British Journal of Anaesthesia 107 (6): 879–90 (2011)

Advance Access publication 2 September 2011 . doi:10.1093/bja/aer268

Incidence and predictors of major perioperative adverse

cardiac and cerebrovascular events in non-cardiac surgery
S. Sabaté 1*, A. Mases 2, N. Guilera 3, J. Canet 4, J. Castillo 5, C. Orrego 6, A. Sabaté 7, G. Fita 8, F. Parramón 10,
P. Paniagua 11, A. Rodrı́guez 3 and M. Sabaté 9, on behalf of the ANESCARDIOCAT Group†
1
Department of Anaesthesiology, Fundació Puigvert (IUNA), Carrer Cartagena 340, 08025 Barcelona, Spain
2
Department of Anaesthesiology, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
3
Department of Anaesthesiology, Hospital de Sabadell, Sabadell, Spain
4
Department of Anaesthesiology, Hospital Germans Trias i Pujol, Badalona, Spain
5
Department of Anaesthesiology, Hospital de l’Esperança, Parc de Salut Mar, Barcelona, Spain
6
Avedis Donabedian Institute, Autonomous University of Barcelona, and CIBER Epidemiology and Public Health (CIBERESP),
Barcelona, Spain
7
Department of Anaesthesiology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain
8
Department of Anaesthesiology and 9 Department of Cardiology, Hospital Clinic, Barcelona, Spain
10
Department of Anaesthesiology, Hospital Universitari Josep Trueta, Girona, Spain
11
Department of Anaesthesiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

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* Corresponding author. E-mail: 29285sst@comb.cat

Editor’s key points
† Outcome of over 3000
patients undergoing
anaesthesia and surgery
was studied
prospectively.
† The incidence of at least
one major cardiovascular
or cerebrovascular
incident was 4.3%.
† The risk factors included
the presence of coronary
artery disease, heart
failure, kidney disease,
cerebrovascular disease,
abnormal ECG,
intraoperative
hypotension, and blood
transfusion.
† This large study presents
important data on risk
factors in patients
undergoing non-cardiac
surgery.
Background. Major adverse cardiac and cerebrovascular events (MACCE) represent the most
common cause of serious perioperative morbidity and mortality. Our aim was to identify risk
factors for MACCE in a broad surgical population with intermediate-to-high surgery-specific
risk and to build and validate a model to predict the risk of MACCE.
Methods. A prospective, multicentre study of patients undergoing surgical procedures
under general or regional anaesthesia in 23 hospitals. The main outcome was the
occurrence of at least one perioperative MACCE, defined as any of the following
complications from admittance to discharge: cardiac death, cerebrovascular death, non-
fatal cardiac arrest, acute myocardial infarction, congestive heart failure, new cardiac
arrhythmia, angina, or stroke. The MACCE predictive index was based on b-coefficients
and validated in an external data set.
Results. Of 3387 patients recruited, 146 (4.3%) developed at least one MACCE. The
regression model identified seven independent risk factors for MACCE: history of coronary
artery disease, history of chronic congestive heart failure, chronic kidney disease, history
of cerebrovascular disease, preoperative abnormal ECG, intraoperative hypotension, and
blood transfusion. The area under the receiver-operating characteristic curve was 75.9%
(95% confidence interval, 71.2 –80.6%).
Conclusions. The risk score based on seven objective and easily assessed factors can
accurately predict MACCE occurrence after non-cardiac surgery in a population at
intermediate-to-high surgery-specific risk.
Keywords: cerebrovascular disorders/complications; cohort studies; heart diseases/
complications; operative statistics and numerical data; postoperative complications;
prospective studies; risk assessment; risk factors; safety management
Accepted for publication: 2 June 2011

Major adverse cardiac and cerebrovascular events (MACCE) after
non-cardiac surgery, although infrequent, are life-threatening.
They represent the most common cause of serious periopera-
tive morbidity and mortality, with reported incidence rates
ranging between 1% and 7%, depending on which population
was studied.1 – 8 Most MACCE-related deaths after major
surgery arise from cardiovascular complications such as myo-
cardial ischaemia or infarction, arrhythmias, and stroke.6 7 In
Europe, the incidences of postoperative myocardial infarction
and cardiovascular mortality have been estimated to be 1%
and 0.3%, respectively.9 These rates have remained stable in
recent years.9 10

†
The ANESCARDIOCAT investigators are listed in the Appendix.

& The Author [2011]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com
BJA Sabaté et al.

The incidence of coronary disease in European Mediterra-
nean countries is relatively low, despite the high prevalence
of cardiovascular risk factors.11 12 In a study of one northeast-
ern Spanish region, myocardial infarction occurred in 349/
100 000 men and 109/100 000 women aged 35–74 yr,12 and
this event was found to be the leading cause of death in
men and the third-leading cause in women in the same area
in another study.13 Given the prevalence of cardiovascular
disease in our setting, we considered that a population-based
study of the occurrence of perioperative MACCE could help
identify relevant risk factors. This study therefore aimed to
determine the incidence of MACCE in a broad surgical popu-
lation undergoing non-cardiac surgery, to identify periopera-
tive variables that might indicate risk, and to build and
validate a model to predict the risk of cardiovascular events.
Methods
Recruitment took place during 6 weeks between October
2007 and June 2008, with data collection occurring in all hos-
pitals simultaneously. The weeks were randomly selected by a
computer, subject to a single constraint, that a minimum inter-
val of 30 days should occur between two sampling weeks.
Participants
We recruited all middle-aged to elderly patients (≥40 yr of
age) undergoing scheduled or emergency non-cardiac oper-
ations of intermediate-to-high surgery-specific risk according
to the guidelines of the American College of Cardiology (ACC)
and American Heart Association (AHA).3
All enrolled patients received general or spinal–epidural
anaesthesia, and in all cases, the hospital stay for reasons
related to surgery was expected to be longer than 24
h. Local teams regularly and assiduously checked records
to ensure the completeness of data collection daily, starting
from admission. Exclusion criteria were (i) age ,40 yr, (ii)

