Original Investigation | Anesthesiology

NT-proBNP or Self-Reported Functional Capacity in Estimating Risk

of Cardiovascular Events After Noncardiac Surgery
Giovanna Lurati Buse, MD, MSc; Jan Larmann, MD, PhD; Hans-Jörg Gillmann, MD; Katarzyna Kotfis, MD, PhD; Michael T. Ganter, MD; Daniel Bolliger, MD;
Miodrag Filipovic, MD; Luca Guzzetti, MD; Frédérique Chammartin, PhD; Eckhard Mauermann, MD, PhD; Daniela Ionescu, MD, PhD; Wojciech Szczeklik, MD, PhD;
Stefan De Hert, MD; Beatrice Beck-Schimmer, MD; Simon J. Howell, MD; for the METREPAIR NTproBNP Subcohort Investigators

Abstract Key Points

Question Does the addition of
IMPORTANCE Nearly 16 million surgical procedures are conducted in North America yearly, and
N-terminal pro–B-type natriuretic
postoperative cardiovascular events are frequent. Guidelines suggest functional capacity or B-type
peptide (NT-proBNP) to clinical risk
natriuretic peptides (BNP) to guide perioperative management. Data comparing the performance of
scores provide a better estimate of risk
these approaches are scarce.
of major adverse cardiac events (MACE)
among patients undergoing noncardiac
OBJECTIVE To compare the addition of either N-terminal pro-BNP (NT-proBNP) or self-reported
surgery than the addition of self-
functional capacity to clinical scores to estimate the risk of major adverse cardiac events (MACE).
reported functional capacity measures?

DESIGN, SETTING, AND PARTICIPANTS This cohort study included patients undergoing inpatient, Findings In this cohort study including
elective, noncardiac surgery at 25 tertiary care hospitals in Europe between June 2017 and April 3597 patients, discrimination for MACE
2020. Analysis was conducted in January 2023. Eligible patients were either aged 45 years or older with the addition of NT-proBNP to
with a Revised Cardiac Risk Index (RCRI) of 2 or higher or a National Surgical Quality Improvement clinical scores did not significantly differ
Program, Risk Calculator for Myocardial Infarction and Cardiac (NSQIP MICA) above 1%, or they were when compared with self-reported
aged 65 years or older and underwent intermediate or high-risk procedures. functional capacity. Benefit analysis
favored NT-proBNP if true positives
EXPOSURES Preoperative NT-proBNP and the following self-reported measures of functional were valued at least 20 times more than
capacity were the exposures: (1) questionnaire-estimated metabolic equivalents (METs), (2) ability to false positives.
climb 1 floor, and (3) level of regular physical activity.
Meaning The results of this study raise
concerns about the clinical applicability
MAIN OUTCOME AND MEASURES MACE was defined as a composite end point of in-hospital
of a NT-proBNP–based preoperative
cardiovascular mortality, cardiac arrest, myocardial infarction, stroke, and congestive heart failure
assessment.
requiring transfer to a higher unit of care.

RESULTS A total of 3731 eligible patients undergoing noncardiac surgery were analyzed; 3597 + Supplemental content
patients had complete data (1258 women [35.0%]; 1463 (40.7%) aged 75 years or older; 86 [2.4%] Author affiliations and article information are
experienced a MACE). Discrimination of NT-proBNP or functional capacity measures added to clinical listed at the end of this article.

scores did not significantly differ (Area under the receiver operating curve: RCRI, age, and 4MET,
0.704; 95% CI, 0.646-0.763; RCRI, age, and 4MET plus floor climbing, 0.702; 95% CI, 0.645-0.760;
RCRI, age, and 4MET plus physical activity, 0.724; 95% CI, 0.672-0.775; RCRI, age, and 4MET plus
NT-proBNP, 0.736; 95% CI, 0.682-0.790). Benefit analysis favored NT-proBNP at a threshold of 5%
or below, ie, if true positives were valued 20 times or more compared with false positives. The
findings were similar for NSQIP MICA as baseline clinical scores.

