with atrial fibrillation (The NIHR Health Informatics Collaborative
TROP-AF study)
Amit Kaura, MRCP (UK);* Ahran D. Arnold, MRCP (UK);* Vasileios Panoulas, PhD; Benjamin Glampson, MSc; Jim Davies, DPhil; Abdulrahim
Mulla, BTech; Kerrie Woods, BA (Hons); Joe Omigie, BSc; Anoop D. Shah, PhD; Keith M. Channon, MD; Jonathan N. Weber, PhD; Mark R.
Thursz, MD; Paul Elliott, PhD; Harry Hemingway, FMedSci; Bryan Williams, MD; Folkert W. Asselbergs, PhD; Michael O’Sullivan, PhD;
Graham M. Lord, PhD; Narbeh Melikian, PhD; David C. Lefroy, MB BChir; Darrel P. Francis, MD; Ajay M. Shah, MD; Rajesh Kharbanda, PhD;
Divaka Perera, MD; Riyaz S. Patel, MD; Jamil Mayet, MD
Background-—Patients presenting with atrial fibrillation (AF) often undergo a blood test to measure troponin, but interpretation of
the result is impeded by uncertainty about its clinical importance. We investigated the relationship between troponin level,
coronary angiography, and all-cause mortality in real-world patients presenting with AF.
Methods and Results-—We used National Institute of Health Research Health Informatics Collaborative data to identify patients
admitted between 2010 and 2017 at 5 tertiary centers in the United Kingdom with a primary diagnosis of AF. Peak troponin results
were scaled as multiples of the upper limit of normal. A total of 3121 patients were included in the analysis. Over a median follow-
up of 1462 (interquartile range, 929–1975) days, there were 586 deaths (18.8%). The adjusted hazard ratio for mortality associated
with a positive troponin (value above upper limit of normal) was 1.20 (95% CI, 1.01–1.43; P<0.05). Higher troponin levels were
associated with higher risk of mortality, reaching a maximum hazard ratio of 2.6 (95% CI, 1.9–3.4) at 250 multiples of the upper
limit of normal. There was an exponential relationship between higher troponin levels and increased odds of coronary angiography.
The mortality risk was 36% lower in patients undergoing coronary angiography than in those who did not (adjusted hazard ratio,
0.61; 95% CI, 0.42–0.89; P=0.01).
Conclusions-—Increased troponin was associated with increased risk of mortality in patients presenting with AF. The lower hazard
ratio in patients undergoing invasive management raises the possibility that the clinical importance of troponin release in AF may
be mediated by coronary artery disease, which may be responsive to revascularization. (J Am Heart Assoc. 2020;9:e013684.
DOI: 10.1161/JAHA.119.013684.)
Key Words: angiography •atrial fibrillation •coronary artery disease •mortality •troponin
Patients presenting to the hospital with atrial fibrillation
(AF), the most prevalent tachyarrhythmia,
1
often undergo
measurement of cardiac biomarkers.
2,3
In particular, troponin
levels are measured, ostensibly, to diagnose an acute coronary
syndrome (ACS) manifesting as AF.
4
However, interpretation of
the result ishampered by uncertainty over the clinical importance
of troponin levels in AF. The diagnostic and prognostic utility of
troponin in ACS,
5
and other cardiac presentations, such as heart
From the National Institute Of Health Research (NIHR) Imperial Biomedical Research Centre, Imperial College London and Imperial College Healthcare National Health
Service (NHS) Trust, London, United Kingdom (A.K., A.D.A., V.P., B.G., A.M., J.N.W., M.R.T., P.E., D.C.L., D.P.F., J.M.); NIHR Oxford Biomedical Research Centre, University of
Oxford and Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom (J.D., K.W., K.M.C., R.K.); NIHR King’s Biomedical Research Centre, King’s College
London and King’s College Hospital NHS Foundation Trust, London, United Kingdom (J.O., N.M., A.M.S.); NIHR University College London Biomedical Research Centre,
University College London and University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.D.S., H.H., B.W., F.W.A., R.S.P.); Health Data
Research UK, University College London, London, United Kingdom (P.E., H.H.); NIHR Cambridge Biomedical Research Centre, University of Cambridge and Cambridge
University Hospitals NHS Foundation Trust, Cambridge, United Kingdom (M.O’.); NIHR King’s Biomedical Research Centre, King’s College London and Guy’s and St Thomas’
NHS Foundation Trust, London, United Kingdom (G.M.L., D.P.); and Faculty of Biology Medicine and Health, University of Manchester, United Kingdom (G.M.L.).
Accompanying Data S1, Table S1, and Figures S1 through S3 are available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.119.013684
*Dr Kaura and Dr Arnold contributed equally to this work.
Correspondence to: Jamil Mayet, MD, Imperial College Healthcare NHS Trust, Hammersmith Hospital, National Heart and Lung Institute Offices, B Block Second
Floor, Du Cane Road, London W12 0HS, United Kingdom. E-mail: j.mayet@imperial.ac.uk
Received July 25, 2019; accepted November 13, 2019.
ª2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DOI: 10.1161/JAHA.119.013684 Journal of the American Heart Association 1
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failure,
6
is firmly established. However, these predictive rela-
tionships may not be observed in AF, where troponin release may
be related to rapid ventricular response and the mechanical
effects of fibrillation on the atria rather than coronary artery
disease (CAD).Observational analysis of patients presenting with
AF have identified associations between troponin level and
clinically important outcomes, but these studies did not assess
mortality. In clinical practice, small troponin increases in AF
presentations are typically ignored and do not routinely prompt
investigation for CAD.
The aims of our study were to explore the relationship
between troponin level and mortality in patients presenting to
the hospital with AF, to understand the pattern of referral for
coronary angiography in relation to troponin level, and to
determine the role of coronary angiography in the relationship
between troponin and mortality in these patients.