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The ANESCARDIOCAT study was a prospective, multicentre
cohort study in patients undergoing non-cardiac surgery invol-
ving intermediate-to-high surgery-specific risk3 under general
or regional anaesthesia. The study was approved by the
research ethics committee of Hospital Germans Trias i Pujol
(approval reference number EO-07-027) on behalf of all
centres and was conducted in accordance with the Declaration
of Helsinki. Signed patient consent was waived, because no care
interventions were mandated and no protected health infor-
mation was collected. Interventions other than routine care
were not carried out. The investigators—all anaesthetists—
did not modify a centre’s customary management of patients.
Twenty-three hospitals in Catalonia, Spain, participated.
These centres perform over 40% of all in-hospital anaesthetic
procedures that could fulfil the inclusion criteria in the area,
according to the ANESCAT survey of workload in 2003.14
childbirth or any obstetrical procedure related to pregnancy,
(iii) exclusive use of local or peripheral nerve anaesthesia, (iv)
procedures outside the operating theatre, (v) surgical pro-
cedures related to a previous postoperative complication,
and (vi) ambulatory surgery.
Variables and data collection
The occurrence of an intra- or postoperative MACCE was the
main outcome. Definitions of MACCE are shown in Table 1; a
MACCE was recorded if any of these complications were
present from admission to the operating theatre to discharge
from hospital. To find events that fulfilled any MACCE defi-
nition, patients with postoperative complications were ident-
ified by consulting medical records in real time while they
were developing.

Table 1 Definitions of MACCE

MACCE
Non-fatal cardiac arrest
Acute myocardial infarction15
Congestive heart failure
New cardiac arrhythmia
Angina
Stroke
Cardiovascular death
Cerebrovascular death
Definition
An absence of cardiac rhythm or presence of chaotic rhythm requiring any component of basic or
advanced cardiac life support
Increase and gradual decrease in troponin level16 or a faster increase and decrease of creatine kinase
isoenzyme as markers of myocardial necrosis in the company of at least one of the following: ischaemic
symptoms, abnormal Q waves on the ECG, ST-segment elevation or depression; or coronary artery
intervention (e.g. coronary angioplasty) or a typical decrease in an elevated troponin level detected at its
peak after surgery in a patient without a documented alternative explanation for the troponin elevation17
New in-hospital signs or symptoms of dyspnoea or fatigue, orthopnoea, paroxysmal nocturnal dyspnoea,
increased jugular venous pressure, pulmonary rales on physical examination, cardiomegaly, or
pulmonary vascular engorgement
ECG evidence of atrial flutter, atrial fibrillation, or second- or third-degree atrioventricular conduction
block
Dull diffuse substernal chest discomfort precipitated by exertion or emotion and relieved by rest or
nitroglycerin
Embolic, thrombotic, or haemorrhagic event lasting at least 30 min with or without persistent residual
motor, sensory, or cognitive dysfunction; if the neurological symptoms continue for .24 h, a person is
diagnosed with stroke, and if lasting ,24 h the event is defined as a transient ischaemic attack18
Any death, unless an unequivocal non-cardiovascular cause could be established16
A death caused by cerebrovascular disease

