JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
7, 2019
Letters
Modified HEART Score
and High-Sensitivity
Cardiac Troponin in
Patients With
Suspected Acute
Myocardial Infarction
Wide variation in the rates of hospitalization of
patients with chest pain who are at low risk of
acute myocardial infarction (AMI) across different in-
stitutions reflects the clinical uncertainty in the diag-
nostic process. To balance patients’ safety with
economic and societal needs, diagnostic algorithms
using high-sensitivity cardiac troponin (hs-cTn) were
developed combining very high safety with high
efficacy (1–4). It is undisputable that they should
always be used in conjunction with full clinical
assessment and the electrocardiogram, but it is a
matter of ongoing controversy whether clinical
assessment should include a formal risk score. The
HEART score, originally composed of history (H),
electrocardiographic findings (E), age (A), and risk
factors (R) modified by combination with markers
of cardiac injury, was further modified by using
hs-cTnT/I (T) (5). The incremental value of the
modified HEART score (m-HS) when using hs-cTn–
based rapid algorithms for rule-out of AMI is largely
unknown. To address this major gap in knowledge,
we aimed to evaluate the safety and efficacy when
using the m-HS in addition to the European Society of
Cardiology (ESC) hscTnT/I-0/1h and 0/2h algorithms.
Our prospective, international, multicenter study
enrolled adult patients presenting with symptoms
suggestive of AMI with an onset or peak within the last
12 h (2–4). Patients with ST-segment elevation AMI, on
chronic dialysis, or missing hs-cTnT/I concentrations,
and patients used for the derivation of the studied al-
gorithms were excluded from analysis. We further
excluded patients with an unknown diagnosis after
adjudication and elevated hs-cTn concentrations
possibly indicating AMI (2.9% to 3.3% of patients).
Sensitivity analyses with inclusion of these patients
showed no effect on findings. Final diagnoses
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ISSN 0735-1097/$36.00
were adjudicated by 2 independent cardiologists
(inter-rater reliability of 90.1%) applying the universal
definition of AMI using all available medical records
obtained during hospitalization, study-specific as-
sessments including detailed chest pain characteris-
tics, serial hs-cTnT blood concentrations, cardiac
imaging, and clinical follow-up. The study protocol
remained unchanged during the whole enrollment
period and was independent from local triage pro-
tocols. The ESC hs-cTnT/I-0/1h algorithms and both
0/2h algorithms were applied as suggested by current
guidelines and as described previously (1–4). The m-HS
was assessed retrospectively by study investigators
and was considered low-risk if #3 (5). Rule-out by the
hs-cTnT/I-0/1h and 0/2h algorithms (T component)
in combination with an m-HS #3 was considered
for classification of patients as low-risk. Safety
(quantified by sensitivity and negative predictive
value [NPV]) and efficacy (defined as the proportion
of ruled-out patients) for rule-out of AMI during the
index event were the coprimary diagnostic measures.
Death/AMI at 30 days was the prognostic endpoint.
Follow-up was complete in all patients (100%).
Among 2,716 patients, 16% had an AMI. Overall, all
4 hs-cTnT/I–based rapid algorithms provided very
high sensitivity (99.3% to 100%) and NPV (99.8% to
100%), as well as high efficacy (50% to 66%) for rule-
out of AMI (Figure 1). Adding an m-HS #3 to the rule-
out arm of each of the 4 hs-cTnT/I-0/1h and 0/2
algorithms reduced efficacy by 8% to 13% (all p <
0.001) and did not further increase sensitivity or
NPV. Similar findings emerged for rule-out of death/
AMI at 30 days for the hs-cTnT 0/1h algorithm, the
hs-cTnT-0/2h algorithm, and the hs-cTnI-0/2h
algorithm. In contrast, adding an m-HS #3 slightly
increased sensitivity from 98.0% (95% confidence
interval [CI]: 95.8% to 99.1%) to 99.3% (95% CI:
97.6% to 99.8%; p ¼ 0.045) and NPV (99.4% [95%
CI: 98.7% to 99.7%] to 99.8% [95% CI: 99.1% to
99.9%; p ¼ 0.072]) using the ESC hs-cTnI-0/1h
algorithm. While interpreting the results, the
retrospective methods of HEART score calculation
used for analysis should be considered a limitation.
In conclusion, the m-HS does not provide incre-
mental value when using hs-cTn–based algorithms for
rule-out of AMI. It may help to rule out death/AMI at
30 days.
874 Letters JACC VOL. 73, NO. 7, 2019
FEBRUARY 26, 2019:873–7