Methods
The National Institute of Health Research Health Informatics
Collaborative database consists of routinely collected elec-
tronic health record data from patients attending 5 large UK
tertiary care centers with emergency departments (Imperial
College Healthcare, University College Hospital, Oxford
University Hospital, Kings College Hospital, and Guy’s and
St Thomas’Hospital) between 2010 (2008 for University
College Hospital) and 2017. The data acquisition and analysis
plan is found in Data S1. The National Institute of Health
Research Health Informatics Collaborative study was regis-
tered at ClinicalTrials.gov, NCT03507309. This work used
data provided by patients and collected by the National Health
Service as part of their care and support. No verbal or written
informed consent from individual patients was required for
data set generation. This study was approved by the London–
South East Research Ethics Committee (16/HRA/3327).
Eligibility Criteria
We identified patients from the National Institute of Health
Research Health Informatics Collaborative database who were
admitted to the hospital with a primary diagnosis of AF and
underwent at least one troponin measurement. Patients with a
concomitant secondary diagnosis of AF were not eligible for
inclusion in the study. Diagnoses were established from
routinely recorded International Classification of Diseases,
Tenth Revision (ICD-10), discharge codes and were therefore
established by the clinical team after inpatient investigations
and management were complete. Patients meeting the eligibil-
ity criteria were followed up using routinely collected data, until
death or censoring on April 1, 2017.
Troponin Level
All analyses on troponin were performed using the peak
troponin level. For patients who had a single troponin
measurement, the peak troponin was based on this measure-
ment. In the remainder of the patients who had >1 troponin
test in the same hospital episode of care, the peak troponin
value was defined as the highest of all measurements. For
patients with multiple episodes of care for which troponin was
tested, the first episode of care was used.
In clinical practice, troponin levels are frequently dichot-
omized into “positive”(meaning >99th percentile of the upper
limit of normal [ULN] for the troponin assay) or “negative.”
Furthermore, troponin levels may have a progressive relation-
ship with prognosis, too, but the shape of this relationship is
not known across the full spectrum of values; and making the
assumption of a linear relationship of mortality with troponin
(or log troponin) may not be secure in our study participants.
For these reasons, we treated the data in 2 ways. First, we
dichotomized the results as being either positive or negative.
Second, we used troponin on a continuous scale by
standardizing the many troponin assays, by scaling the
results using the ratio of the observed troponin value divided
by the ULN for that particular troponin assay.
Coronary Angiography and Revascularization
Patients undergoing coronary angiography, or revasculariza-
tion with either percutaneous coronary intervention or
coronary artery bypass grafting, during the follow-up period
were identified. To account for outpatient procedures,
patients were categorized as having angiography or interven-
tion if performed within 3 months of the peak troponin level.
Clinical Perspective
What Is New?
•Elevated troponin levels in patients presenting to the
hospital with atrial fibrillation are associated with a high
risk of mortality, with higher levels associated with worse
prognosis.
•The risk of mortality associated with troponin increase was
lower in patients who underwent coronary angiography than
in those who did not undergo coronary angiography.
What Are the Clinical Implications?
•Even troponin elevations mildly above the upper limits of
normal should be taken seriously in patients presenting with
atrial fibrillation.
•Consideration should be given to investigate for underlying
coronary artery disease in patients presenting with atrial
fibrillation and an increased troponin level.
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Follow-Up
Using a retrospective cohort study design, all patients were
followed up until death or censoring on April 1, 2017. Life
status was ascertained using routinely collected data on the
National Health Service Spine Application, which was linked to
the Office of National Statistics, and thereby to the national
registry of deaths.
Statistical Analysis
Descriptive statistics are displayed as median (interquartile
range) for continuous variables and number (percentage) for
categorical variables. Comparisons of baseline characteristics
between patients who did and did not undergo angiography
were explored by Mann-Whitney Utest or v
2
test.
The relationship between dichotomous troponin level (above
ULN or not), or continuous troponin, and all-cause mortality was
performed using Cox proportional hazards regression modeling,
using log transformation because ofthe positive skew of troponin
values. The proportional hazard assumption was supported by a
nonsignificant relationship between the Schoenfeld residuals
and time. This test was not statistically significant for each of the
covariates included in the Cox regression model.
Using Martingale residuals, nonlinearity was detected in
the relationship between the log hazard and all continuous
covariates (age, creatinine, hemoglobin, platelet count, white
blood cell count, and troponin level). To model nonlinear
relationships, we used restricted cubic splines for Cox
regression and logistic regression analyses to calculate
mortality hazard ratio and odds of angiography outcomes,
respectively. Preliminary analyses suggested that 4 unforced
knots should be used to model troponin level in the restricted
cubic spline analyses. Splines were adjusted for demographic
characteristics, hematological and biochemical blood results,
cardiovascular risk factors, and comorbidities. Subgroup
analyses were performed in angiography and no angiography
subgroups. Kaplan-Meier survival curves were plotted accord-
ing to angiography status.
P<0.05 was considered significant. Statistical analyses
were performed using the R 3.5.0 statistical package (the R
Core Team, Vienna, Austria). Survival analyses were per-
formed using the Survminer and Survival R packages.
Results
A total of 3121 patients admitted to the hospital with a primary
diagnosis of AF, according to ICD-10 discharge codes, underwent
troponin measurement during the study period. Their baseline
characteristics are displayed in Table 1. Mean age was 73 years
(95% CI, 62–82 years), and 55.7% were men. Most of these
patients (60.4%) recorded a peak troponin level that was within
the normal range (<1 multiple of the ULN [xULN]) (Figure 1).