880
Cardiovascular events risk index
Potential risk factors were chosen based on the investi-
gators’ consensus on measurable preoperative variables,
and the results of previous studies.1 2 4 – 10 Candidate
factors included any active cardiac condition3 (unstable cor-
onary syndromes, decompensated heart failure, significant
arrhythmias, severe valvular disease), clinical risk factors
(history of coronary artery disease, congestive heart failure,
cerebrovascular disease, chronic kidney disease, diabetes
mellitus), minor predictors [age .70 yr, abnormal ECG3
(left ventricular hypertrophy, left bundle-branch block, ST-T
abnormalities), rhythm other than sinus, and hypertension],
and other perioperative variables (Supplementary Table S1).
Preoperative information was obtained by a member of
the local research team from the preoperative clinic visit
(Appendix); all members were trained to fill in a structured
questionnaire (Supplementary Table S1). These researchers
also reviewed all charts of enrolled patients daily until dis-
charge. The treatment of any abnormal findings was left to
the judgement of the attending physician in keeping with
protocols in use at each centre. The surgical procedures
included are listed in Supplementary Table S2. A centralized
database and applications for remote data recording were
developed in a secure protocol with quality-control algo-
rithms to validate online data entry.
Bias and limitation
A potential limitation inherent to the multicentre design
involving the participation of a large number of anaesthetists
in 23 teaching hospitals could have caused defects in data
collection. To prevent variability in patient selection or data
collection, we trained all participants to uniformly apply cri-
teria and record data, especially regarding the definitions
of the outcome and the major medical conditions.
Sample size
A pilot study in 185 patients showed a 5.6% incidence of car-
diovascular events, in accordance with previous studies.19 In
the ANESCAT study,14 the 23 participating centres were
jointly able to include over 3000 patients in 6 weeks and
report more than 100 cardiovascular events. A sample size
of at least 3000 patients was considered large enough to
be able to construct a logistic regression model with at
least 10 cardiovascular events per predictor;20 the resultant
model would then be validated in an external data set
from a similar population-based study carried out in the
same geographic area.19 If the sample proved to be insuffi-
cient for entering more predictor candidates in the logistic
regression model, a resampling method would be used to
verify the robustness of the model (see details below).
Statistical analyses
Potential risk factors were evaluated for unadjusted bivariate
association with MACCE occurrence based on the t-test (con-
tinuous variables) or the Fisher exact test or x 2 test (categori-
cal variables). Bivariate odds ratios (ORs) and 95%
confidence intervals (CIs) were also calculated. In order to
BJA
assess collinearity between categorical variables, the
relationships were tested with the Cramer V test (between
nominal variables) and Kendall’s t b-coefficient (between
ordinal variables).
The logistic regression model was constructed using a
backward stepwise selection procedure in which the pres-
ence of a MACCE was the dependent variable. Independent
variables were selected for the model on the basis of bivari-
ate analysis (P,0.05) and collinearity between variables (cor-
relation coefficients ,0.25). At each step, the likelihood ratio
was used to evaluate a potential risk factor. The cut-off for
variable removal was set at a significance level of 0.05. We
then calculated the adjusted OR and corresponding 95%
CI. The calibration of the logistic regression model was
assessed by the Hosmer–Lemeshow goodness-of-fit statistic.
If we had fewer than 10 cardiovascular events per predic-
tor as candidates for entry into regression analysis, our plan
was to use a bootstrap method for internal validation of the
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subset of factors.21 A total of 1000 computer-generated
samples, each including the total study sample less one
patient, would be derived by random selection with replace-
ment. Within each bootstrap sample, the b-coefficient would
be calculated using all selected independent variables. The
robustness of the model and, thus, the reliability of predictor
variables in the final regression model would be estimated by
the 80% CI of the b-coefficient in the bootstrap samples.
Reliable predictors were expected to be retained if the 80%
CI of bootstrap samples indicated statistical significance
(P,0.05). To assess the discriminative performance of the
model and its predictive ability, we would use the c-statistic
expressed as a percentage [area under the receiver-
operating characteristic curve (AUC)].
A simplified risk score was obtained by rounding off the
logistic regression b-coefficient. The simplified scores were
added together to produce an overall MACCE risk score for
each patient. Based on that score, we divided that subsample
into four groups, each containing a similar number of
patients with MACCE (using a method based on the
minimum description length principle22 supervised by the
outcome). The resulting groups reflected very low (0 risk
factors), low (1 risk factor), intermediate (2 risk factors),
and high risk (3 or more risk factors) for MACCE.
The model was retested in an external data set, from the
ARISCAT study,19 of a similar spectrum of 2464 surgical
patients who underwent in-hospital surgical procedures in
the same geographic area in 2006. The ARISCAT main objec-
tive was finding predictors for postoperative pulmonary com-
plications. Compiled in 59 hospitals, 23 of which also
participated in the current study, ARISCAT offered a con-
venient comparable sample in which to validate the
present study’s model for predicting MACCE.
c-statistics (expressed as AUCs) were also used to assess
the ability of the revised cardiac risk index of Lee and col-
leagues7 to predict MACCE in both our data set and the
ARISCAT data set.
Statistical analyses were performed using PASW 18 soft-
ware (SPSS Inc., Chicago, IL, USA), with the exception of
881
BJA Sabaté et al.

the AUC calculations and comparisons, for which we used
Medcalc software (version 11.1.0.0, Medcalc, Mariakerke,
Belgium).
Results
From a total of 3519 surgical patients recruited, 132 were lost
to follow-up for outcome. Thus, data for 3387 patients
entered the analysis as shown in the flowchart (Fig. 1).
Patient and procedure characteristics are given in Table 2.
At least one MACCE was recorded for 146 patients (4.3%).
Postoperative arrhythmia or atrioventricular block developed
in 51 (1.5%), congestive heart failure in 39 (1.2%), angina in
23 (0.7%), stroke in 15 (0.4%), myocardial infarction in 11
(0.3%), and non-fatal cardiac arrest in 7 (0.2%). Twenty
(13.7% of the patients with such complications) died from
a cardiac (15) or cerebrovascular (five) cause. The most fre-
quent postoperative arrhythmia was atrial fibrillation (31) fol-
percentage (41.9%), followed by respiratory failure (23.3%)
and multiorgan failure (13.9%).
The median (10th – 90th percentile) postoperative
length of stay was longer in patients with a MACCE [12
days (4.7–35.3 days)] than in those without a MACCE
[6 days (2–15 days)].
In Table 4, we show the results of bivariate analysis for 23
independent variables that were included in logistic
regression. Four additional significant variables (ASA physical
status classification, revised cardiac risk index, previous
cardiac intervention, and number of units of red blood cells
transfused) are shown in the same table, although they
were rejected as candidates for the model due to high
collinearity (correlation coefficient .0.250) with other vari-
ables (history of coronary disease, congestive heart failure,
and red blood cell transfusion or not). BMI, emergency
surgery, chronic obstructive pulmonary disease, laparoscopic
approach, and type of anaesthesia were unrelated (P≥0.05)