CONCLUSIONS AND RELEVANCE In this cohort study of nearly 3600 patients with elevated
cardiovascular risk undergoing noncardiac surgery, there was no conclusive evidence of a difference
between a NT-proBNP–based and a self-reported functional capacity–based estimate of MACE risk.

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

Abstract (continued)

TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03016936

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Introduction
For North America, the estimated need for surgical procedures amounts to 4647 per 100 000
individuals per year or 15.8 million operations annually.1 With over 4 million deaths worldwide every
year,2 postoperative mortality represents a major population health problem. Major noncardiac
surgery is associated with significant cardiovascular morbidity3 and the attributable fraction for
30-day mortality of myocardial injury after noncardiac surgery was estimated at 16%.4
To inform patients as a basis for shared decision-making and to tailor perioperative
management to expected risk, clinicians need to estimate the probability of adverse events. National
and international guidelines5-7 all consider the extent of the planned procedure and cardiovascular
history for preoperative evaluation. As an additional crucial factor of risk estimation, relevant
guidelines suggest different approaches. While American guidelines6 rely on functional capacity
expressed in metabolic equivalents (either measured during cardiopulmonary exercise test or
self-reported), Canadian guidelines5 rely on B-type natriuretic peptide (BNP) measurement.
European guidelines7 suggest either self-reported functional capacity expressed by the ability to
climb stairs or Duke Activity Status Index (DASI) or on BNP (class IIa).
The association between preoperative BNP concentrations and cardiovascular events after
noncardiac surgery has been extensively explored.8-11 By the addition of the N-terminal pro-Brain
Natriuretic Peptide (NT-proBNP) to the Revised Cardiac Risk Index (RCRI), the discrimination gain,
expressed as the difference in area under the curve of receiver operating curve (ROC AUC) for major
cardiac events (MACE) 30 days postsurgery ranged between 0.02 and 0.22. The corresponding value
for 30-day all-cause mortality and MACE ranged between 0.06 and 0.07.11
Data directly comparing BNP and functional capacity are exceedingly rare. In the Measurement
of Exercise Tolerance before Surgery Study, measures of functional capacity were assessed along
with NT-proBNP (1347 participants).12 The discrimination (ROC AUC) for a composite of 30-day
mortality and myocardial infarction was 0.67 for the RCRI plus DASI and 0.65 for the RCRI plus
NT-proBNP (95% CI not reported). As such, while preoperative BNP concentrations appear to
improve the projection of cardiovascular events after noncardiac surgery over clinical scores,11 their
value compared with self-reported measures of functional capacity is not established.
The main objective of the MET: Reevaluation for Perioperative Cardiac Risk (MET-REPAIR)–NT-
proBNP substudy was to compare the discrimination for MACE of models including NT-proBNP and
validated clinical scores (Revised Cardiac Risk Index [RCRI]13 and National Surgical Quality
Improvement Program, Risk Calculator for Myocardial Infarction and Cardiac [NSQIP MICA],14
respectively) with models that included self-reported functional capacity and those clinical scores. A
secondary objective was to examine if estimates were improved by the addition of NT-proBNP to
models including clinical scores and self-reported functional capacity measures.

Methods
Study Design and Setting
The MET-REPAIR NT-proBNP subcohort is a cohort study nested in MET-REPAIR, an international
multicenter prospective cohort study.15 At the beginning of the study, centers could opt for
participation in the subcohort. Enrollment occurred in 25 centers in 10 European countries between
June 2017 and April 2020.

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

The study was carried out in accordance with the published research plan and the principles
enunciated in the Declaration of Helsinki16 and the ICH-GCP Guidelines E6(R2).17 Prior to study
initiation, local or national principal investigators (PI), as applicable, obtained approval from the
responsible ethical board. All patients were informed and consented in writing using a dedicated
METREPAIR–NT-proBNP informed consent form prior to enrollment. The project office and the
principal PI trained the national PIs via teleconference on all aspects of the study and provided
written definitions and data entry manuals to the centers. National PIs trained local PIs. This report
follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)
reporting recommendations (eMethods in Supplement 1).