Relationship Between Troponin Level and
Coronary Angiography
A total of 216 patients (6.9%) underwent coronary angiog-
raphy, with 78 (36.1%) of these patients subsequently
undergoing coronary revascularization by percutaneous
coronary intervention (93.6%), coronary artery bypass graft-
ing (2.6%), or both (3.8%). A total of 39 patients (1.2%) had
a secondary diagnosis of ACS. Most coronary angiograms
(89.8%; Figure 2A) and 43.6% of revascularization proce-
dures (Figure 2B) occurred within 72 hours of the peak
troponin level. The baseline characteristics of patients who
did and did not undergo angiography are displayed in
Table 2. The demographic and clinical factors associated
with undergoing coronary angiography are shown in Fig-
ure S1 and Table S1.
Table 1. Baseline Characteristics of Patients
Characteristics
Patients With Primary
Presentation of AF
(n=3121)
Demographic characteristics
Age, y 73 (62–82)
Men 1738 (55.7)
Hematology and biochemistry results
CRP, mg/dL (n=2796) 5.0 (2.0–14.9)
Creatinine, lmol/L (n=3086) 82 (69–100)
Hemoglobin, g/dL (n=3075) 13.8 (12.5–15.0)
Platelet count, 910
9
/L (n=3071) 226 (187–274)
Troponin, xULN 0.5 (0.003–2.0)
White blood cell count, 910
9
/L (n=3075) 8.2 (6.6–10.2)
Cardiovascular risk factors
Diabetes mellitus 355 (11.4)
Hypercholesterolemia 448 (14.4)
Hypertension 1062 (34.0)
Cardiovascular disease
Aortic stenosis 53 (1.7)
Heart failure 302 (9.7)
Previous myocardial infarction 341 (10.9)
Other comorbidities
Malignancy 207 (6.6)
Obstructive lung disease 146 (4.7)
Data represent median (interquartile range) or value (percentage). Num bers in
parentheses indicate the number of patients who had data available for the relevant
variable. AF indicates atrial fibrillation; CRP, C-reactive protein; xULN, 99th percentile of
the upper limit of normal.
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The relationship between troponin level and likelihood of
undergoing coronary angiography was nonlinear (Figure 3B).
At troponin levels less than the ULN, increasing troponin level
was not associated with increasing likelihood of coronary
angiography. Above the ULN, there was a direct relationship
between troponin level and odds of angiography, with an
exponential distribution at troponin levels >5 xULN. There was
a direct relationship between odds ratio of undergoing
coronary revascularization and troponin level (Figure S2). A
patient with a peak troponin of 10 xULN was 2.7 times more
likely to undergo coronary revascularization compared with a
patient with a troponin level of 1.
Relationship Between Troponin Level and
Mortality
Over a median follow-up of 48.1 (interquartile range, 30.5–
64.9) months, there were 586 deaths (18.8%), with a 1-year
mortality rate of 4.8%. The hazard ratio for mortality associated
with a positive troponin result (value above ULN) was 1.20 (95%
CI, 1.01–1.43; P<0.05) after adjustment for key demographic
and baseline clinical factors. The relationship between contin-
uous troponin level and mortality was demonstrated using
restricted cubic spline Cox regression analysis, adjusted for the
same demographic and baseline clinical factors (Figure 3A).
Although troponin levels <1.3 xULN showed no significant
relationship with hazard ratio, at higher troponin levels, a
significant positive relationship was demonstrated.
Figure 3C and 3D shows the relationship between troponin
level and mortality for patients presenting with AF who
underwent coronary angiography (Figure 3C) and patients
who did not (Figure 3D). Although there was no significant
relationship between troponin level and mortality in patients
who underwent angiography (Figure 3C), a significant rela-
tionship was observed in patients who did not undergo
angiography with troponin levels above the ULN (Figure 3D).
Kaplan-Meier survival analysis demonstrated worse short-
term survival in patients who did not undergo angiography
(P=0.02; Figure 4A). This difference in mortality persisted at
4-year follow-up (P=0.02; Figure 4B). On multivariate Cox
regression analysis, after adjustment for demographic and
clinical factors, including troponin level, angiography was
associated with a 39% reduction in mortality during follow-up
(hazard ratio, 0.61; 95% CI, 0.42–0.89; P=0.01). For those
patients who were referred for angiography, there was a
nonsignificant trend toward revascularization being associ-
ated with a reduction in mortality during follow-up (hazard
ratio, 0.36; 95% CI, 0.12–1.10; P=0.07). The relationship
between troponin and mortality in patients who underwent
angiography without revascularization and the relationship in
those who did not undergo angiography are shown in
Figure S3. This figure shows that increasing troponin was
associated with increasing mortality risk in both groups but
with wide CIs around the point estimates for unrevascularized
patients who underwent angiography; it is not clear that there
is a difference in the troponin-mortality relationship between
these groups.
Discussion
This is the first study investigating the relationship between
troponin level, coronary angiography, and mortality in patients
admitted to the hospital with a primary diagnosis of AF. This is
also the largest study to report the association between
troponin level and all-cause mortality in this group.
Figure 1. Bar chart of numbers of patients according to troponin level. xULN indicates 99th percentile of
the upper limit of normal.
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Abnormal Troponin Levels Predict Mortality in AF
In 3121 patients presenting with AF, whose troponin was
measured, there was a significant association between troponin
levels (above the ULN) and higher mortality, even after adjusting
for key demographic and clinical factors. Associations derived
from dichotomizing continuous variables, such as troponin, can
be driven by extreme values. However, even low-level troponin
elevations above the normal range (1–10 xULN) were associ-
ated with higher mortality risk. Abnormal troponin levels, at any
level, appear to have prognostic importance in AF; and higher
troponin levels appear to confer worse prognosis.