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lowed by atrioventricular conduction block (nine patients,
three of them requiring a pacemaker) and tachyarrhythmia
(six patients: four supraventricular tachycardia and two
atrial flutters). Table 3 shows the in-hospital mortality, inten-
sive care unit admission rate, and postoperative lengths of
stay for each MACCE. The majority of MACCE took place on
the ward (53.4%), but 27.4% occurred in the postoperative
recovery unit and 19.2% in the operating theatre. Thoracic
surgery had the highest incidence of MACCE (8.3%), followed
by vascular surgery (7.5%) and neurosurgery (6.0%). Fewer
MACCE occurred in orthopaedic (3.2%), ear–nose –throat
(1.5%), and gynaecology (1.4%) operations.
Forty-three patients died from non-cardiovascular compli-
cations. Septic shock was responsible for the largest
to the presence of a MACCE (Supplementary Table S3).
Multivariable logistic regression selected seven predictors
of MACCE: history of coronary artery disease, history of
congestive heart failure, chronic kidney disease, history of
cerebrovascular disease, intraoperative hypotension, ECG
abnormalities, and red blood cell transfusion. The bootstrap-
ping technique (1000 subsamples of 3386 cases) to validate
the model internally retained all seven predictors in more
than 80% of bootstrap subsamples. Table 5 shows the
raw and adjusted ORs for variables that were selected for
the model, along with the 80% CI for each OR after
bootstrapping.
The c-statistics indicated acceptable AUC percentages for
a model incorporating the b-coefficients of predictors from

Surgical population available for enrolment 3519

(intermediate-to-high surgery-specific risk of non-cardiac interventions)

Excluded for missing data 7 (0.2%)

(lack of intervention date, outcome, demographic
information, clinical history)

Eligible patients 3512 (99.8%)

Patients lost to follow-up for outcome 125 (3.6%)

(lack of discharge date, more than 10 missing
data per case, inconsistencies within variables)

Participants 3387 (96.2%)

Fig 1 Recruitment flowchart.

882
Cardiovascular events risk index BJA
In Supplementary Table S4, we show the sensitivity, speci-
Table 2 Patient and clinical characteristics. ENT, ear– nose – ficity, and positive-likelihood ratio (PLR) and negative-
throat surgery
likelihood ratio (NLR) for every risk level in the simplified
Gender, male [n (%)] 1637 (48.3) risk index.
Age [yr, median (10th –90th 67 (47 –81) When we assessed the predictive ability of the revised
percentile)] cardiac risk index to predict the development of an MACCE
BMI [kg m22 (10th –90th percentile)] 27.2 (22.2 –33.9) in our sample and ARISCAT data set, the AUCs were 65.2%
ASA physical status [n (%)] (95% CI, 60.1 –70.3%) and 64.0% (95% CI, 57.9–70.1%),
I 265 (7.8) respectively (see Supplementary Fig. S2 for the receiver-
II 1878 (55.4) operating characteristic curves).
III 1104 (32.6) On observing that atrial fibrillation accounted for a high
IV 140 (4.2) percentage of postoperative complications and that thoracic
Emergency surgery [n (%)] 242 (7.1) surgery, which is associated with atrial fibrillation,23 24 was
Preoperative haemoglobin [g dl21 13.5 (10.9 –15.5) associated with the highest incidence of MACCE, we
(10th – 90th percentile)] decided to perform additional post hoc sensitivity analyses
Surgical risk [n (%)] to further access the robustness of the risk pattern revealed
Intermediate 3211 (94.8) by the regression model. For the first analysis, we removed
High 176 (5.2) cases with atrial fibrillation from the data set, for the