Study Population
Consecutive, consenting patients scheduled for inpatient noncardiac surgery were eligible if they were
either (1) aged 45 years or older and undergoing elective elevated-risk noncardiac surgery as defined by
either a RCRI of 2 or higher13 or a NSQIP MICA above 1%14; or (2) aged 65 years or older and undergoing
elective intermediate or high-risk procedures.18 The exclusion criteria were: nonelective surgery (ie,
within 72 hours of diagnosis), acute coronary syndrome or uncontrolled congestive heart failure within
30 days or stroke within 7 days of the planned day of surgery, outpatient surgery (ie, no overnight inpa-
tient stay planned), patients unable to ambulate due to congenital or longstanding conditions, inability
to complete the functional capacity questionnaire (language or literacy barriers), inability to consent or
unwillingness to participate, and previous enrollment.

Definition and Assessment of End Points

The primary end point was major adverse cardiac events (MACE), a composite end point of intra- or
postoperative in-hospital cardiovascular mortality, nonfatal cardiac arrest, acute myocardial
infarction (MI),19 stroke, and congestive heart failure requiring transfer to a higher unit of care or
prolonging stay on intensive care unit or intermediate care (lasting 24 hours or longer). Study
outcomes were adjudicated by the local PI based on standardized definitions after reviewing
in-hospital records and any other relevant documentation obtained during the 30-day follow-up
(eMethods in Supplement 1).3,19 Patients were followed-up until 30 days after surgery by phone or by
mail. In case of events, relevant documents were requested from hospitals or general practitioners.

Main Explanatory Variables

Preoperative NT-proBNP concentration was the main explanatory variable. NT-proBNP was sampled
no longer than 30 days prior to surgery and analyzed locally using an NT-proBNP immune assay
(Roche Diagnostics). The decision to conduct the measurements daily or in batches was at the
discretion of the local PI and local laboratory. In the case of sample storage, storage temperature at
–20 °C was recommended. Preoperative NT-proBNP concentrations were categorized according to
the cut-off concentrations published by Duceppe et al8 as below 100 pg/mL, 100 to 200 pg/mL, 200
to 1500 pg/mL, and above 1500 pg/mL (to convert to nanograms per liter, multiply by 1.0).

Self-Reported Measures of Functional Capacity

Self-reported measures of functional capacity consisted of functional capacity in METs (estimated
using a 10-item questionnaire), ability to climb 1 floor, and level of regular physical activity.20 Patients
completed the questionnaire20 no more than 30 days before surgery. If the operation was postponed
for more than 30 days, patients were asked to complete the questionnaire again. Self-reported
measures of functional capacity were categorized a priori. Self-reported METs were dichotomized at
the cut-off endorsed by the relevant American guidelines6 (under 4 METs). The ability to climb 1 floor
was categorized to mimic the recommendation of the ESC7 (less than 1 floor corresponding to less
than 2 flights of stairs), and the self-reported level of regular physical activity was categorized as
established in the METREPAIR parent sample (inactive defined as 20 minutes of activity per week or
less).15

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Covariables
Other independent variables were the RCRI and age in the primary analysis and the NSQIP MICA in a
planned additional analysis (age is part of the NSQIP MICA and was therefore not added). Race and
ethnicity were not considered as covariables because they have not been shown to be associated
with the primary outcome in previous studies. Both clinical risk scores are validated and commonly
used for cardiovascular risk estimation prior to noncardiac surgery.6,8,11,21