F I G U R E 1 Diagnostic Performance of the ESC 0/1h-Algorithms Alone and in Combination With the m-HS

A B
100%
p = 0.16 p = 0.16
99%

98%

97%
Sensitivity (95% CI)

96%

95% AMI – AMI + AMI – AMI +

94%
Rule-out

Rule-out
– 646 417 – 668 287
93%
+ 1,650 3 + 970 2
92%

91% Sens.: 99.3% (95% CI: 97.9–99.8) Sens.: 99.3% (95% CI: 97.5–99.8)
NPV: 99.8% (95% CI: 99.5–100) NPV: 99.8% (95% CI: 99.3–99.9)
90%

100%
p = 0.22 p = 0.16
99%
Negative Predictive Value (95% CI)

98%

97%

96%

95% AMI – AMI + AMI – AMI +

Rule-out
– 825 289
Rule-out

94% – 950 419

93% + 1,346 1 + 813 0

92%
Sens.: 99.8% (95% CI: 98.7–100) Sens.: 100% (95% CI: 98.7–100)
91%
NPV: 99.9% (95% CI: 99.6–100) NPV: 100% (95% CI: 99.5–100)
90%

80%
p < 0.001 p < 0.001
70%

60%

50%
Efficacy (%)

40%

30%

20%

10%

0%
ESC hs-cTnT ESC hs-cTnT ESC hs-cTnl ESC hs-cTnl
0/1h-Algorithm 0/1h-Algorithm 0/1h-Algorithm 0/1h-Algorithm
and m-HS ≤3 and m-HS ≤3