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Type of anaesthesia [n (%)] second analysis patients who underwent thoracic surgery,
General 1656 (48.9) and for the third, both patients with atrial fibrillation and
Neuroaxial blockade 1274 (37.6) those who underwent thoracic surgery were removed. The
Combined (general+neuraxial 423 (12.5) model had similar ability to discriminate risk for developing
blockade) MACCE in all three data sets: the AUCs were 77.0% (95%
Plexus block+general 34 (1.0) CI, 71.8 –82.3%), 77.3% (95% CI, 42.5–82.1%), and 78.2%
Duration of surgery [min, median 120 (60 –248) (95% CI, 73.0– 83.4%), respectively (see Supplementary
(10th – 90th percentile)]
Table S5 and Fig. S3 for differences between models).
Surgical speciality [n (%)]
Orthopaedics 1152 (34.0)
General and digestive 968 (28.6) Discussion
Urology 400 (11.8)
The 4.3% incidence of MACCE we observed in a representa-
Gynaecology 276 (8.2)
tive non-cardiac surgical population fell within the range of
Vascular 213 (6.3)
1–7% reported in the literature.1 – 8 One out of 10 patients
Thoracic 141 (4.2)
who developed a MACCE died during the hospital stay.
Neurosurgery 133 (3.9)
Seven preoperative and intraoperative variables provided a
ENT 68 (2.0)
risk profile with a high degree of discrimination (c-statistic,
Maxillofacial 35 (1.0)
0.767). Four of the risk factors—history of coronary artery
Revised cardiac risk index7
disease, history of congestive heart failure, chronic kidney
I 2553 (75.4)
disease, and history of cerebrovascular disease—have been
II 607 (17.9)
described previously.7 In addition, our model included intra-
III 155 (4.6)
operative hypotension, ECG abnormalities (left ventricular
IV 72 (2.1)
hypertrophy, left bundle branch block, ST-T abnormalities),
and red blood cell transfusion as risk factors for MACCE. We
were unable to confirm the relevance of two revised
cardiac risk index predictors:7 insulin-dependent diabetes
Table 5. The AUC for the curve constructed for the simplified mellitus and high-risk surgery. Our finding for surgery-
score (sum of rounded b-coefficients) was 75.9% (95% CI, specific risk is consistent with the recent study of Kheterpal
71.2 –80.6%), and the seven-variable regression model had and colleagues,2 who were also unable to demonstrate high-
good calibration (Hosmer– Lemeshow x 2 ¼0.828; P¼0.844). risk surgery as a predictor for MACCE, in contrast to earlier
When we further tested the simplified score by validating studies.1 6 – 8 Our definition of major vascular surgery as high-
the model externally using the similarly constituted risk according to the latest version of the joint guidelines of
ARISCAT data set,15 there was good discrimination, with a the American College of Cardiology and the American
percentage AUC of 75.6% (95% CI, 70.8–80.5%) (Supplemen- Heart Association3 could explain the discrepancy between
tary Fig. S1). our findings and previous studies. The 2007 guidelines do
When the ANESCARDIOCAT sample was stratified into four not include anticipated prolonged surgical procedures other
groups by risk (very low, low, intermediate, and high), there than vascular surgery; nor do they include procedures associ-
was a significant increase in both incidence of MACCE and ated with large fluid compartmental shifts and/or blood loss,
postoperative length of stay between all risk strata (Fig. 2). both of which were mentioned in the earlier version.25

883
BJA Sabaté et al.

Table 3 Associated in-hospital mortality, ICU admission rate, and postoperative length of stay according to the development of MACCE. ICU,
intensive care unit; MACCE, major adverse cardiac and cerebrovascular events; PLoS, postoperative length of stay

MACCE Number of In-hospital Cardiac or Other cause ICU admission PLoS (days) [median
patients mortality [n (%)] cerebrovascular cause [n (%)] rate [n (%)] (10th –90th percentile)]
[n (%)]
None 3241 34 (1.1) 0 (0) 34 (100) 64 (2.0) 6.0 (2.0– 15.0)
Non-fatal cardiac arrest 7 3 (42.9) 3 (100) 0 (0) 6 (85.7) 13.0 (7.0– 34.0)
Acute myocardial 11 3 (27.3) 3 (100) 0 (0) 7 (63.6) 7.0 (1.2– 17.8)
infarction
Stroke 15 5 (33.3) 5 (100) 0 (0) 5 (33.3) 18.0 (4.8– 57.8)
Angina 23 1 (4.3) 0 (0) 1 (100) 0 (0) 11.0 (5.0– 38.4)
Congestive heart failure 39 8 (20.5) 8 (100) 0 (0) 10 (25.6) 14.0 (7.0– 35.0)
A-V block and other 20 4 (20.0) 1 (25) 3 (75) 6 (30.0) 12.5 (4.3– 65.4)
dysrhythmias
Atrial fibrillation 31 5 (16.1) 0 5 (100) 9 (29.0) 10.0 (2.2– 33.8)
Total 3387 63 (1.9) 20 (31.7) 43 (68.3) 107 (3.2) 6.0 (2.0– 16.0)