Statistical Analysis
For this nested cohort, we aimed for 3500 patients, corresponding to 70 composite events assuming
an incidence of 2% for the primary composite end point.22-25 The estimated number of events was
expected to allow adjustment with up to 6 to 7 covariates.26
Baseline characteristics and clinical outcomes were summarized as counts with percentages.
For comparisons of outcomes, we used mixed-effects logistic regression to model binary clinical
outcomes where the log odds of the outcome were modeled as a linear function of a mixture of fixed
effects of the independent variables and a random effect by country. Model performance was
evaluated using the area under the curve (AUC) of the receiver operation characteristics (ROC) curve
and the Brier score. We tested for AUC equality between models including RCRI, age, and NT-proBNP
vs RCRCI, age, and functional capacity measures using the DeLong test for 2 correlated ROC curves.27
During the review process, DeLong tests were additionally calculated for RCRI plus age vs RCRI, age,
and NT-proBNP and for RCRI plus age vs RCRI, age, and functional capacity measures. The same
applied for NSQIP MICA-based models. Each model’s apparent performance was assessed in the
studied data set. This allowed us to quantify performance for model comparison. We did not correct
model performance for optimism with bootstrapping since the aim was model comparison only and
not model validation.
In addition, we compared the models using net benefit approaches28-30: we plotted net benefit
at misclassification cost ranging from 0 to 15% (decision curves). A misclassification cost of 5% (1 in
20) corresponded to the acceptance of 20 false positives for 1 true positive; a misclassification cost of
15% (1 in 6.7) is the acceptance of 6.7 false positives for 1 true positive. We calculated weighted
comparison (WC = change in sensitivity + [(1 − prevalence/prevalence) × relative cost
(FP/TP) × change in specificity]) at the observed incidence for each in-hospital MACE and 30-day
MACE and a misclassification cost predefined at 10%, ie, a trade-off at 10 false positives per 1 true
positive, corresponding to a 10-fold higher relative weighting of true positive over false positive.28 To
aid interpretation, we converted WC to net benefit equivalent (incremental number of true positives
per 1000 patients).30 We conducted a full-case analysis. We applied 2-sided level of significance at
P < .05.
All statistical analyses were performed using R version 4.1.2 (R Project for Statistical
Computing). Mixed-effects logistic models were fitted using the glmer function of the R statistical
package lme4. The analysis was conducted in January 2023.

Results
Descriptive Data
Among 3597 of 3731 patients with complete data, 1258 (35.0%) were women and 1463 (40.7%) were
aged 75 years or older (Table 1). Baseline characteristics of METREPAIR patients eligible for the
NT-proBNP substudy who declined participation or were not captured are reported in eTable 1 in
Supplement 1. Of 3597 patients, 86 developed in-hospital MACE (2.4%) (Figure). These consisted of
23 (0.6%) cardiac deaths, 27 (0.8%) myocardial infarctions, 16 (0.4%) nonfatal cardiac arrests, 17
(0.5%) heart failures requiring transfer to a higher unit of care or prolonged stay in intensive care unit
(ICU) or intermediate care (ie, 24 hours or longer), and 9 (0.3%) strokes. At 30 days, 103 of 3593
patients (2.9%) had suffered a MACE. Six patients (0.2%) had incomplete answers to the METs
questions. Therefore, the analyses on METs based on 86 in-hospital MACE in 3591 patients and 103

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

30-day MACE in 3587 patients. NT-proBNP was sampled within 1 day prior to surgery in 3119 patients
(86.7%) and 7 days prior to surgery in 3475 (96.6%) of the patients.

Estimated Risk of MACE Occurrence Using RCRI Plus NT-proBNP vs RCRI

Plus Self-Reported Functional Capacity
The addition of NT-proBNP to a model of RCRI plus age significantly increased discrimination for
in-hospital MACE ROC AUC (0.736; 95% CI, 0.682-0.790; P = .03) but not for 30-day MACE (0.721;
95% CI, 0.670-0.771; P = .39) (Table 2) The discrimination gain by the addition of functional capacity
measures to RCRI plus age was not significant (Table 2). The addition of NT-proBNP to the RCRI plus

Table 1. Baseline Characteristics of the Whole Cohort and by In-Hospital MACE

Participants, No. (%)