Nonlinear Relationship Between Troponin and
Mortality
The relationship between troponin level and adjusted hazard
ratio for mortality in patients presenting with AF is nonlinear
when considering the entire spectrum of troponin values,
including detectable troponin within the normal range. Below
the ULN of troponin, there does not appear to be any
relationship between higher troponin levels and increased
hazard ratio for mortality. A similar nonlinear pattern between
troponin level and mortality has previously been observed in
an unselected group of patients without ACS.
7
Specifically, in
our AF cohort, above the ULN there is a direct relationship
between troponin level and mortality, reaching a hazard ratio
Figure 2. Histogram of numbers of patients undergoing
coronary angiography (A) and revascularization (B) at different
time points after measurement of peak troponin level at
presentation.
Table 2. Baseline Characteristics of Patients Who Did and
Did Not Undergo Angiography
Characteristics
Angiography
(n=216)
No Angiography
(n=2905) PValue*
Demographic characteristics
Age, y 73.5
(65.3–79.0)
73.0
(63.0–83.0)
0.47
Men 144 (66.7) 1594 (54.9) 0.001
Hematology and biochemistry results
CRP, mg/dL 6.1 (2.03–16.5) 5.0 (1.9–14.8) 0.08
Creatinine, lmol/L 84.0
(73.3–100.8)
81.0
(69.0–100.0)
0.04
Hemoglobin, g/dL 13.9
(12.5–15.0)
13.8
(12.5–15.0)
0.78
Platelet count,
910
9
/L
224 (182–270) 226 (187–275) 0.53
Troponin, xULN 1.4 (0.003–5.6) 0.5 (0.003–2.0) <0.0001
White blood cell
count, 910
9
/L
8.5 (6.8–10.6) 8.2 (6.6–10.2) 0.21
Cardiovascular risk factors
Diabetes mellitus 32 (14.8) 323 (11.1) 0.12
Hypercholesterolemia 41 (19.0) 407 (14.0) 0.06
Hypertension 74 (34.3) 988 (34.0) 0.94
Cardiovascular disease
Aortic stenosis 8 (3.7) 45 (1.5) 0.03
Heart failure 27 (12.5) 275 (9.5) 0.15
Previous myocardial
infarction
65 (30.1) 276 (9.5) <0.0001
Other comorbidities
Malignancy 7 (3.2) 200 (6.9) 0.03
Obstructive
lung disease
12 (5.6) 134 (4.6) 0.50
Data represent median (interquartile range) or value (percentage). CR P indicates C-
reactive protein; xULN, 99th percentile of the upper limit of normal.
*Comparison between angiography and no angiography groups using Mann-Whitney U
test for continuous variables and v
2
test for categorical variables.
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of 2.6 at 263 xULN. The inflection near ULN may represent
a genuine cutoff in the importance of troponin and supports
the use of the 99th percentile in determining the “normal”
range. Although this does not mean all patients presenting
with AF should undergo invasive investigation, it does suggest
that the troponin threshold for investigating for CAD may be
lower than current practice.
Coronary Angiography Is Performed at Higher
Troponin Levels
Coronary angiography was performed in <7% of patients
presenting with AF who had troponin measured. Below the
ULN for troponin, higher troponin levels were not associated
with an increased likelihood of coronary angiography. Above
the ULN, there was an exponential relationship between
troponin level and likelihood of coronary angiography. How-
ever, even at the highest troponin levels, less than half of
patients underwent coronary angiography. This is consistent
with typical clinical practice; small troponin increases in AF
presentations are not deemed to be a useful marker of CAD
by clinicians and even when troponin increases to high values,
alternative explanations are often invoked. Other factors also
influenced the likelihood of coronary angiography in this
population: understandably, patients with malignancies were
less likely to undergo coronary angiography and patients with
prior infarcts were more likely to undergo coronary angiog-
raphy. However, women were also less likely to undergo
coronary angiography than men, despite other variances
being accounted for in the multivariate analysis. This reflects
Figure 3. Multivariate restricted cubic spline modeling of association between troponin level and hazard ratio (A); association between
troponin level and odds of coronary angiography (B); and association between troponin level and hazard ratio in angiography (C) and no
angiography (D) subgroups. Data were adjusted for age, sex, CRP (C-reactive protein), creatinine, hemoglobin, platelet count, white blood cell
count, diabetes mellitus, hypercholesterolemia, hypertension, aortic stenosis, heart failure, previous myocardial infarction, malignancy, and
obstructive lung disease. The shaded area denotes the 95% CI.
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a growing understanding that women with cardiac disease
present, and are managed, in different ways to men,
potentially to the detriment of women’s health outcomes.
Coronary Angiography Alters the Troponin-
Mortality Relationship
In patients who underwent coronary angiography, higher
troponin levels above ULN were associated with higher
mortality, but the relationship was weak, with a shallow
gradient, and not statistically significant. In patients who did
not undergo coronary angiography, there was a clear, direct
relationship between higher troponin levels (above ULN) and
higher risk of mortality. Coronary angiography appeared to be
associated with a 36% reduction in mortality across the
spectrum of troponin values. One possible explanation for this
is that we may be selecting a relatively low-risk group of
patients for coronary angiography compared with those we
choose to treat medically. An alternative explanation is that
invasive management may improve the prognosis of patients
presenting with AF and abnormal troponin elevations, with
greater improvement at higher troponin levels. Coronary
angiography at higher troponin levels is more likely to reveal
clinically important CAD that is amenable to prognosis-
improving treatment. Data on the rate of medical therapy for
CAD were not available in this analysis, but coronary
revascularization was performed in 36.1% of patients who
underwent coronary angiography and there was a trend
toward improved mortality with revascularization, although
this did not reach statistical significance. The utility of
routinely investigating for CAD in these patients requires
testing in clinical trials.