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Finally, our results in this respect are consistent with those of
Ackland and colleagues26 and similar to those of a recent
systematic review.27 Regarding insulin-dependent diabetes
mellitus, this condition may not have been identified as a
predictor for MACCE in our study because end-organ compli-
cations of diabetes mellitus could have had more weight
than diabetes itself in the model.
The simplified risk score we built remains well associated
with MACCE occurrence (Fig. 2). Testing the model in the
external ARISCAT19 data set also supported its stable predic-
tive ability. That data set included a similar but slightly
younger spectrum of patients, yet the ANESCARDIOCAT
model remained predictive, suggesting it to be valid even
in populations with apparently lower cardiovascular risk.
When we compared the predictive ability of the ANESCAR-
DIOCAT index to the ability of the revised cardiac risk index
of Lee and colleagues7 of 1999, both proved useful, but our
score predicted more actual events in both data sets. The
lower performance of the older index may arise from the
fact that the definition of high surgery-specific risk has
changed during the past decade, during which some pro-
cedures have become less invasive and interventions have
been introduced to reduce risk by preparing high-risk
patients for non-cardiac surgery. The ANESCARDIOCAT
index takes into account two intraoperative variables (hypo-
tension and blood transfusion) that were not considered by
the revised cardiac risk index and that according to our
results may influence outcome, supporting the clinical use
of the index we propose. Nor did Lee and colleagues count
stroke and atrial fibrillation as adverse cardiovascular
events, yet we found these factors to confer risk.
The ANESCARDIOCAT study, the largest multicentre cohort
study on risk for MACCE to date, was designed to overcome
some of the limitations of previous studies. We collected data
from a representative random sample of surgical patients
undergoing a broad spectrum of operations involving
intermediate-to-high surgery-specific risk. To prevent
discrepancies in applying criteria, a structured, focused
questionnaire guided data collection from patient charts and
previous training was provided. Variables were chosen for
their clinical relevance and the likelihood that they would
define risk for MACCE.
A limitation of our study is that we excluded procedures of
low surgery-specific risk such as common orthopaedic,
gynaecologic, and ear– nose–throat procedures. We did not
record complications during outpatient follow-up; therefore,
we potentially underestimated long-term complications. Fur-
thermore, our study protocol did not include the monitoring
of surveillance biomarkers and ECGs, so clinically silent
ischaemic events which are known to confer increased long-
term mortality and morbidity risk28 would not have been
detected. Another limitation of our study was that the
sample size was not large enough to adequately develop a
multivariable regression model in which 23 predictors were
entered (23 variables in relation to 146 outcomes). As we
anticipated that this might be the case based on the
ARISCAT experience,19 we planned to resample the data set
using a bootstrapping technique. The purpose was to avoid
overfitting and to estimate the stability of the data set.
This procedure confirmed that the seven variables initially
identified by multivariable regression could be retained in
the model.
The ACC/AHA guidelines note that preoperative ECG abnorm-
alities may predict postoperative cardiac events or death in
high-risk surgery,29 yet this factor has not always been found
to improve the predictive value of a model.30 Our model,
however, does include ECG abnormalities as one of the seven
predictors of MACCE (OR, 2.9), probably related to the fact that
arrhythmia or atrioventricular block accounted for 43% of all
MACCE in our study. These events may point to previous ECG
abnormalities, which, if found in the preoperative setting,
should lead to a search for underlying cardiopulmonary
disease, ongoing myocardial ischaemia or infarction, drug tox-
icity, or metabolic derangements.31 – 33 In particular, among the

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Cardiovascular events risk index BJA

Table 4 Bivariate analysis for independent predictors of major adverse cardiac and cerebrovascular events (MACCE). *One or more of the
following: unstable coronary syndromes, decompensated heart failure, significant arrhythmias, severe valvular disease (according to the
American College of Cardiology/American Heart Association guidelines).3 †These significant variables were rejected as candidates for the model
due to high collinearity with the following variables: history of coronary disease, congestive heart failure, and red blood cell transfusion or not.
CABG, coronary artery bypass graft surgery; MET, metabolic equivalent of a task; PCI, percutaneous coronary intervention; RBC, red blood cell

Total number of patients Number of patients with MACCE (%) P-value

Total 3387 146 (4.3)
Variables entered into the multiple regression model
Gender
Male 1637 83 (5.1) 0.042
Female 1750 63 (3.6)
Advance age (.70 yr)
No 2011 61 (3.0) 0.00001
Yes 1376 85 (6.2)
Surgical risk
Intermediate 3211 132 (4.1) 0.021
High 176 14 (8.0)

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Active cardiac condition*
No 3271 130 (4.0) ,0.0001
Yes 116 16 (13.8)
History of coronary artery disease
No 3098 110 (3.6) ,0.0001
Yes 289 36 (12.5)
History of congestive heart failure
No 3165 115 (3.6) ,0.0001
Yes 222 31 (14.0)
History of cerebrovascular disease
No 3165 121 (3.8) ,0.0001
Yes 222 25 (11.3)
Diabetes mellitus
No 2794 108 (3.9) 0.010
Oral medication or diet 429 22 (5.1)
On insulin 164 16 (9.8)
Chronic kidney disease
No 3148 114 (3.6) ,0.0001
Yes 227 31 (13.7)
Abnormal ECG (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities)3
No 2752 83 (3.0) ,0.0001
Yes 467 48 (10.3)
Arrhythmia (other than sinus rhythm)
No 3175 118 (3.7) ,0.0001
Yes 211 28 (13.3)
Vascular peripheral disease
No 3159 123 (3.9) ,0.0001
Yes 228 23 (10.1)
Hypertension
No 1780 50 (2.8) ,0.0001
Yes 1607 96 (6.0)
Hyperlipidaemia
No 2527 96 (3.8) 0.015
Yes 860 50 (5.8)

Continued

885
BJA Sabaté et al.

Table 4 Continued

Total number of patients Number of patients with MACCE (%) P-value

Smoking status
Never smoker 2160 88 (4.1) 0.005
Current smoker 524 14 (2.7)
Former smoker 696 44 (6.3)
Functional capacity (METs)
≥4 1944 61 (3.1) ,0.0001
,4 or unknown 428 34 (7.9)
Not reported 1015 51 (5.0)
Anaemia (,12 g dl21 in females; ,13 g dl21 in males)
No 2515 84 (3.3) ,0.0001
Yes 825 62 (7.5)
Liver disease
No 3277 134 (4.1) 0.001
Yes 102 12 (11.8)