Characteristics All (n = 3597) MACE (n = 86) No MACE (n = 3511)
Age, y
45-74 2134 (59.3) 37 (43.0) 2097 (59.7)
≥75 1463 (40.7) 49 (57.0) 1414 (40.3)
Sex
Female 1258 (35.0) 27 (31.4) 1231 (35.1)
Male 2339 (65) 59 (68.6) 2280 (64.9)
RCRI
Abbreviations: MACE, major adverse cardiac events;
Low (≤1 point) 1474 (41.0) 22 (25.6) 1452 (41.4)
MET, metabolic equivalent; NT-proBNP, N-terminal
Moderate (2 points) 1343 (37.3) 33 (38.4) 1310 (37.3)
pro–brain natriuretic peptide; NSQIP MICA, National
High (≥3 points) 780 (21.7) 31 (36.0) 749 (21.3) Surgical Quality Improvement Program, Risk calculator
NSQIP-MICA risk, % for Myocardial Infarction and Cardiac; RCRI, Revised
Mean (SD) 1.84 (1.77) 2.31 (1.94) 1.83 (1.76) Cardiac Risk Index.
a
Median (IQR) 1.34 (0.58-2.46) 2.08 (0.78-3.23) 1.33 (0.58-2.46) Six of 3597 patients had incomplete answers to the
Range 0.02-15.06 0.10-11.61 0.02-15.06 METs questions; the analyses on METs based on 86
in-hospital MACE in 3591 patients and 103 MACE in
NT-proBNP, pg/mL
3587 patients.
<100 1131 (31.5) 15 (17.4) 1116 (31.8) b
Referring to brisk walking, jogging or running,
100-200 825 (22.9) 11 (12.8) 814 (23.2) cycling, swimming, or vigorous sports at a
200-1500 1320 (36.7) 38 (44.2) 1282 (36.5) comfortable pace or other activities requiring similar
≥1500 321 (8.9) 22 (25.6) 299 (8.5) levels of exertion; MACE is defined as a composite
Self-reported functional capacity of intra- or postoperative in-hospital cardiovascular
mortality, nonfatal cardiac arrest, acute myocardial
<4 METsa 454 (12.6) 19 (21.1) 435 (12.4)
infarction, stroke, and congestive heart failure
Stair climbing <1 floor 402 (11.2) 15 (17.4) 387 (11.0) requiring transfer to a higher unit of care or
Inactive or regular physical activity ≤20 2216 (61.6) 67 (78.0) 2194 (62.5) prolonging stay on intensive care unit or
min/wk activityb
intermediate care 24 hours or longer.

Figure. Study Flowchart

4630 Screened

1153 Excluded
1026 Unwilling to consent (22%)
127 NTproBNP missing (3.4%)

3604 Patients enrolled

MACE indicates major adverse cardiac events; NSQIP
MICA, National Surgical Quality Improvement
3731 Excluded Program, Risk calculator for Myocardial Infarction and
Missing information on self-reported regular physical activity (0.08%)
Missing information on floor climbing ability (0.06%) Cardiac; NT-proBNP, N-terminal pro–brain natriuretic
Missing information for RCRI (0.03%) peptide; RCRI, Revised Cardiac Risk Index.
Missing information for NSQIP MICA (0.03%) a
Six additional patients had incomplete answers to
the METs questions; the analyses on METs based on
86/3597a In-hospital MACE 86 in-hospital MACE in 3591 patients and 103 MACE
103/3593 30-d MACE
in 3587 patients.

