European Heart Journal (2020) 41, 4508–4517 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehaa570 Arrhythmias

A practical risk score for early prediction of

neurological outcome after out-of-hospital
cardiac arrest: MIRACLE2
Nilesh Pareek1,2*, Peter Kordis 3, Nicholas Beckley-Hoelscher4,

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

Dominic Pimenta 5, Spela Tadel Kocjancic3, Anja Jazbec3, Joanne Nevett6,
Rachael Fothergill6, Sundeep Kalra5, Tim Lockie 5, Ajay M Shah 1,2,
Jonathan Byrne1,2, Marko Noc3, and Philip MacCarthy1,2
1
Department of Cardiology, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE59RS, UK; 2School of Cardiovascular Medicine and Sciences, BHF Centre
of Excellence, King’s College London, 125 Coldharbour Lane, London SE5 9NU, UK; 3Centre for Intensive Internal Medicine, University Medical Center, Zaloska 7, Ljubljana
1000, Slovenia; 4School of Population Health and Environmental Sciences, King’s College London, London SE1 1UL, UK; 5Department of Cardiology, Royal Free Hospital NHS
Foundation Trust, Pond St, Hampstead, London NW3 2QG, UK; and 6London Ambulance Service NHS Trust, 220 Waterloo Rd, London SE1 8SD, UK

Received 26 March 2020; revised 25 May 2020; editorial decision 17 June 2020; accepted 1 July 2020; online publish-ahead-of-print 30 July 2020

See page 4518 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa673)

Aims The purpose of this study was to develop a practical risk score to predict poor neurological outcome after out-of-
hospital cardiac arrest (OOHCA) for use on arrival to a Heart Attack Centre.
...................................................................................................................................................................................................
Methods From May 2012 to December 2017, 1055 patients had OOHCA in our region, of whom 373 patients were
and results included in the King’s Out of Hospital Cardiac Arrest Registry (KOCAR). We performed prediction modelling with
multivariable logistic regression to identify predictors of the primary outcome to derive a risk score. This was ex-
ternally validated in two independent cohorts comprising 473 patients. The primary endpoint was poor neurological
outcome at 6-month follow-up (Cerebral Performance Category 3–5). Seven independent predictors of outcome
were identified: missed (unwitnessed) arrest, initial non-shockable rhythm, non-reactivity of pupils, age (60–80
years—1 point; >80 years—3 points), changing intra-arrest rhythms, low pH <7.20, and epinephrine administration
(2 points). The MIRACLE2 score had an area under the curve (AUC) of 0.90 in the development and 0.84/0.91 in
the validation cohorts. Three risk groups were defined—low risk (MIRACLE2 <_2—5.6% risk of poor outcome);
intermediate risk (MIRACLE2 of 3–4—55.4% of poor outcome); and high risk (MIRACLE2 >_5—92.3% risk of poor
outcome). The MIRACLE2 score had superior discrimination than the OHCA [median AUC 0.83 (0.818–0.840);
P < 0.001] and Cardiac Arrest Hospital Prognosis models [median AUC 0.87 (0.860–0.870; P = 0.001] and equivalent
performance with the Target Temperature Management score [median AUC 0.88 (0.876–0.887); P = 0.092].
...................................................................................................................................................................................................
Conclusions The MIRACLE2 is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA,
which has been developed for simplicity of use on admission.