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Duration of surgery (h)
,2 1659 50 (3.0) 0.0003
2 –3 1043 49 (4.7)
.3 651 44 (6.8)
Intraoperative hypotension
No 3074 111 (3.6) ,0.0001
Yes 313 35 (11.2)
Intraoperative tachycardia
No 3281 125 (3.8) ,0.0001
Yes 106 21 (19.8)
Intraoperative bradycardia
No 3239 130 (4.0) 0.001
Yes 148 16 (10.8)
RBC transfusion
No 2774 82 (3.0) ,0.0001
Yes 613 64 (10.4)
Significant variables not entered into the multiple regression model due to high collinearity (correlation coefficients .0.25)†
ASA
I 265 2 (0.8) ,0.0001
II 1878 44 (2.3)
III 1104 78 (7.1)
IV 140 22 (15.7)
Revised cardiac risk index7
I 2553 72 (2.8) ,0.0001
II 607 37 (6.1)
III 155 22 (14.2)
IV 72 15 (20.8)
Previous cardiac intervention (PCI, CABG, or both)
No 3299 133 (4.0) ,0.0001
Yes 82 13 (15.9)
Number of RBC units
0 2774 82 (3.0) ,0.0001
1 –2 398 31 (7.8)
≥3 215 33 (15.3)

new cardiac arrhythmias constituting a MACCE, we included mortality,34 35 consistent with our findings (Table 3). The good
atrial fibrillation, which is associated with a higher rate of inten- performance of the regression model in the data set excluding
sive care unit admission, longer hospital stay, and greater patients with atrial fibrillation supports the appropriateness of

886
Cardiovascular events risk index BJA

Table 5 Risk for MACCE corresponding to each of the variables selected for the logistic regression model. *Logistic regression model
(c-index¼0.759; Hosmer – Lemeshow x 2 ¼0.828; P¼0.844). OR, odds ratio; CI, confidence interval; RBC, red blood cell. See Table 4 for variables
not entered into the final model. Because of a missing value in some variables, data for 251 (7.4%) patients were excluded from the model. †The
simplified risk score was obtained by rounding off the b-logistic regression coefficient

Bivariate analysis Multivariable analysis* Bootstrap resampling b-coefficients Risk score†

[OR (95% CI)], [OR (95% CI)], (1000 bootstrap
n53387 n53136 subsamples) [80%
CI of the OR]
History of coronary artery disease 3.9 (2.6 – 5.7) 2.2 (1.3 –3.5) 1.4 –2.8 0.775 1
History of chronic congestive heart failure 4.3 (2.8 – 6.6) 2.3 (1.4 –3.9) 1.3 –2.9 0.831 1
Chronic kidney disease 4.2 (2.8 – 6.4) 1.9 (1.2 –3.2) 1.2 –2.5 0.674 1
History of cerebrovascular disease 3.2 (2.1 – 5.02) 2.9 (1.7 –4.7) 1.6 –3.4 1.055 1
Abnormal ECG 3.7 (2.5 – 5.3) 1.9 (1.3 –2.9) 1.3 –2.3 0.664 1
Intraoperative hypotension 3.4 (2.3 – 5.01) 2.3 (1.5 –3.7) 1.6 –3.1 0.849 1
RBC transfusion 3.8 (2.7 – 4.4) 2.7 (1.9 –4.1) 1.8 –3.3 1.019 1

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viewed as another step towards an important target for
vigilance, as arterial pressure is potentially modifiable with
15 26%
14 24%
early treatment.
13 22% In our study, packed red blood cell transfusion seemed to
Postoperative length of stay in days

P=0.843
12
P=0.003 20% confer risk for MACCE independently of blood loss and pre-
11
Percentage of MACCE

10
18%
9 P<0.001
16%
8 14%
7 12%
6 10%
P=0.0001
5 8%
4
P=0.004 6%
3
2 4%
P<0.0001
1 2%
1.5% 4.5% 8.9% 20.6%
0
Very low risk Low risk Intermediate risk High risk
0%
n=1792 n=800 n=340 n=204
Risk score
Fig 2 Percentage of MACCE (columns, right axis) and mean and
95% CIs for postoperative length of stay (error bars, left axis)
according to the simplified risk score.
the approach we took in choosing the composite outcome. The
model also performed well in the sensitivity analysis in the data
set from which we excluded cases of thoracic surgery.
We chose the well-established definition of intraoperative
hypotension of .1 h of a ≥20 mm Hg decrease or a 20%
change in mean arterial pressure.36 – 38 By this definition,
hypotension was significantly related to complications.
Recent studies have analysed several levels of mean arterial
pressure and their relationship with 1-yr mortality,39 but no
conclusive results have been reported in terms of systolic or
mean pressure thresholds or episode duration. In the POISE
trial,4 intra- and postoperative hypotension (systolic arterial
pressure ,100 mm Hg) predicted both death (five-fold
increase in risk) and stroke (two-fold increase). In another
study that applied the Apgar score during surgery, intra-
operative hypotension (mean systolic arterial pressure ,40
mm Hg) also predicted cardiovascular events and other
postoperative complications as well.40 Our data should be
operative anaemia. Although others have found blood loss
to predict postoperative morbidity,41 it has not been specifi-
cally associated with perioperative MACCE. The relationship
between preoperative anaemia and adverse outcomes in
non-cardiac surgery has been confirmed in previous
studies,2 41 and transfusion is closely associated with pre-
operative anaemia and intraoperative blood loss. Our
results are consistent with recent findings of Beattie and
colleagues42 who found both anaemia and transfusion to
be independent predictors for mortality. We found that trans-
fused patients had more than two-fold greater risk for
MACCE. In cardiac surgery, transfusion is known to be associ-
ated with increased morbidity, total intensive care unit hours,
and time on the mechanical ventilator.43 44 In this context, it
is also interesting to note that red blood cell transfusion is
associated with an increased risk for new-onset atrial fibrilla-
tion.45 As recent reports have supported a role for inflam-
mation in the development of atrial fibrillation,36 43 44 we
hypothesize that this relationship would explain why both
transfusion and ECG abnormalities were related to increased
occurrence of arrhythmia (the most frequent MACCE in our
study) in non-cardiac surgery too.
In conclusion, we identified simple, objective, and easily
recorded factors associated with MACCE in a broad surgical
population. The model and proposed scoring system stratifies
patients according to risk for MACCE and identifies high-risk
subgroups to watch for postoperative cardiac morbidity.
Our data confirm that history of chronic kidney disease, cer-
ebrovascular disease, coronary artery disease, and conges-
tive heart failure predict MACCE. Adequate preoperative
assessment of cardiovascular risk is thus imperative, at a
key moment that offers an opportunity to optimize medical
treatment in the interest of attenuating the impact of risk
factors in both the perioperative period and long term. It is