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

age measure led to the numerically higher ROC AUC than the addition of any of the self-reported
measures of functional capacity (fewer than 4 METs, less than 1 floor of stairs, and less than 20
min/wk regular physical activity). This applied for each in-hospital and for 30-day MACE (Table 2).
However, the discrimination of the model adding NT-proBNP did not significantly differ from the
models adding functional capacity measures to RCRI and age (Table 2). Of note, in contrast to the
cut-off implemented in the parent METREPAIR study (1 floor or less),15 the ability to climb stairs
dichotomized at 1 floor as suggested by the ESC guidelines (less than 1 floor corresponding to less
than 2 flights of stairs)7 was independently associated with 30-MACE but not with in-hospital MACE
after adjustment by RCRI plus age (eTable 2 in Supplement 1).
The addition of NT-proBNP to 4 METs and to the regular physical activity level, respectively,
improved discrimination for in-hospital MACE (ROC AUC: RCRI, age, 4MET, and NT-proBNP, 0.741;
95% CI, 0.688-0.795 vs RCRI, age, and 4MET, 0.704; 95% CI, 0.646-0.763; P = .03; RCRI, age,
physical activity, and NT-proBNP, 0.750; 95% CI, 0.699-0.801 vs RCRI, age, and physical activity,
0.724; 95% CI, 0.672-0.775; P = .04) (Table 2; eTable 3 in Supplement 1). The addition of NT-proBNP
to the ability to climb stairs did not significantly improve discrimination for in-hospital MACE
compared with a model based only on stair climbing. Brier scores were similar for all models (eTable 3
in Supplement 1). The addition of NT-proBNP to each self-reported measure of functional capacity
significantly improved discrimination for 30-day MACE; however, the effect size was limited
(eTable 3 in Supplement 1).
Decision curves suggested that the net benefit of models including NT-proBNP was largest for
misclassification cost of 5% or less, ie, at trade-offs in the order of 20 or more false positives per 1 true
positive (or relative weighting of 20 or more for true positive over false positive) (eFigures 1 and 2 in
Supplement 1). At the incidence of in-hospital MACE of 2.4% and of 30-day MACE of 2.9%,
respectively, and at a misclassification cost of 10% (ie, acceptance of 10 false positives per 1 true
positive), benefit equivalent for models including NT-proBNP was marginal (depending on the model
in the order of 1 to 10 incremental true positive patients per 1000 patients) (Table 3; eTable 4 in
Supplement 1).

Projection of MACE Occurrence Using NSQIP MICA Plus NT-proBNP vs NSQIP MICA
Plus Self-Reported Functional Capacity
The addition of NTPproBNP to the NSQIP-MICA significantly improved discrimination for in-hospital
MACE (ROC AUC, 0.732; 95% CI, 0.681-0.783; P = .04) but not for 30-day MACE (DeLong test,
P = .19) (Table 4). The discrimination gain by the addition of functional capacity measures to NSQIP
MICA was not significant. The addition of NT-proBNP to the NSQIP MICA led to the numerically higher

Table 2. Results for In-Hospital and 30-Day MACE From Mixed Effect Logistic Regression Models Based on Revised Cardiac Risk Index (RCRI)a

In-hospital MACE 30-d MACE

P value to P value to
Variable Brier score ROC AUC (95% CI) NT-proBNP model Brier score ROC AUC (95% CI) NT-proBNP model
RCRI + age 0.023 0.694 (0.636-0.753) NA 0.023 0.687 (0.628-0.745) NA
RCRI, age, and NTproBNP 0.023 0.736 (0.682-0.790) NA 0.027 0.721 (0.670-0.771) NA
RCRI, age, <4 METsb 0.023 0.704 (0.646-0.763) .12 0.027 0.681 (0.625-0.736) .06
RCRI, age, and <1 floor 0.023 0.702 (0.645-0.760) .08 0.027 0.685 (0.632-0.738) .07
RCRI, age, and <20 min/w, 0.023 0.724 (0.672-0.775) .56 0.027 0.686 (0.634-0.739) .10
regular physical activityc
b
Abbreviations: AUC, area under the receiving operator curve; MACE, major adverse Six of 3597 patients had incomplete answers to the METs questions; the analyses on
cardiac events; METs, metabolic equivalents; NA, not applicable; NT-proBNP, N-terminal METs based on 86 in-hospital MACE in 3591 patients and 103 MACE in 3587 patients.
pro–brain natriuretic peptide; RCRI, Revised Cardiac Risk Index. c
Regular physical activity to brisk walking, jogging or running, cycling, swimming, or
a
De Long tests for comparisons: RCRI, age, and NT-proBNP vs RCRI plus age, P = .03 for vigorous sports at a comfortable pace or other activities requiring similar levels of
in-hospital MACE, P = .39 for 30-day MACE; RCRI, age, and 4 METs vs RCRI plus age, exertion.
P = .35 for in-hospital MACE, P = .45 for 30-day MACE; RCRI, age, and stair climbing vs
RCRI plus age, P = .23 for in-hospital MACE, P = .28; RCRI, age, physical activity vs RCRI
plus age, P = .07 for in-hospital MACE, P = .32 for 30-day MACE.