*Corresponding author. Tel: 020 3299 9000, Email: nileshpareek@nhs.net

C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
The MIRACLE2 score 4509

Graphical Abstract

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏

Keywords Out-of-hospital cardiac arrest • Hypoxic brain injury • Prediction

..
Introduction .. Methods
..
Out-of-hospital cardiac arrest (OOHCA) occurs in over a quarter of
..
.. Study setting
a million patients a year globally and presents a major public health .. A standardized systematic protocol was established in 2012 in
challenge.1 There is an increasing recognition of a primary cardiac
..
.. London whereby patients who have sustained OOHCA with return
aetiology in OOHCA with the presence of a culprit coronary lesion .. of spontaneous circulation (ROSC) and an electrocardiogram (ECG)
.. showing ST segment elevation (STEMI) are taken directly to a HAC.
in 50–90% of patients.2–4 As a result, a significant proportion of ..
OOHCA patients are taken directly to a Heart Attack Centre .. Patients without ST elevation were brought directly to the HAC if
.. there was high suspicion of a cardiac aetiology (presence of chest pain
(HAC) for the consideration of trans-thoracic echocardiography, ..
early coronary angiography, and mechanical circulatory support
.. before arrest, a history of established coronary artery disease and ab-
.. normal or uncertain ECG results) or after exclusion of non-cardiac
(MCS), such as percutaneous left ventricular assist devices and extra- ..
.. causes in the emergency department.10 King’s College Hospital is the
corporeal membranous oxygenation. These approaches have the po- .. main HAC in South East London, treating a population in excess of 1
tential to improve survival after OOHCA but are invasive and costly .. million. On arrival, a decision to perform coronary angiography is
..
and, despite their application, a majority of patients still sustain poor .. made by the admitting Interventional Cardiologist and after treat-
outcomes due to hypoxic brain injury incurred prior to admission.5 .. ment, patients are transferred to the Intensive Care Unit (ICU) for
..
Furthermore, the clinical features of neurological injury are usually .. ongoing supportive care.
delayed until 72 h after admission, by which point, much resource has
..
..
already been expended.6 .. Development cohort study population
..
Early predictors of outcome that would support emergency .. We included all patients over the age of 18 years who presented with
clinical decision-making in the HAC are urgently required to pre- .. OOHCA and had ROSC in the community between 1 May 2012 and
..
vent instigating costly and intensive resources in cases of futility, .. 31st December 2017. Inclusion criteria for the registry were all
to inform family discussions, and to guide clinical decision-making. .. patients with ST elevation on ECG and patients without ST elevation
..
The OHCA,7 Cardiac Arrest Hospital Prognosis (CAHP),8 and .. if there was absence of a non-cardiac aetiology, since this group rep-
target temperature management (TTM) risk tools9 have been
.. resents patients recommended for the consideration of an early inva-
.. sive approach by European Association of Percutaneous
developed, but these are presented as relatively complex nomo- ..
.. Cardiovascular Interventions (EAPCI) and European Society of
grams, thereby potentially limiting their routine use in emergency .. Cardiology (ESC) guidelines.10–12 Patients who died before arrival to
settings. ..
.. our centre, with evidence of an obvious non-cardiac cause of arrest
Accordingly, the purpose of this study was to develop a practical .. (suicide, trauma, drowning, substance overdose), confirmed intra-
point-based risk score, which can be applied to patients with ..
.. cerebral bleeding, prior neurological disability [Cerebral Performance
OOHCA on arrival to a HAC to reflect long-term prognosis and sup- .. Category (CPC) 3 or 4], or any survival limiting disease (comorbidity
port clinical decision-making.
.. leading to life expectancy <6 months) were excluded. Any patients
4510
..
with intact conscious status [defined as a Glasgow Coma Score
(GCS) of 15/15] on arrival were also excluded. The study was per-
formed according to the principles of Declaration of Helsinki and
received approval by the Research Ethics Committee.
Data collection
Data were collected using a dedicated database, and patients were identi-
fied using the Utstein criteria.13,14 We formed a data collaboration with
the London Ambulance Service to ensure the accurate collection of pre-
hospital data, including zero-flow [duration from the cardiac arrest to
commencement of cardio-pulmonary resuscitation (CPR)] and low-flow
times (duration of CPR until ROSC), initial rhythm and use of bystander
CPR. Medical records were collected and included index arterial blood
gases and standard biochemical and haematological measures (within
30 min of arrival). We also collected baseline cardiovascular investigations
including ECG, emergency echocardiography and coronary angiography
where appropriate.
Figure 1 Flow chart of patient flow from the King’s Out of Hospital Cardiac Arrest Registry cohort in the study. CPC, Cerebral Performance
Category; KCH, King’s College Hospital; OOHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation.
N. Pareek et al.
.. Outcome
.. The primary endpoint was poor neurological outcome, classified as CPC
..
.. 3–5 (severe disability—death) at follow-up of 6 months (blinded analysis).
.. Cerebral Performance Category is a five-category ordinal scale, which is
..
.. recommended by the Utstein reporting style for outcome after
.. OOHCA.15 Briefly, CPC 1 represents normal function, CPC 2 is moder-
.. ate impairment but with independent living, CPC 3 is consciousness with
..
.. severe impairment, CPC 4 is a persistent coma and CPC 5 represents
.. death. Out-patient clinic follow-up is carried out routinely after 6 months
..
.. and CPC was recorded accordingly using the medical records. Patients
.. without a clinical consultation who were known to be alive from commu-
.. nity records were then approached by telephone interview. For those
..
.. patients with CPC 3–4 at 6-month follow-up, the interview was per-
.. formed with a nominated consultee or carer. All patients who died be-
Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021
..
.. fore 6 months were classed as CPC 5 other than those who were known
.. to be CPC 1–2 before a non-neurological cause of death—these patients
.. remained in this class for the purposes of the primary endpoint analysis
..
. (two patients).
The MIRACLE2 score
..
Statistical analysis
We developed the risk score in accordance with the TRIPOD
(Transparent Reporting of a multivariable prediction model for Individual
Prognosis Or Diagnosis) methodology.16 In accordance with the guide-
lines, logistic regression was used over Cox regression analysis owing to a
shorter follow-up duration.16 An exploratory univariable analysis was
performed for 14 selected candidate predictors (Table 3 and
Supplementary material online, Figure S1). Based on a combination of im-
mediate availability of variables, clinical importance, and strength of statis-
tical association with outcome, a smaller subset of predictor variables
was entered into a multivariable model. Simplified versions of the multi-
variable model were then used to develop a simple additive risk score
based on influential cut-off points for continuous variables where appro-
priate. Variables that exhibit higher association with the primary outcome
based on the coefficients from the multivariable analysis are assigned only
one point for simplicity of use in an emergency setting. However, varia-
bles with a strong or non-linear association could be assigned extra
points, where this does not affect practicality of use. Akaike information
criterion (AIC) model values were calculated to ensure model accuracy.
A receiver operating characteristic (ROC) curve for each risk score was
plotted, with the area under the curve (AUC) measuring the discrimin-
ation. Missing predictor variable values used in the multivariable model
were investigated for associations with other variables, with appropriate
multiple imputation methods used to handle missing values. An internal
validation was performed using 1000 bootstrap iterations, generating
bias-corrected and accelerated (BCa) confidence intervals (CIs). The risk
scores were then calculated for patients in the validation cohorts, with
the discrimination and calibration measured by the AUC and calibration
slope, respectively. Finally, a post hoc analysis evaluating the performance
of the risk score for patients based on presenting 12 lead ECG and under-
going early angiography was performed. Calibration slopes were used to
measure the calibration of the scores rather than the Hosmer–
Lemeshow goodness-of-fit test in accordance with current expert con-
sensus.17 All analyses were undertaken using R version 3.5.3.
Validation cohort study populations
External validation was performed in two cohorts from the University
Medical Center, Ljubljana, Slovenia, and the Royal Free Hospital (RFH),
London, UK. Both of these centres are HACs providing primary percu-
taneous coronary intervention (PCI) with on-site emergency depart-
ments, each serving a population of ~1 million. Similar to the
development cohort, both centres follow EAPCI and ESC guidelines with
regard to pathways of care for OOHCA patients and all patients met in-
clusion and exclusion criteria. Patients from Ljubljana were recruited
from January 2013 and December 2017, the primary endpoint was poor
neurological outcome (CPC 3–5) at hospital discharge as evaluated by
the medical records. Patients from RFH were recruited between 1
January 2016 and 30 March 2018. Out-patient follow-up is conducted
routinely at 6 months and the primary endpoint was poor neurological
outcome at 6 months (CPC 3–5). Patients lost to follow-up were
excluded from the study. There was also no overlap of any patients be-
tween any cohorts.
Results
Development cohort
Between 1 May 2012 and 31 December 2017, 1055 patients suffered
OOHCA in the South London area, of whom 291 failed to regain
ROSC with the emergency medical services. From this cohort, 129
died before reaching our tertiary centre, 635 patients reached with
4511
.. ROSC, and 232 patients were deemed to have a non-cardiac aeti-
.. ology for the cardiac arrest. After excluding conscious patients
..
.. (defined as a GCS of 15/15) and those lost to follow-up (1 patient),
.. 373 patients were included in the development registry (Figure 1).
..
.. The median age was 64.0 years, the majority of patients were male
.. (74.3%), the median zero-flow time was 2 min (0–7), and low-flow
..
.. time was 25 min (17–38). Most patients had cardiac arrest at home
.. (n = 211/373, 56.6%) and 262 patients (70.2%) had shockable
..
.. rhythms. A total of 210/373 patients had ST elevation/left bundle
..
.. branch block (56.3%) and 40 patients (10.7%) had ST depression on
.. 12-lead ECG. Two hundred eighty-five patients (76.4%) had early
..
.. coronary angiography and 176 of these patients (61.8%) underwent
Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021
.. PCI. The remaining 88 patients (23.6%) did not have coronary angiog-
..
.. raphy based on clinician discretion. The primary endpoint of poor
.. neurological outcome (CPC 3–5) occurred in 223 patients (59.8%)
..
.. (Tables 1 and 2).
..
..
.. Predictors of outcome
.. A set of candidate predictor variables were initially investigated for
..
.. associations with the primary outcome by univariable logistic regres-
..
.. sion—results of which can be found in Table 3. In a full model, only
.. lactate and pH were co-linear; pH was selected for use in the multi-
..
.. variable model owing to clinical relevance and stronger statistical as-
.. sociation. To minimize overfitting, further model refinement involved
..
.. selecting variables with the strongest evidence of clinical relevance,
.. statistical association, and practical availability for application at the
..
.. point of arrival to a HAC. This led to a reduced set of seven predictor
.. variables used in the final model: age, unwitnessed arrest, initial
..
.. rhythm, presence of changing rhythms (defined as two out of three
..
.. of ventricular fibrillation/pulseless electrical activity/asystole in a sin-
.. gle ROSC cycle), use of any epinephrine during the cardiac arrest,
..
.. pH, and absent pupil reactivity (Table 3).
.. Frequency of missing variables of each predictor was deemed to
..
.. be missing completely at random and so multiple imputation was
.. considered to be an appropriate method of handling the missing pre-
..
.. dictor variable data, for which 50 imputations were performed, the
.. results of which were pooled using Rubin’s rule.18
..
.. For risk score development, all variables exhibiting significant asso-
.. ciations in the multivariable analysis were assigned 1 point, for simpli-
..
.. city of use in an emergency setting (Table 3). However, since age and
..
.. administration of epinephrine had particularly large effect sizes, add-
.. itional points were assigned to these variables (two for epinephrine).
..
.. Continuous variables (age and pH) were also categorized. A value of
.. 7.20 was used for pH and, since age showed a quadratic relationship
..
.. with the outcome, three age categories were used with cut-off points
.. at 60 years (one point) and 80 years for age (two extra points—three
..
.. points in total). These thresholds all gave low AIC model values and
..
.. were deemed clinically relevant.
..
.. Derivation of the MIRACLE risk score
.. 2
.. A simplification of the above multivariable model was used to create
..
.. the final risk score. The MIRACLE2 score assigns a point for each cat-
.. egory in the model and also assigns an additional two points for those
..
.. over 80 years and for those on epinephrine, thus ranging from 0 to
.. 10 (Take-home figure). Rates of patients in each MIRACLE score are
.. 2
. shown in Supplementary material online, Figure S2.
4512 N. Pareek et al.