Relationship With Existing Evidence
This is the largest study to assess the relationship between
troponin and mortality in patients presenting to the hospital
with AF. Other studies have assessed the effects on
revascularization, stroke, cardiovascular death, and other
clinically important outcomes. However, all such diagnoses,
including fatal stroke and cardiovascular death, risk inaccu-
racy and bias to varying extents. All-cause mortality is the only
AB
Figure 4. Kaplan-Meier survival curves according to angiography status over 12 months (A) and 48 months (B) of follow-up. Tick marks
denote censored events. Survival curves compared using log-rank statistic.
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outcome where the diagnosis is free from such bias. Larger
subanalyses of randomized controlled trials comparing direct
oral anticoagulants with warfarin have assessed the relation-
ship between troponin and mortality in patients with AF
3,8
and
found a significant correlation. However, this is an entirely
different population of patients with a background of AF,
rather than patients presenting to the hospital with a primary
diagnosis of AF. In stable patients diagnosed with AF
previously, increased troponin will inevitably be predictive of
poor prognosis but troponin screening for patients in a stable
phase of AF is rare and not a clinically relevant problem. How
to interpret troponin increases in short-term presentations
with AF is an extremely common clinical dilemma, which is
addressed in this study.
Conti et al prospectively enrolled 3627 patients presenting
with recent-onset (<48-hours) AF, but excluded patients with
ACS, clinical instability, or severe comorbidity,
4
and offered
coronary angiography if the troponin level was elevated above
the ULN. Troponin elevation (above the ULN) was associated
with angiographic CAD, revascularization, and increased
likelihood of adverse cardiovascular events, but mortality
was not measured, and troponin was dichotomized at the
ULN. We have shown that higher troponin levels are
associated with a higher mortality risk, indicating that the
magnitude of troponin increase as a continuous variable is
important for decision making. Supporting our findings,
Alghamry et al demonstrated, in a retrospective study of
200 patients, that troponin dichotomized at the ULN had poor
ability to predict CAD, whereas peak troponin, analyzed
continuously, did predict CAD.
9
We did not find an association
between higher levels of troponin below the ULN and
increased mortality, despite a large number of patients
analyzed at a long follow-up duration. A smaller study
(n=330) suggested detectable troponin level below the ULN
does predict mortality, but this may have been a chance
finding as our study population for this group of patients was
4 times larger and found no association.
10
Mechanisms of Troponin Release in AF
Troponin I and T bind to tropomyosin in the intracellular
sarcomeric contraction complex, but they are also found in
the cytosol.
11
In ACS, obstruction of epicardial coronary
arteries results in myocyte necrosis, releasing troponin into
the circulation, with larger infarcts both releasing more
troponin and risking worse and more likely clinical sequelae,
including death.
5
The explanation for the relationship between
troponin and mortality in ACS is, thus, clear, but troponin
increases carry prognostic significance in several settings,
such as heart failure, pulmonary embolism, and sepsis.
6
The
cause of circulating troponin in AF is particularly disputed,
however, which is one reason for the relatively low importance
clinicians place on troponin leak in AF.
11
Type II myocardial
infarction caused by ventricular myocyte death during rapidly
conducted AF in the context of preexisting CAD is a putative
mechanism. Although it is likely that this often plays a key
role, as rate control can reduce troponin leak,
12
troponin
release also occurs at normal ventricular rates. Furthermore,
CAD identified is not always severe or physiologically
significant, which makes treatment decisions, particularly
the role of revascularization, uncertain. Although it is not
known whether atrial myocytes themselves release troponin
during fibrillation (regardless of ventricular rate), there is a
large body of evidence for atrial scarring in AF,
12
suggesting
this may be the case. However, acute atrial necrosis may only
be the mechanism for new-onset AF as opposed to the first
presentation of chronic AF. Patients with AF experience
troponin increases in the short-term phase of stroke,
13
implicating sympathetic activation as a cause for troponin
release and a marker of mortality risk. AF as a manifestation
of acute type I myocardial infarction, where there is sponta-
neous thrombotic occlusion of coronary arteries, is thought to
occur rarely. This may be more common than diagnosed and
would be another explanation of the link between troponin
and mortality.
We cannot directly infer, from our analysis, a mechanism
for troponin release nor the mechanism via which troponin
increases are associated with worse prognosis, but our
findings raise the possibility that the clinical importance of
troponin release in AF may mediated by CAD.
Limitations
Although this study benefits from having been conducted
using real-world clinical data in a large number of patients
from multiple centers, there are some limitations. This study
was retrospective, with data extracted from electronic
medical records and subject to the limitations of this
approach, including difficulty in accounting for all potential
confounding factors. Bias may be introduced because of
inaccuracies in routine data collection. In routine clinical
practice, patients with larger troponin increases are more
likely to be given a primary diagnosis of ACS on discharge,
even if their presentation was with AF, altering the overall risk
status of the patients with AF as the primary diagnosis. The
data set also includes only those patients who had a troponin
measurement potentially altering the overall risk profile.
Furthermore, the subtype of AF (paroxysmal or new onset)
was not recorded, preventing analysis by chronicity of AF, and
the role of stress testing was not available in the data set.
We could not directly infer mechanisms for the importance of
troponin increases in AF. Routinely collected data fromelectronic
health records lack resolution for fine details of clinical
encounters. For this reason, we could not analyze the data for
DOI: 10.1161/JAHA.119.013684 Journal of the American Heart Association 8
TROP-AF Study Kaura et al
ORIGINAL RESEARCH
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the effect of troponin on cardiovascular outcomes and compare
this with all-cause mortality. However, as previously discussed,
all-cause mortality is the only outcome to be free from bias, which
is of particular relevance in observational analyses.