Diagnostic performance of the (A) ESC hs-cTnT-0/1h algorithm and (B) ESC hs-cTnI-0/1h algorithm alone and in combination with m-HS
#3 for rule-out of acute myocardial infarction. AMI ¼ acute myocardial infarction; CI ¼ confidence interval; ESC ¼ European Society of
Cardiology; hs-cTnI ¼ high-sensitivity cardiac troponin I; hs-cTnT ¼ high-sensitivity cardiac troponin T; m-HS ¼ modified Heart Score;
NPV ¼ negative predictive value; Sens ¼ sensitivity.
JACC VOL. 73, NO. 7, 2019
FEBRUARY 26, 2019:873–7
Beata Morawiec, MD
Jasper Boeddinghaus, MD
Desiree Wussler, MD
Patrick Badertscher, MD
Luca Koechlin, MD
Fabiola Metry, MD
Raphael Twerenbold, MD
Thomas Nestelberger, MD
Damian Kawecki, MD
*Christian Mueller, MD
for the APACE Investigators
*Cardiovascular Research Institute Basel, and
Department of Cardiology
University Hospital Basel
Petersgraben 4
CH-4031 Basel
Switzerland
E-mail: christian.mueller@usb.ch
Twitter: @UniBasel_en
https://doi.org/10.1016/j.jacc.2018.12.013
Ó 2019 by the American College of Cardiology Foundation. Published by Elsevier.
Please note: The study was supported by research grants from the Swiss Na-
tional Science Foundation, the European Union, the Swiss Heart Foundation,
Abbott, Beckman Coulter, Biomerieux, BRAHMS, Roche, Siemens, 8sense,
Nanosphere, Singulex, the University of Basel, and the University Hospital
Basel. The sponsors had no role in designing or conducting the study and no
role in gathering or analyzing the data or writing the manuscript. The investi-
gated hs-cTn assays were donated by the manufacturers, who had no role in the
design of the study, the analysis of the data, the preparation of the manuscript,
or the decision to submit the manuscript for publication. Dr. Boeddinghaus has
received research grants from the University of Basel (Division of Internal
Medicine), the Swiss Academy of Medical Sciences, and the Gottfried and Julia
Bangerter-Rhyner Foundation; and has received speaker honoraria from
Siemens and Roche, outside of the submitted work. Dr. Twerenbold has
received research support from the Swiss National Science Foundation
(P300PB-167803/1), the University of Basel, and the University Hospital of Basel;
and has received speaker honoraria/consulting honoraria from Abbott, Amgen,
BRAHMS Thermo Scientific, Roche, Siemens, and Singulex outside of the sub-
mitted work. Dr. Rubini has received research support from the Swiss Heart
Foundation; and has received honoraria from Abbott outside of the submitted
work. Dr. Reichlin has received research grants from the Goldschmidt-
Jacobson-Foundation, the Swiss National Science Foundation (PASMP3-
136995), the Swiss Heart Foundation, the Professor Max Cloëtta Foundation,
the Uniscientia Foundation Vaduz, the University of Basel, and the Department
of Internal Medicine, University Hospital Basel; and has received speaker
honoraria from Brahms and Roche outside of the submitted work. Dr. Mueller
has received research support from the Swiss National Science Foundation, the
Swiss Heart Foundation, the KTI, the Stiftung für kardiovaskuläre Forschung
Basel, Abbott, Alere, AstraZeneca, Beckman Coulter, Biomerieux, Brahms,
Roche, Siemens, Singulex, Sphingotec, and the Department of Internal Medi-
cine, University Hospital Basel; and has received speaker honoraria/consulting
honoraria from Abbott, Alere, AstraZeneca, Biomerieux, Boehringer Ingelheim,
Bristol-Myers Squibb, Brahms, Cardiorentis, Novartis, Roche, Siemens, and
Singulex. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose. The authors are indebted to
the patients who participated in the study and to the emergency department
staff as well as the laboratory technicians of all participating sites for their most
valuable efforts. In addition, the authors wish to thank Irina Klimmeck, RN,
Fausta Chiaverio, RN (all University Hospital Basel, Switzerland), Esther Gar-
rido, MD (Hospital del Mar, IMIM, Barcelona, Spain), Helena Mañé Cruz, Car-
olina Isabel Fuenzalida Inostroza (Hospital Clinic, Barcelona, Spain), and Miguel
Angel García Briñón (Hospital Clínico San Carlos, Madrid, Spain). (Advanta-
geous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study
[APACE]; NCT00470587)
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Short-Term Risk of
Aortoiliac Aneurysm or
Dissection Associated With
Fluoroquinolone Use
Fluoroquinolones have been associated with aortic
aneurysm or dissection (1–4); the European Medicines
Agency recently warned against this risk (5). We
added to the existing body of evidence using: 1) a
self-controlled design; and 2) amoxicillin as an
active comparator for fluoroquinolones.
We performed case-time-control analyses using
the French health insurance nationwide databases
(SNIIR-AM) covering >60 million inhabitants. Cases
were patients age 18 years or older with incident
aortoiliac aneurysm or dissection who were diag-
nosed between July 1, 2010, and December 31, 2015;
had been exposed to fluoroquinolones (or amoxi-
cillin) during the 180 days before the date of outcome
occurrence (i.e., index date); and were not hospital-
ized in the 180 days before the outcome (no infor-
mation on in-hospital antibiotic exposure available
from the database). Drug exposures were identified
from out-hospital reimbursements, and outcomes
from in-hospital diagnoses (International Classifica-
tion of Diseases-10th Revision codes) and medical
procedures. The main outcome of interest corre-
sponded to aortoiliac ruptured aneurysm and/or
dissection; it was extended to unruptured events for
secondary analyses.
To estimate the association using each patient as his or
her own control, frequency of exposure to fluo-
roquinolone was compared between a defined risk win-
dow (day 30 to day 1 before the outcome) and matched
control windows (day 120 to day 91, day 150 to day 121,
and day 180 to day 151 before the outcome). Trend for
exposure along the period was controlled using a refer-
ence group of randomly selected subjects free of the
event who were individually matched to cases regarding
age and sex (up to 10 per case).