Table 1 Patient baseline characteristics

Variables Total (n 5 373) Good outcome Poor outcome P-value

(n 5 150; 40.2%) (n 5 223; 59.8%) (good vs. poor outcome)
....................................................................................................................................................................................................................
Age (years), median (IQR) 64 (52–75) 59 (49–68) 68 (56–78) <0.0001
Male gender, n/total n (%) 277/373 (74.3) 110/150 (73.3) 167/223 (74.9) 0.736
Cardiovascular risk factors, n/total, n (%)
Diabetes mellitus 66/373 (17.7) 13/150 (8.7) 53/223 (23.8) 0.002
Smoking 221/373 (59.2) 83/150 (55.3) 138/223 (61.9) 0.207
ECG, n/total n (%)
ST elevation/left bundle branch block 210/373 (56.3) 93/150 (62.0) 117/223 (52.5)
ST depression 40/373 (10.7) 20/150 (13.3) 20/223 (9.0) 0.002

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

Right bundle branch block 45/373 (12.1) 7/150 (4.7) 38/223 (17.0)
Normal 78/373 (20.9) 30/150 (20.0) 48/223 (21.5)
LVEF, n/total n (%)
Normal 72/329 (21.9) 26/131 (19.8) 46/198 (23.2)
Mild 44/329 (13.4) 21/131 (16.0) 23/198 (11.6) 0.01
Moderate 95/329 (28.9) 51/131 (38.9) 44/198 (22.2)
Severe 118/329 (35.9) 33/131 (25.2) 85/198 (42.9)
Coronary angiography, n/total, n (%) 285/373 (76.4) 140/150 (93.3) 145/223 (65.0) <0.0001
PCI, n/total, n (%) 176/285 (61.8) 91/140 (65.0) 85/145 (58.6) 0.147

ECG, electrocardiogram; IQR, inter-quartile range; LVEF, left ventricular ejection fraction (normal > 52%, mild = 45–52%, moderate = 35–45%, severe < 35%); PCI, percutaneous
coronary intervention.

Table 2 Out-of-hospital cardiac arrest circumstances

Variables Total (n 5 373) Good outcome Poor outcome P-value

(n 5 150; 40.2%) (n 5 223; 59.8%) (good vs. poor outcome)
....................................................................................................................................................................................................................
Residence, n/total n (%) 211/373 (56.6) 71/150 (47.3) 140/223 (62.8) 0.0001
Witnessed, n/total n (%) 294/373 (78.8) 138/150 (92.0) 156/223 (70.0) <0.0001
Bystander CPR, n/total n (%) 268/373 (71.8) 118/150 (78.7) 150/223 (67.3) <0.0001
AED use, n/total n (%) 16/373 (4.3) 15/150 (10.0) 1/223 (0.4) <0.0001
Zero-flow time (min), median (IQR) 2 (0–7) 1 (0–4) 3 (0–8) 0.0001
Low-flow time (min), median (IQR) 25 (17–38) 19.0 (13.0–27.0) 31 (21.0–43.0) <0.0001
Shockable rhythm, n/total n (%) 262/373 (70.2) 140/150 (93.3) 122/223 (54.7) <0.0001
Reactive pupils, n/total n (%) 144/321 (44.9) 88/127 (69.3) 56/194 (28.9) <0.0001
Changing rhythms, n/total n (%) 155/367 (42.2) 26/150 (17.3) 129/217 (59.4) <0.0001
Epinephrine, n/total n (%) 266/370 (71.9) 63/149 (42.3) 203/221 (91.9) <0.0001
Admission pH, median (IQR) 7.21 (7.08–7.30) 7.27 (7.20–7.33) 7.17 (7.03–7.27) <0.0001
Blood lactate (mmol/L), median (IQR) 4.90 (2.4–8.9) 3.1 (1.7–5.6) 6.2 (3.2–10.0) <0.0001
Serum troponin I (ng/L), median (IQR) 2132 (376–13 225) 2696 (519–22 592) 1600.5 (271–9946) 0.006
Serum creatinine (mmol/L), median (IQR) 108 (86.0–134.0) 91.0 (74.0–111.0) 120.0 (100.0–152.0) <0.0001

AED, automated external defibrillator; CPR, cardio-pulmonary resuscitation, IQR, inter-quartile range.