Conclusions
Abnormally elevated troponin at any level is associated with
increased risk of mortality in patients presenting with AF, and
higher troponin levels confer worse prognosis. Coronary
angiography is rarely performed unless AF is associated with
large troponin increases, but when it is performed, it is
associated with lower mortality. This raises the question of
whether the prognostic significance of troponin could be
mediated by CAD and may be responsive to revascularization.
Clinical trials are warranted to clarify the role of investigating
and treating CAD in patients presenting with AF with elevated
troponin levels.
Acknowledgments
This research has been conducted using National Institute of Health
Research (NIHR) Health Informatics Collaborative (HIC) data
resources. The NIHR HIC is a joint initiative between the NIHR
Biomedical Research Centres at Imperial, Oxford, University College
London Hospitals, Guy’s and St Thomas’, and Cambridge, which has
provided data services, infrastructure, and expertise. Ethical
approval: This study was approved by the London–South East
Research Ethics Committee (REC reference: 16/HRA/3327). Data
sharing: The data sets generated and/or analyzed during the current
study are not publicly available because of information governance
restrictions. Transparency: The guarantor (Dr Mayet) affirms that this
article is an honest, accurate, and transparent account of the study
being reported; that no important aspects of the study have been
omitted; and that any discrepancies from the study as planned have
been explained. The article follows the STROBE guidelines for the
reporting of observational studies.
Sources of Funding
This article reports independent research led and funded by
the National Institute for Health Research (NIHR) Imperial
Biomedical Research Centre (BRC), as part of the NIHR Health
Informatics Collaborative with the NIHR Oxford BRC, the NIHR
University College London Hospitals BRC, the NIHR Guy’s and
St Thomas’BRC, and the NIHR Cambridge BRC. The views
expressed in this publication are those of the authors and not
necessarily those of the National Health Service, the National
Institute for Health Research, or the Department of Health. Dr
Elliott and H. Hemingway received Health Data Research
funding.
Disclosures
None.
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TROP-AF Study Kaura et al
ORIGINAL RESEARCH
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Supplemental Material
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Data S1.
NIHR Health Informatics Collaborative TROP-AF Study
DATA COLLECTION PLAN
Author: Amit Kaura
Approvers: Jamil Mayet
Date: 07/03/2017
DATABASE PROTOCOL
Introduction
This document outlines the specifications and procedures for the NIHR Health
Informatics Collaborative (NIHR HIC) Cardiovascular research database and
defines the processes for the collection of the NIHR HIC Cardiovascular
research data and onward sharing with researchers. The central research
database is held within Imperial College Healthcare NHS Trust (ICHNT).
Data for all patients receiving a troponin test are collected locally at the
following Trusts and submitted pseudonymously to ICHNT:
• Imperial College Healthcare NHS Trust
• University College London Hospitals NHS Foundation Trust
• Oxford University Hospitals NHS Foundation Trust
• Kings College Hospital NHS Foundation Trust
• Guys and St Thomas’ Hospital NHS Foundation Trust
This document covers the processes for local collection of data at all sites.
The main database and systems are hosted at ICHNT as the lead
organisation for the Cardiovascular Theme.
NIHR HIC Cardiovascular Database Definitions
Local data store
Each Trust will have a local store of NIHR HIC Cardiovascular data; this
collects their information in an identifiable form from clinical systems. The
data will then be de-identified within the local NHS Trust. These de-identified
data will be passed to the central research database.
Research database
The research database will contain only de-identified information. This
database combines the data from each site (including ICHNT). The database
will contain some secondary patient identifiers (e.g. date of procedure, date of
death) which will not be made directly available to researchers. A further
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anonymised view of the data will be prepared by ICHNT staff which will
involve converting all dates to the number days since the first troponin test.
This view of the data will contain only the variables necessary to complete the
study rather than the full database.
Procedures for local data collection into local stores
Data will be collected automatically from primary clinical systems within each
Trust. NHS staff will enter data into clinical systems during routine clinical
care of patients, or data will be generated as a result of clinical tests. Data in
the primary clinical systems will be processed in accordance with each Trusts
clinical guidelines and subject to local quality and governance procedures.
Data will be extracted automatically and validated processes for data
extraction, transformation and loading (ETL) have been designed to import
the data into the local secure data stores.
Access to local data stores
Access to identified data will be limited to those justified and approved by the
local information governance teams and will always be NHS staff in
accordance with the duty of confidentiality required by law. Anonymisation
procedures will be automated after implementation.
Local data stores will be the only areas that hold any patient identifiers. De-
identification is completed at this stage prior to passing data into any research
databases and datasets.
De-identification
The data will be pseudonymised locally within each Trust; anonymisation
processes will be automated and set up by NHS staff in accordance with:
• advice from local information governance procedures
• the HIC Standard Operating Procedure (SOP) for data sharing and
anonymisation
• the Clinical Data transfer policy
The data items summarised in Table 1 will be anonymised. Anonymisation
will be approved locally by information governance teams before data are
sent externally to ICHNT. De-identified data are then shared in accordance
with the overarching data sharing agreement.
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Demographic
Anonymisation
Local
Identifier Provided if NHS number is missing
NHS Number
Use local pseudonymisation
algorithm (key to be retained at
source)
Rename field to subject ID
Family Name
To be removed – LOCAL use
Given Name
To be removed – LOCAL use
Date of Birth
YYYY
Date of Death
DD-MM-YYYY
Table 1. Anonymisation of data elements
Each site will hold two versions of the database, one identifiable and one with
de-identified, pseudonymised data. The de-identified version is for use in
research and shared with the central research database at ICHNT. The
identifiable database is held so that if necessary patients can be re-identified
if it is of importance to re-contact the patient via their care team.