887
BJA
also an ideal moment to recommend changes in lifestyle.
Carrying out non-invasive stress testing in high-risk patients
at this time, for example, has been shown to improve survival
rates and shorten hospital stays after non-cardiac surgery.46
More studies are needed to define which patients would
benefit from such a strategy, however, and our scoring
system could help to identify them. We also provide new
insights regarding intraoperative hypotension, ECG abnorm-
alities, and blood transfusion, which also seem to play a
role in the development of MACCE. Strategies to reduce
intraoperative hypotension episodes and blood transfusions
in the intermediate- and high-risk subgroups should be
tested with controlled trials in order to minimize the
incidence of perioperative MACCE.
Supplementary material
Supplementary material is available at British Journal of
Anaesthesia online.
Acknowledgements
In memory of Dr Juan Castaño, who drove this project
forward and mentored many anaesthetists. The authors
thank all the anaesthetists for their collaboration and Mary
Ellen Kerans for revision of English language usage in some
versions of the manuscript.
Conflict of interest
None declared.
Funding
Supported by the Catalan Public Health Service (Departament
de Salut de la Generalitat de Catalunya) within the frame-
work of World Alliance of Patient Safety in Catalonia, Spain.
The funding sources had no role in the design or conduct
of the study; the collection, management, analysis, or
interpretation of the data; or the preparation, review, or
approval of the manuscript. Presented in part at Euro-
anaesthesia 2009 Congress, Milan, Italy, June 6–9, 2009.
Appendix
ANESCARDIOCAT Study Group
Beatriz Martin, MD, Maite Rivilla, MD, Marta Giné, MD (Funda-
ció de Gestió Sanitària de l’Hospital de la Santa Creu i Sant
Pau, Barcelona); Marc Sadurnı́, MD, Miriam Fau, MD, Raquel
Arroyo, MD, Amèlia Rojo, MD (Parc de Salut Mar, Barcelona);
Elisenda Pujol Rosa, MD, Irene Rovira, MD, Amalia Alcón, MD
(Hospital Clinic, Barcelona); Marta Lacambra, MD, Albert Pi,
MD, Diana Campello, MD (Hospital Universitari de Bellvitge,
L’Hospitalet de Llobregat); Pilar Sierra, MD, Ana Arnal, MD
[Fundació Puigvert (IUNA), Barcelona]; Covadonga Llorente,
MD, Valentin Mazo, MD (Hospital Universitari Germans Trias
i Pujol, Badalona); Silvia Lopez, MD, Novella Calo, MD, Mª
Jesús Laso, MD (Hospital de Sabadell); M. Angels Subirana,
MD, Janete Andrade, MD (Hospital Comarcal de l’Alt
888
Sabaté et al.
Penedes, Vilafranca del Penedés); Guillem Brugal, MD (Hospi-
tal Arnau de Vilanova, Lleida); Olga Ramiro, MD (Hospital Uni-
versitari de Tarragona Joan XXIII); Teresa Vilalta, MD, Gràcia
Cárdenas, MD (Fundació Hospital-Asil de Granollers);
Carmen Hernández, MD, Xavier March, MD, Alfred Muñoz,
MD (Hospital Universitari Josep Trueta, Girona); Patricia
Ciurana, MD (Hospital Universitari de la Vall d’Hebrón, Barce-
lona); Albert Canadell, MD, Lisette Jiménez, MD, Gentxo
Balev, MD (Althaia Xarxa Assistencial, Manresa); Ester
Lombán, MD, Carmen Martı́n, MD (Hospital de Terrassa);
Teresa Planella, MD, Jordi Serrat, MD (Hospital General de
Vic); Josep Lluis Casbas, MD, Laura Mahillo, MD (Hospital
Sant Rafael, Barcelona); Joan Fornaguera, MD, Lluis Martinez,
MD (Hospital Municipal de Badalona); Mª Paz Villalba, MD,
Dolors del Pozo, MD (Hospital de la Santa Maria, Lleida);
Fabián Ibañez, MD (Hospital de Sant Jaume, Olot); Antonio
Garcés, MD (Hospital Sant Joan de Deu, Barcelona); and
Alfonso Alonso, MD (Fundació Sanitària d’Igualada).
Downloaded from http://bja.oxfordjournals.org/ by guest on December 15, 2013
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