..
MIRACLE2 had a discrimination of 0.90 AUC with internal valid- .. frequency of predictor variables used in the final risk score described
ation median bootstrap estimate of 0.90 (95% BCa CI 0.865–0.928). .. above was lower in the Ljubljana and RFH cohorts than in the devel-
..
The ROC curve for the MIRACLE2 score in the development cohort .. opment dataset (Supplementary material online, Table S1). The
can be found in Figure 2. There was a significant and stepwise increase
.. model was not re-calibrated in the validation cohorts but was applied
..
in the primary endpoint as the MIRACLE2 score increased with good .. in a finalized form from the development set. After imputing missing
..
calibration (P < 0.0001) (Take-home figure). .. values, MIRACLE2 had an AUC of 0.84 in the Ljubljana validation co-
.. hort with a calibration slope of 0.744. The MIRACLE2 score per-
..
Validation cohorts .. formed more favourably in the RFH external validation cohort with
Three hundred and twenty-five patients were recruited in the .. an AUC of 0.91 and a calibration slope of 0.834 (Figure 2 and
..
Ljubljana cohort and 148 were recruited in the RFH cohort. The . Supplementary material online, Figures S3 and S4).
The MIRACLE2 score 4513

Table 3 Univariable and multivariable analyses for predictors associated with primary endpoint

Predictor Univariable Multivariable

.................................................... .................................................................................
OR (95% CI) P-value OR (95% CI) P-value log(OR)
....................................................................................................................................................................................................................
Unwitnessed 4.40 (2.40–8.65) <0.001 2.78 (1.22–6.33) 0.015 1.02
Initial non-shockable rhythm 12.97 (6.62–28.58) <0.001 5.29 (2.25–12.44) <0.001 1.67
Changing rhythms 7.41 (4.52–12.53) <0.001 3.35 (1.76–6.40) <0.001 1.21
Age category (ref group: <_60)
60–80 1.97 (1.27–3.08) 0.003 3.07 (1.56–6.02) 0.001 1.12
>80 8.97 (3.66–27.06) <0.001 21.37 (5.34–85.48) <0.001 3.06
pH <7.20 4.76 (3.01–7.68) <0.001 2.26 (1.18–4.34) 0.015 0.82

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

Unreactive pupils 5.56 (3.44–9.14) <0.001 2.49 (1.28–4.81) 0.007 0.91
Any epinephrine 15.40 (8.79–28.25) <0.001 7.67 (3.51–16.75) <0.001 2.04
Bystander CPR 0.53 (0.32–0.85) 0.009 — — —
LVEF (%) 0.98 (0.96–1.00) 0.058 — — —
Zero-flow time (min) 1.11 (1.05–1.17) <0.001 — — —
Low-flow time (min) 1.05 (1.03–1.06) <0.001 — — —
Serum creatinine (mmol/L) 1.03 (1.02–1.04) <0.001 — — —
GFR (mL/min) 0.95 (0.94–0.96) <0.001 — — —
SCAI shock grade (ref group = A) — — —
B 0.80 (0.44–1.44) 0.446
C 1.91 (0.99–3.69) 0.054 — — —
D 2.33 (1.27–4.29) 0.006 — — —
E 5.80 (2.06–16.30) 0.001 — — —

CI, confidence interval; CPR, cardio-pulmonary resuscitation; GFR, glomerular filtration rate; LVEF, left ventricular ejection fraction; OR, odd’s ratio; SCAI, Society for
Cardiovascular Angiography and Interventions

.. discrimination performance than MIRACLE with a median AUC of

Discrimination performance of the .. 2

MIRACLE2 by risk groups .. 0.83 (0.818–0.840) and a calibration of 0.797 (P < 0.001). The CAHP
..
Three risk groups were created (low—MIRACLE2 0–2; intermedi- .. score also showed lower discrimination with a median AUC of 0.87
.
ate—MIRACLE2 3–4; high—MIRACLE2 >_5). From patients with .. (0.860–0.870) (P = 0.001), and the TTM score was equivalent with a
.
complete data in the King’s Out of Hospital Cardiac Arrest Registry ... median AUC of 0.88 (0.876–0.887) (P = 0.092) (Figure 3). For those
(KOCAR) registry, 72 (23.5%) patients were in the low-risk group, ... classified as high risk, the positive predictive value of OHCA (>32.5)
92 (29.9%) patients were in the intermediate group, and 143 (46.6%) ... was 89.6%, for CAHP (>200) was 90.6%, and for TTM (>16) was
patients were in the high-risk group. The primary endpoint occurred ... 92.5%. For those classified as low risk, the negative predictive value of
.
in 5.6% of those with low risk, 55.4% of those with intermediate risk, .. OHCA (<2) was 87.2%, for CAHP (<150) was 76.4%, and for TTM
.
and 92.3% with high risk. Patients with low risk (MIRACLE2 <_ 2) had .. (<10) was 84.3%. Full model performance and calibration are shown
.
a negative predictive value of 94.4% in the development cohort and .. in Table 4 and Supplementary material online, Tables S3–S5.
.
81.8% and 91.5% in the external validation cohorts. Patients with high ..
.
risk (MIRACLE2 >_ 5) had a high risk of poor neurological outcome .. Performance of the MIRACLE2 score by
.
with a positive predictive value of 92.3% in the development cohort .. clinical presentation and treatment
.
and 92.8% and 89.6% in the external validation cohorts .. A post hoc analysis of the performance of the MIRACLE2 score in
..
(Supplementary material online, Table S2). .. sub-groups of clinical presentation based on presenting ECG (STEMI/
..
. without STEMI) and provision of early invasive therapy was per-
Comparison of MIRACLE2 discrimination ... formed. Complete data were available in 307 patients and the AUC
performance with the OHCA, Cardiac ..
.. for the primary endpoint with STEMI was 0.89 (calibration slope
Arrest Hospital Prognosis, and Target .. 1.021) and for those without STEMI was 0.91 (calibration slope
..
Temperature Management risk models .. 0.979) (Supplementary material online, Figure S6). Early angiography
.
Using tools provided in the original manuscripts, we calculated scores ... was performed in 285 patients from the KOCAR registry, of whom
for the OHCA, CAHP, and TTM tools in 50 imputations of each co- ... 236 had complete data. From these patients, the AUC for the pri-
hort, performed a ROC curve analysis, and evaluated calibration ... mary endpoint was 0.89 with a calibration slope of 1.013. A total of
.
where complete regression data were available (only MIRACLE2/ .. 90.1% of patients treated with an early invasive strategy and a
.
OHCA). In the KOCAR registry, the OHCA score had lower . MIRACLE score of >_5 had poor neurological outcome. 2
4514 N. Pareek et al.