NHS numbers and hospital numbers are pseudonymised using locally
approved procedures. Names are removed from the dataset and date of birth
is transformed to year of birth. Date of death is shared, however, is converted
in to relevant survival rates on provision of data to researchers. Researchers
will never see the full date of death or be able to calculate it from other
information (all dates are provided as delta for first troponin). The provision of
date of death has been agreed by each of the information governance offices
at each of the sites in the following de-identification and anonymisation
protocol for the study:
• The exact date of death is required to evaluate mortality after
diagnosis.
• Patients presenting with suspected acute coronary syndromes are
likely to have a high frequency of cardiac events and a high short-term
mortality rate. An accurate measure of death is therefore required to
fully evaluate this.
• To redact the date of death to year only would misrepresent the
survival of these patients, particularly for those who survive for less
than one year. The clinical leads at our BRCs have underlined the
importance of having the date in full for the study.
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Data validity and quality
Prior to pseudonymisation within the clinical systems, NHS number, date of
birth and patient names will be automatically checked to remove duplication
of patients.
Samples of data will be clinically validated by members of the clinical team to
ensure that the transformation process is correct and data are attributed to
the correct patients prior to pseudonymisation. After clinical validation is
complete, the data will be transformed to a standardised XML format and
validated (Figure 1).
Figure 1. Data import and validation process.
Data sharing between Trusts
Data are shared in accordance with the SOP for data sharing. Data are
encrypted in transit via sFTP on the N3 network (Figure 1). The sFTP is set
up and hosted by ICHNT.
Procedures for secure research database
Data validity and quality
ICHNT validate the data to ensure that the structure, data items, units and
data types are in accordance with the standardised data model. Data will be
rejected if validation fails. On rejection, the files will be archived and the data
manager will contact the data provider to review the submission and resend
once corrected.
Once imported into the secure research database, data are subject to clinical
validation by Cardiovascular clinical experts; these validations will be
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completed by the clinical researchers using de-identified data. Data will be
reviewed for data completeness, spread and actual data point values. If data
appears invalid it will be rejected.
Data quality reports will be generated and provided to the research team and
local data provider after each submission. These will be reviewed after each
submission to ensure all areas are populated.
Research Database software
The database will be built using Microsoft SQL server 2014, Microsoft’s
principle database management system software. The installation of the
software was carried out by certified technical consultants and tested by the
Trust ICT team and data warehouse team in accordance with Trust ICT
procedures and policies.
Database management
The database will be fully backed up on a daily basis. The back-ups are
standardised for all Trust databases within the Trust data warehouse.
Backups can be restored at any point by warehouse staff. Data are secondary
copies from clinical systems; at any point the participating Trusts can re-
extract the data from primary sources. Each site will submit data on a
quarterly basis to the database. Data integrity checks will be completed to
ensure correct structure is maintained and duplicates are not present.
Once entered on the system, data will not be changed. All access will be
‘read only’ except via exception, approved by the research Informatics
Programme Manager and Clinical Leads group.
The database will be managed by the data manager (Ben Glampson) and
developer (Abdul Mulla). Any database changes will be controlled by the
research informatics Programme manager (Ben Glampson), and sanctioned
by the NIHR HIC Cardiovascular scientific steering committee (chaired by
Jamil Mayet). All staff are substantive NHS employees at ICHNT.
Data extracts taken for research will be stored within the data warehouse and
retained for the period specified in the data request. All information pertinent
to the request will be retained and tracked by the data manager.
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DATA ACCESS FOR RESEARCH
Author: Amit Kaura
Approvers: Jamil Mayet
Date: 09/08/2018
TROP-AF STUDY dataset
All analyses for the TROP-AF STUDY will be completed on fully de-identified
data. This includes further de-identification to remove dates.
A designated clinical researcher (Amit Kaura) froze a copy of the database on
1st April 2017, so a static dataset can be used for analysis. This will be
retained separately from the live database to allow reproducible analyses.
The study dataset will comprise all patients who had a troponin measured at
each of the five academic centres between 2010 (2008 for University College
Hospital) and 2017.
Dates will be converted to delta dates, with date zero being the date of the
first troponin test. All further dates will be provided as number of days from
date zero. Age will be provided in years, at the time of the first troponin test.
Date of death will be converted to the number of days since date zero. All
patients will be retrospectively followed up, using routinely collected data on
the NHS Spine Application, Summary Care Record, until death or censoring
on 1st April 2017.
Data elements
The database model includes 156 data points, grouped into demographics,
emergency department attendance and inpatient episodes, biochemistry,
diagnosis, angiography, revascularization, echocardiography and mortality.
Diagnostic data will be based on International Statistical Classification of
Diseases and Related Health Problems (ICD) discharge codes.
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DATA ANALYSIS PLAN
Author: Amit Kaura
Approvers: Jamil Mayet / Darrel Francis
Date: 09/08/2018
Study population
The study dataset will include all patients who have had a troponin measured
at each of the five academic centres between 2010 (2008 for University
College Hospital) and 1st April 2017.
The study population will be focussing on those with a primary diagnosis of
atrial fibrillation: ICD-10 code I48: Atrial fibrillation and flutter.
We will exclude all patients with a secondary diagnosis of atrial fibrillation.
Data variables
Troponin data
In clinical practice, troponin levels are frequently dichotomised into “positive”
(meaning a result above the 99th percentile of the upper limit of normal (ULN))
or “negative”. Troponin levels may have a progressive relationship with
prognosis, too, but the shape of this relationship is not known across the full
spectrum of values and making the assumption of a linear relationship of
mortality with troponin (or log troponin) may not be secure.
For these reasons, we will treat the data in two ways:
1. We will dichotomise the peak troponin level as being either positive or
negative based on the ULN for each troponin assay. This makes no
assumption of the shape of the relationship.