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

Figure 2 Receiver operating curve for the development and external validation cohorts. (A) The area under the curve in the development cohort
was 0.90 and (B) was 0.84 in the Ljubljana cohort (red) and 0.91 in Royal Free Hospital (green). AUC, area under the curve.

Figure 3 Comparison of the discrimination performance for the MIRACLE2, OHCA, Cardiac Arrest Hospital Prognosis, and Target Temperature
Management scores. (A) The median area under the curve (range) in the King’s Out of Hospital Cardiac Arrest Registry for MIRACLE2 was 0.90, for
OHCA was 0.83 (0.818–0.840), for Cardiac Arrest Hospital Prognosis was 0.87 (0.860–0.870), and for target temperature management was 0.88
(0.876–0.887) in 50 imputed samples. (B and C) Median area under the curve for MIRACLE2, OHCA, and Cardiac Arrest Hospital Prognosis as shown.
Colours represent different scores. AUC, area under the curve; CAHP, Cardiac Arrest Hospital Prognosis; KOCAR, King’s Out of Hospital Cardiac
Arrest Registry; OHCA, out-of-hospital cardiac arrest; RFH, Royal Free Hospital; TTM, target temperature management.

..
Discussion ..
..
Association (AHA) and ESC recommend emergency coronary angi-
ography in patients with ST elevation and without ST elevation in the
..
We have derived and validated the MIRACLE2 risk score as a prac- .. absence of a non-cardiac cause with evidence of ongoing ischae-
tical tool to predict poor neurological outcome at the time of index .. mia.10,12,20 Furthermore, there is increasing availability of MCS devi-
..
admission to a HAC. A MIRACLE2 score of >_5 predicted poor .. ces, which might be used in cases of haemodynamic instability
neurological outcome in nearly half of all patients with a specificity of .. associated with OOHCA, either at specialist centres or pre-hospital
..
90.8% . .. in the community. However, hypoxic brain injury sustained prior to
With increased provision of bystander CPR, early defibrillation, .. arrival is the main driver of mortality and morbidity in survivors, with
..
and regionalization of care, increasing numbers of patients are surviv- .. concomitantly high rehabilitation costs.21 Neurological outcome can
ing OOHCA to be admitted to HACs.19 The American Heart
.. often only be reliably determined at 72 h and neurological risk
The MIRACLE2 score 4515

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

Take-home figure The MIRACLE2 score. Each variable is applied on admission and is assigned points as shown in the figure. An extra two
points are gained for age >80 years (maximum of 3 if >80 years) and for epinephrine use during the cardiac arrest. A nomogram shows prediction of a
poor outcome from the logistic regression model fitted to the risk score (R package rms). The right-hand panel shows the observed and expected
event rates (as a dotted line based on a logistic regression model of the risk score) of poor neurological outcome (Cerebral Performance Category
3–5) at 6 months. The risk changes in a non-linear fashion to the score and is most sensitive to changes in the score in the middle of the scale. PEA,
pulseless electrical activity; ROSC, return of spontaneous circulation; VF, ventricular fibrillation.

..
stratification on arrival is not currently possible.6 The EAPCI and ..
AHA guidelines suggest that ‘favourable cardiac arrest circumstances’ ..
..
should be present before consideration for angiography; however, ..
this guidance is ambiguous and of limited benefit in deciding which
..
..
patients should undergo invasive investigation.11,20 Consonant with ..
this, the recently published Coronary Angiography after Cardiac
..
..
Arrest (COACT) trial demonstrated no mortality benefit of early ..
..
compared to delayed angiography with outcome primarily driven by ..
hypoxic brain injury.22 ..
..
Several tools for risk prediction have been developed but have po- ..
tential limitations in the primary cardiac OOHCA cohort. The CAHP ..
..
score is a nomogram, which was derived at the time of hospital ad-
mission with a derivation AUC of 0.93 but is potentially more time-
consuming to use in an emergency situation, only predicts short-term
survival (ICU discharge) so could underestimate late recovery and
had poorer performance in an independent external validation co-
hort (AUC 0.75).8,9 The TTM score is also a relatively complex 10
variable multi-point score only applied at the time of ICU admission
with satisfactory performance of an AUC of 0.84 but without exter-
nal validation to date.9
The MIRACLE2 risk score has been designed for ease of use in
OOHCA patients at the point of admission to inform immediate
decision-making. We allocated a single point to each parameter for
ease of use in an emergency setting, other than age and the use of epi-
nephrine. Satisfactory discrimination performance in two external
validation cohorts with differing rates of predictors provides robust
assurance of its validity in this setting. The score predicted a low risk
of poor outcome (MIRACLE2 <_ 2) in over a quarter of patients while
also predicting high risk (MIRACLE2 >_ 5) in nearly half of patients,
suggesting clinical applicability across a range of comatose patients
with OOHCA. When compared with the OHCA, CAHP, and TTM
scores, the MIRACLE2 score showed superior or equivalent
discrimination performance across all three cohorts but with the
added significant advantage of practicality for clinical use and ease of
application on admission. It is important to note that the intention of
the score is not to replace clinical assessment but to provide a prac-
tical means for objective evaluation of neurological risk prior to deliv-
ery of potentially expensive and invasive therapies.
Several established variables, such as a witnessed arrest, initial
rhythm, and age were incorporated into the score with the exception
of bystander CPR, perhaps reflecting the higher importance of effect-
ive chest compressions.23,24 An association between public access
defibrillation and improved outcome is well established but low appli-
.. cation (5–10% in registries) impaired its potential role as a predictor
.. in the score.25,26 The intra-arrest use of epinephrine in the
..
.. PARAMEDIC-2 trial was not associated with improvement in post-
.. discharge neurological recovery compared with placebo and this may
..
.. represent an important surrogate of prolonged low-flow time and
..
.. haemodynamic instability.27 Current guidelines continue to recom-
.. mend its routine use during OOHCA, but this practice might vary in
..
.. other geographic locations, which could affect the discrimination
.. value of the score in other healthcare settings.28,29 Arterial blood gas
... values inputted into the score were available immediately on admis-
..
.. sion (within 30 min of arrival). Since it is established that resuscitative
.. efforts might alter the values of pH, later measurement might have a
..
.. significant negative impact on the performance of the score. The spe-
.. cificity of pupillary reflexes after ROSC in isolation for neurological
..
.. outcome after OOHCA is 50%, which might be due to confound-
..
.. ing factors such as ambient light and drug administration, but had an
.. odds ratio of 2.49 in our multivariable analysis and remained a useful
..
.. objective parameter in this prediction model.30 While several varia-
.. bles, such as zero- and low-flow times have previously been well
..
.. established markers of a poor outcome, they are often unknown or
.. inaccurately recorded at the time of admission.23 This can lead to
4516 N. Pareek et al.

Table 4 Discrimination performance of the risk scores in the King’s Out of Hospital Cardiac Arrest Registry cohort

Risk score Scores

....................................................................................................................................................................................................................
MIRACLE2 >2 >4
n (%) 235 (76.5) 143 (46.6)
Sensitivity, % (95% CI) 97.9 (94.6–99.4) 70.6 (63.5–77.0)
Specificity, % (95% CI) 56.7 (47.3–65.7) 90.8 (84.2–95.3)
PPV, % (95% CI) 77.9 (72.0–83.0) 92.3 (86.7–96.1)
NPV, % (95% CI) 94.4 (86.4–98.5) 66.5 (58.7–73.6)
OHCA >2.0 >17.4 >32.5
n (%) 266 (85.0) 199 (63.6) 115 (36.7)

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

Sensitivity, % (95% CI) 96.9 (93.4–98.9) 77.9 (71.5–83.6) 52.8 (45.6–60.0)
Specificity, % (95% CI) 34.7 (26.2–44.1) 60.2 (50.7–69.1) 89.8 (82.9–94.6)
PPV, % (95% CI) 71.1 (65.2–76.4) 76.4 (69.9–82.1) 89.6 (82.5–94.5)
NPV, % (95% CI) 87.2 (74.3–95.2) 62.3 (52.7–71.2) 53.5 (46.3–60.6)
TTM >10 >13 >16
n (%) 207 (71.4) 148 (51.0) 106 (36.6)
Sensitivity, % (95% CI) 92.6 (87.7–96.0) 73.9 (66.7–80.2) 55.7 (48.0–63.2)
Specificity, % (95% CI) 61.4 (51.8–70.4) 84.2 (76.2–90.4) 93.0 (86.6–96.9)
PPV, % (95% CI) 78.7 (72.5–84.1) 87.8 (81.5–92.6) 92.5 (85.7–96.7)
NPV, % (95% CI) 84.3 (74.7–91.4) 67.6 (59.2–75.2) 57.6 (50.1–64.8)
CAHP >150 >200
n (%) 216 (66.3) 117 (35.9)
Sensitivity, % (95% CI) 87.1 (81.6–91.4) 52.7 (45.6–59.8)
Specificity, % (95% CI) 67.2 (58.2–75.3) 91.2 (84.8–95.5)
PPV, % (95% CI) 81.0 (75.1–86.0) 90.6 (83.8–95.2)
NPV, % (95% CI) 76.4 (67.3–83.9) 54.5 (47.5–61.4)

CAHP, Cardiac Arrest Hospital Prognosis; CI: confidence interval; KOCAR, King’s Out of Hospital Cardiac Arrest Registry; NPV, negative predictive value; OHCA, out-of-
hospital cardiac arrest; PPV, positive predictive value; TTM, target temperature management.

..
challenges in predicting neurological outcome on arrival, especially in
comatose patients treated with hypothermia. Hence, there remains
significant ambiguity and limited objective guidance to support early
decision-making at HACs, which should have as high a specificity as
possible to avoid under-treatment of cases where interval neuro-
logical recovery remains possible.
We included OOHCA patients who are currently considered for
an early invasive approach by current ESC and EAPCI guidelines, and
while there is often significant heterogeneity in their presentations
and outcomes, this is the group where objective guidelines are
required to support decision-making.10–12 The accurate prediction of
poor outcome in patients with STEMI, where the primary cause of
mortality remains hypoxic brain injury, suggests an ability to identify
inherent risk distinct to clinical presentation. Furthermore, equally
strong discrimination in those treated with early angiography (AUC
0.89), where in this study 90.1% of patients with a score of >_5 sus-
tained a poor outcome, provides assurance of its validity in contem-
porary pathways of care.11 Together, these findings might enable
characterization of sub-groups of patients where an early invasive ap-
proach might be ultimately futile. Similarly, the score has substantial
potential in guiding appropriate provision of MCS devices after
OOHCA, where robust indications for use in a centre or in the com-
munity (e-CPR) are essential for effective resource allocation but
.. currently remain crude.31 Finally, methods of early neuro-
.. prognostication after OOHCA might be useful in under-resourced
..
.. medical systems or in times of crisis such as a global pandemic, to
.. avoid loss of life while pragmatically preserving precious resources.
..
.. Hence, the MIRACLE2 score, with further evaluation, has the poten-
.. tial to be incorporated into future research studies evaluating optimal
..
.. treatment strategies for OOHCA by improving patient selection and
.. excluding patients with severe neurological insult.
..
..
.. Limitations
..
.. The risk score was derived and validated in retrospective cohorts, al-
..
.. beit with a thorough methodology and with internal and external val-
.. idation. While this enabled collection of a rich dataset with a highly
..
.. protocolized pathway of care, there is a risk of bias. The predictive
.. accuracy may not be transferrable to non-HACs without access to
..
.. immediate 24-h coronary angiography, MCS, cardio-thoracic surgery,
.. and specialist intensive care expertise. The primary outcome in one
..
.. validation group differed by time-point due to the availability of data
.. and this may have affected the results, though it is established that
..
.. neurological injury at discharge is usually sustained up to 1 year after
.. discharge.32 A proportion of pupil reactivity and blood gas analysis in
..
.. the Ljubljana cohort were recorded on ICU admission, which might
.. have affected the discriminant thresholds of these variables and might
The MIRACLE2 score 4517