2. We will use troponin on a continuous scale by standardising the many
troponin assays, by scaling the results using the ratio of the observed
troponin value divided by the ULN for that particular troponin assay.
For example, a patient with a troponin value of 96 using an assay
which has an ULN of 40 would have a scaled result of 96/40 = 2.4
xULN.
All analyses on troponin will be performed using the peak troponin level. For
patients who have a single troponin measurement, the peak troponin will be
based on this measurement. In the remainder of the patients who have more
than one troponin test in the same hospital episode, the peak troponin value
will be defined as the highest of all measurements.
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Revascularisation status
Acute revascularisation will be defined as having PCI or CABG in the time
window between 48 hours before and 3 months after the first troponin
measurement. This will account for patients who had revascularisation, in
particular PCI, as an emergency prior to their first troponin blood test and to
capture revascularisation, in particular CABG, performed as an outpatient
following their index admission.
Follow-up
• Using a retrospective cohort study design, all patients will be followed
up until death or censoring on 1st April 2017.
• Life status will be ascertained using routinely collected data on the
NHS Spine Application, which is linked to the Office of National
Statistics, and thereby to the national registry of deaths.
Outcomes
Primary outcome
The primary outcome will be all-cause mortality. The nature of the data
sources means that this is the outcome that will be available and it will be
available with high fidelity.
Secondary outcomes
The secondary outcomes will be:
• Angiography
• Revascularisation (coronary artery bypass grafting CABG),
percutaneous coronary intervention (PCI))
Statistical Methods
Baseline data
Baseline and demographic characteristics of patients with a primary
presentation of atrial fibrillation will be summarised by standard descriptive
summaries:
• means (standard deviation) for continuous variables which are
normally distributed
• median (interquartile range) for continuous variables which are not
normally distributed
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• number (percentage) for categorical variables
These characteristics will also be described for patients who did and did not
undergo coronary angiography.
Comparison between angiography and no angiography groups will be made
using Mann-Whitney U test or unpaired t-test for continuous variables and
Chi-square test for categorical variables.
Relationship between troponin level, coronary angiography and
mortality
The relationship between dichotomous troponin level (above ULN or not), or
continuous troponin, and all-cause mortality will be performed using
multivariate Cox proportional hazards regression modelling.
The proportional hazard assumption will be tested, with a violation indicated
by a significant relationship between Schoenfield residuals of a covariate and
time. If the proportional hazards assumption is violated, Cox regression
analysis with time-dependent covariates will be used with follow-up time
divided into time intervals within which the proportional hazard assumptions
are met.
Furthermore, using Martingale residuals, if non-linearity is detected in the
relationship between the log hazard and a continuous covariate, the non-
linear relationship will be modelled using restricted cubic splines.
Splines will be adjusted for demographic characteristics, haematological and
biochemical blood results, cardiovascular risk factors and comorbidities.
Subgroup analyses will be performed in angiography and no angiography
subgroups. Kaplan-Meier survival curves will be plotted according to
angiography status.
Statistical significance
All hypothesis tests will be 2-tailed. A p-value of <0.05 will be considered
statistically significant. No correction will be implemented for multiple testing.
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Statistical package
Statistical analyses will be performed using SPSS software version 24 (SPSS
Inc., Chicago, Illinois, United States) or R 3.3.2 statistical package (the R
Core Team, Vienna, Austria).
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Table S1. Odds ratio of undergoing coronary angiography.
Odds ratio (95% CI)
P-value
Male (vs female)
1.6 (1.2 – 2.1)
0.004
Diabetes mellitus
1.1 (0.7 – 1.7)
0.68
Hypercholesterolaemia
1.1 (0.8 – 1.7)
0.52
Hypertension
0.8 (0.6 – 1.2)
0.29
Aortic stenosis
2.1 (0.9 – 4.6)
0.07
Heart failure
1.1 (0.7 – 1.7)
0.67
Previous myocardial infarction
3.7 (2.6 – 5.2)
<0.0001
Malignancy
0.4 (0.2 – 0.9)
0.02
Obstructive lung disease
0.9 (0.5 – 1.6)
0.64
Positive troponin
1.5 (1.2 – 2.1)
0.003
Estimates compared to not having the disease, unless otherwise stated.
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Figure S1. Odds ratio of undergoing coronary angiography.
Age (years)
Odds Ratio
CRP (mg/L)
Odds Ratio
Creatinine (µmol/L)
Odds Ratio
Haemoglobin (g/dL)
Odds Ratio
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Platelet (x109/L)
Odds Ratio
White cell count (x109/L)
Odds Ratio
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Figure S2. Odds ratio of undergoing coronary revascularisation according to troponin level.
The figure shows the odds ratios of undergoing coronary revascularisation according to troponin
level, where the comparator troponin level value is of 1 xULN, which is marked with the red dotted
lines. ULN, 99th percentile of the upper limit of normal.
0.001 0.01 0.1 1 10 100 1000
Troponin (xULN)
Odds Ratio
10
3
1
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Figure S3. Multivariate* restricted cubic spline modelling of association between troponin
level and hazard ratio for patients who underwent angiography without revascularisation
(left) and those who did not undergo angiography (right).
*adjustment for age, sex, C-reactive protein, creatinine, haemoglobin, platelet count, white cell
count, diabetes mellitus, hypercholesterolaemia, hypertension, aortic stenosis, heart failure, previous
myocardial infarction, malignancy and obstructive lung disease. The shaded area denotes the 95%
confidence interval. 99th percentile of the upper limit of normal.
Troponin (xULN)
Hazard Ratio
0.001 0.01 0.1 1 10 100
6
5
4
3
2
1
0
Angiography
withoutrevascularisation Noangiography
0.001 0.01 0.1 1 10 100
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