.. 10. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio

explain the marginally reduced performance of the score in this co- ..
hort. In contrast, the score provided higher discrimination value in .. ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
.. Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P; ESC
the RFH validation cohort where all variables were applied directly .. Scientific Document Group. 2017 ESC Guidelines for the management of acute
on admission to the HAC, which might indicate that this tool should .. myocardial infarction in patients presenting with ST-segment elevation: the Task
.. Force for the management of acute myocardial infarction in patients presenting
optimally be applied in this setting and provides an indication of its .. with ST-segment elevation of the European Society of Cardiology (ESC). Eur
validity when applied at this time-point. Nonetheless, the risk score .. Heart J 2018;39:119–177.
..
should be further prospectively validated in larger cohorts, especially .. 11. Noc M, Fajadet J, Lassen JF, Kala P, MacCarthy P, Olivecrona GK, Windecker S,

immediately on arrival to HACs and across different systems of care

.. Spaulding C; European Association for Percutaneous Cardiovascular
.. Interventions; Stent for Life Group. Invasive coronary treatment strategies for
before routine use. .. out-of-hospital cardiac arrest: a consensus statement from the European
.. Association for Percutaneous Cardiovascular Interventions (EAPCI)/Stent for
.. Life (SFL) groups. EuroIntervention 2014;10:31–37.
.. 12. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger
Conclusions ..
.. MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P,

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

.. Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S; ESC Scientific
The MIRACLE2 risk score is a simple and practical tool for application .. Document Group. 2015 ESC Guidelines for the management of acute coronary
on arrival to a HAC, which can predict poor long-term neurological
.. syndromes in patients presenting without persistent ST-segment elevation: Task
.. Force for the Management of Acute Coronary Syndromes in Patients Presenting
recovery with high accuracy. .. without Persistent ST-Segment Elevation of the European Society of Cardiology
.. (ESC). Eur Heart J 2016;37:267–315.
..
.. 13. Langhelle A, Nolan J, Herlitz J, Castren M, Wenzel V, Soreide E, Engdahl J, Steen

Supplementary material .. PA; Utstein Consensus Symposium. Recommended guidelines for reviewing,
.. reporting, and conducting research on post-resuscitation care: the Utstein style.
.. Resuscitation 2005;66:271–283.
Supplementary material is available at European Heart Journal online. .. 14. Cummins, RO Chamberlain, DA, Abramson NS, Allen M, Baskett PJ, Becker L,
.. Bossaert L, Delooz HH, Dick WF, Eisenberg MS, Evans TR, Holmberg S, Kerber
Funding .. R, Mullie A, Ornato JP, Sandoe E, Skulberg A, Tunstall-Pedoe H, Swanson R,
..
This work was partly funded by the King’s College Hospital Research and .. Thies WH. Recommended guidelines for uniform reporting of data from out-of-
.. hospital cardiac arrest: the Utstein style. A statement for health professionals
Development Grant and was supported by the Department of Health via .. from a task force of the American Heart Association, the European
a National Institute for Health Research Biomedical Research Centre .. Resuscitation Council, the Heart and Stroke Foundation of Canada, and the
award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with
.. Australian Resuscitation Council. Circulation 1991;84:960–975.
.. 15. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A,
King’s College London and King’s College Hospital NHS Foundation .. D’Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W,
Trust. ..
.. Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W,

Conflict of interest: none declared.

.. Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F,
.. Tibballs J, Timerman S, Truitt T, Zideman D; International Liaison Committee on
.. Resuscitation; American Heart Association; European Resuscitation Council;
.. Australian Resuscitation Council; New Zealand Resuscitation Council; Heart and
References .. Stroke Foundation of Canada; InterAmerican Heart Foundation; Resuscitation
1. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of- .. Councils of Southern Africa; ILCOR Task Force on Cardiac Arrest and
hospital cardiac arrest and survival rates: systematic review of 67 prospective ..
studies. Resuscitation 2010;81:1479–1487. .. Cardiopulmonary Resuscitation Outcomes. Cardiac arrest and cardiopulmonary

2. Kern KB, Lotun K, Patel N, Mooney MR, Hollenbeck RD, McPherson JA,
.. resuscitation outcome reports: update and simplification of the Utstein templates
.. for resuscitation registries: a statement for healthcare professionals from a task
McMullan PW, Unger B, Hsu CH, Seder DB; INTCAR-Cardiology Registry. .. force of the International Liaison Committee on Resuscitation (American Heart
Outcomes of comatose cardiac arrest survivors with and without ST-segment .. Association, European Resuscitation Council, Australian Resuscitation Council,
elevation myocardial infarction: importance of coronary angiography. JACC .. New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada,
Cardiovasc Interv 2015;8:1031–1040. .. InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa).
3. Dumas F, Cariou A, Manzo-Silberman S, Grimaldi D, Vivien B, Rosencher J, ..
Empana JP, Carli P, Mira JP, Jouven X, Spaulding C. Immediate percutaneous cor- .. Circulation 2004;110:3385–3397.

onary intervention is associated with better survival after out-of-hospital cardiac

.. 16. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a mul-
.. tivariable prediction model for individual prognosis or diagnosis (TRIPOD): the
arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac .. TRIPOD statement. The TRIPOD Group. Circulation 2015;131:211–219.
ArresT) registry. Circ Cardiovasc Interv 2010;3:200–207. .. 17. Cox DR. Two further applications of a model for binary regression. Biometrika
4. Radsel P, Knafelj R, Kocjancic S, Noc M. Angiographic characteristics of coronary .. 1958;45:562–565.
disease and postresuscitation electrocardiograms in patients with aborted car- .. 18. Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley, 2004. ISBN:
diac arrest outside a hospital. Am J Cardiol 2011;108:634–638. .. 978-0-470-31736-5.
5. Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an in-
..
.. 19. Kragholm K, Wissenberg M, Mortensen RN, Hansen SM, Malta Hansen C,
tensive care unit following cardiac arrest. Intensive Care Med 2004;30:2126–2128. .. Thorsteinsson K, Rajan S, Lippert F, Folke F, Gislason G, Kober L, Fonager K, Jensen
6. Sandroni C, Cariou A, Cavallaro F, Cronberg T, Friberg H, Hoedemaekers C, .. SE, Gerds TA, Torp-Pedersen C, Rasmussen BS. Bystander efforts and 1-year out-
Horn J, Nolan JP, Rossetti AO, Soar J. Prognostication in comatose survivors of .. comes in out-of-hospital cardiac arrest. N Engl J Med 2017;376:1737–1747.
cardiac arrest: an advisory statement from the European Resuscitation Council .. 20. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA,
and the European Society of Intensive Care Medicine. Resuscitation 2014;85: .. Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM,
1779–1789. .. Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-
7. Adrie C, Cariou A, Mourvillier B, Laurent I, Dabbane H, Hantala F, Rhaoui A,
..
.. Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs
Thuong M, Monchi M. Predicting survival with good neurological recovery at .. AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA,
hospital admission after successful resuscitation of out-of-hospital cardiac arrest: .. Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW;
the OHCA score. Eur Heart J 2006;27:2840–2845. .. American College of Cardiology Foundation/American Heart Association Task
8. Maupain C, Bougouin W, Lamhaut L, Deye N, Diehl JL, Geri G, Perier MC, .. Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of
Beganton F, Marijon E, Jouven X, Cariou A, Dumas F. The CAHP (Cardiac .. ST-elevation myocardial infarction: a report of the American College of
Arrest Hospital Prognosis) score: a tool for risk stratification after out-of-
.. Cardiology Foundation/American Heart Association Task Force on Practice
..
hospital cardiac arrest. Eur Heart J 2016;37:3222–3228. .. Guidelines. Circulation 2013;127:e362–e425.
9. Martinell L, Nielsen N, Herlitz J, Karlsson T, Horn J, Wise MP, Unden J, Rylander .. 21. Petrie J, Easton S, Naik V, Lockie C, Brett SJ, Stumpfle R. Hospital costs of out-
C. Early predictors of poor outcome after out-of-hospital cardiac arrest. Crit .. of-hospital cardiac arrest patients treated in intensive care; a single centre evalu-
Care 2017;21:96. . ation using the national tariff-based system. BMJ Open 2015;5:e005797.
4517a N. Pareek et al.

22. Lemkes JS, Janssens GN, van der Hoeven NW, Jewbali LSD, Dubois EA, .. Lall R; PARAMEDIC2 Collaborators. A randomized trial of epinephrine in out-
Meuwissen M, Rijpstra TA, Bosker HA, Blans MJ, Bleeker GB, Baak R,
.. of-hospital cardiac arrest. N Engl J Med 2018;379:711–721.
Vlachojannis GJ, Eikemans BJW, van der Harst P, van der Horst ICC, Voskuil M,
..
.. 28. Panchal AR, Berg KM, Hirsch KG, Kudenchuk PJ, Del Rios M, Cabanas JG, Link
van der Heijden JJ, Beishuizen A, Stoel M, Camaro C, van der Hoeven H, .. MS, Kurz MC, Chan PS, Morley PT, Hazinski MF, Donnino MW. 2019 American
Henriques JP, Vlaar APJ, Vink MA, van den Bogaard B, Heestermans T, de Ruijter .. Heart Association focused update on advanced cardiovascular life support: use
W, Delnoij TSR, Crijns H, Jessurun GAJ, Oemrawsingh PV, Gosselink MTM, .. of advanced airways, vasopressors, and extracorporeal cardiopulmonary resusci-
Plomp K, Magro M, Elbers PWG, van de Ven PM, Oudemans-van Straaten HM, .. tation during cardiac arrest: an update to the American Heart Association
van Royen N. Coronary angiography after cardiac arrest without ST-segment ..
elevation. N Engl J Med 2019;380:1397–1407. .. Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular

23. Nerla R, Webb I, MacCarthy P. Out-of-hospital cardiac arrest: contemporary

.. Care. Circulation 2019;140:e881–e894.
.. 29. Soar J, Nolan JP, Böttiger BW, Perkins GD, Lott C, Carli P, Pellis T, Sandroni C,
management and future perspectives. Heart 2015;101:1505–1516. .. Skrifvars MB, Smith GB, Sunde K, Deakin CD, Koster RW, Monsieurs KG,
24. Gallagher EJ, Lombardi G, Gennis P. Effectiveness of bystander cardiopulmonary .. Nikolaou NI; Adult Advanced Life Support Section Collaborators. European
resuscitation and survival following out-of-hospital cardiac arrest. JAMA 1995; ..
274:1922–1925. .. Resuscitation Council guidelines for resuscitation 2015: section 3. Adult
25. Kitamura T, Kiyohara K, Sakai T, Matsuyama T, Hatakeyama T, Shimamoto T, .. advanced life support. Resuscitation 2015;95:100–147.
Izawa J, Fujii T, Nishiyama C, Kawamura T, Iwami T. Public-access defibrillation .. 30. Javaudin F, Leclere B, Segard J, Le Bastard Q, Pes P, Penverne Y, Le Conte P,
.. Jenvrin J, Hubert H, Escutnaire J, Batard E, Montassier E; Gr-ReAC. Prognostic

Downloaded from https://academic.oup.com/eurheartj/article/41/47/4508/5878044 by guest on 16 August 2021

and out-of-hospital cardiac arrest in Japan. N Engl J Med 2016;375:1649–1659.
.. performance of early absence of pupillary light reaction after recovery of out of
26. Weisfeldt ML, Sitlani CM, Ornato JP, Rea T, Aufderheide TP, Davis D, Dreyer J, .. hospital cardiac arrest. Resuscitation 2018;127:8–13.
Hess EP, Jui J, Maloney J, Sopko G, Powell J, Nichol G, Morrison LJ; ROC ..
Investigators. Survival after application of automatic external defibrillators before .. 31. Conrad SA, Rycus PT. Extracorporeal membrane oxygenation for refractory car-
arrival of the emergency medical system: evaluation in the resuscitation outcomes .. diac arrest. Ann Card Anaesth 2017;20:S4–S10.
consortium population of 21 million. J Am Coll Cardiol 2010;55:1713–1720. .. 32. Corrada E, Mennuni MG, Grieco N, Sesana G, Beretta G, Presbitero P.
27. Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, .. Neurological recovery after out-of-hospital cardiac arrest: hospital admission
Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L,
.. predictors and one-year survival in an urban cardiac network experience.
Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S,
.. Minerva Cardioangiol 2013;61:451–460.

Editor’s Note doi:10.1093/eurheartj/ehaa166

Online publish-ahead-of-print 13 March 2020
....................................................................................................................................................
Relates to: ‘Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to pre-
vent coronary heart disease : Consensus Statement of the European Atherosclerosis Society ’ (https://doi.org/10.1093/eurheartj/eht273)

The Editors and authors wish to acknowledge that the information presented in Figure 1 about Switzerland has been cast
into doubt as it has not been formally published in a data set but communicated verbally by an officer of the WHO to
the senior author. Therefore, please also consider the data published by Miserez et al. (Miserez AR, Martin FJ, Spirk D.
Diagnosis and Management Of familial hypercholesterolemia in a Nationwide Design (DIAMOND-FH): Prevalence in
Switzerland, clinical characteristics and the diagnostic value of clinical scores. Atherosclerosis. 2018 Oct;277:282-288. doi:
10.1016/j.atherosclerosis.2018.08.009.)

C The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
V

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com