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

ROC AUC than the addition of any of the self-reported measures of functional capacity. This applied
for each in-hospital and for 30-day MACE (Table 4). However, the discrimination of the model adding
NT-proBNP did not significantly differ from the models adding functional capacity measures to
NSQIP MICA (Table 4).
Corresponding adjusted ORs are reported in eTable 5 in Supplement 1; of note, in contrast to the
cut-off implemented in the parent METREPAIR study,15 the ability to climb stairs dichotomized at 1
floor or less as suggested by the ESC guidelines7 was independently associated with 30-MACE but
not with in-hospital MACE after adjustment by NSQIP MICA.
The addition of NT-proBNP to 4 METs (plus NSQIP-MICA) resulted in a numerically larger ROC
AUC but it missed significance (ROC AUC, 0.737 vs 0.690; P = .05). The addition of NT-proBNP to
stair climbing and to the self-reported level of physical activity improved discrimination (ROC AUC:
NSQIP-MICA, stair climbing, and NT-proBNP, 0.734; 95% CI, 0.684-0.784 vs NSQIP-MICA plus stair
climbing, 0.684; 95% CI, 0.633-0.754; P = .04; NSQIP-MICA, physical activity, and NT-proBNP,
0.742; 95% CI, 0.691-0.793 vs NSQIP-MICA plus physical activity, 0.705; 95% CI, 0.655-0.754;
P = .05). Brier scores were similar for all models. The addition of NT-proBNP to self-reported
measures of functional capacity improved discrimination for 30-day MACE (eTable 6 in
Supplement 1).
Decision curves suggested that the net benefit of NSQIP-MICA-based models including
NT-proBNP was largest for misclassification cost of 5% or below, ie, at trade-offs in the order 20 or
more false positives per each true positive (or relative weighting of true positive to false positive of
20 or more) (eFigures 3 and 4 in Supplement 1). At the incidence of in-hospital MACE of 2.4% and at a
misclassification cost of 10% (ie, trade-off at 10 false positives per 1 true positive) benefit equivalent

Table 3. Weighted Comparison and Benefit Equivalent for In-Hospital MACE

for Revised Cardiac Risk Index (RCRI)-Based Modelsa
Abbreviations: METs, metabolic equivalents;
In-hospital MACE 30-d MACE NT-proBNP, N-terminal pro–brain natriuretic peptide;
Benefit Benefit RCRI, revised cardiac risk index.
Weighted equivalent (per Weighted equivalent (per
a
Comparison comparison 1000 patients) comparison 1000 patients) In-hospital MACE incidence was 2.4%, 30-day MACE
RCRI, age, and NT-proBNP vs RCRI, age, 0.134 3 0.209 6 incidence was 2.9%, and misclassification cost was
and <4 METb set at 10%.
b
RCRI, age, and NT-proBNP vs RCRI, age, 0.270 6 0.241 7 Six of 3597 patients had incomplete answers to the
and <1 floor of stairs METs questions; the analyses on METs based on 86
RCRI, age, and NT-proBNP vs RCRI, age, 0.269 6 0.331 10 in-hospital MACE in 3591 patients and 103 MACE in
and level of physical activityc
3587 patients.

Table 4. Results for In-Hospital and 30-Day MACE From Mixed Effect Logistic Regression Models Based on NSQIP MICAa

In-hospital MACE 30-d MACE

P value to P value to
Variables Brier Score ROC AUC (95% CI) NT-proBNP model Brier Score ROC AUC (95% CI) NT-proBNP model
NSQIP MICA 0.023 0.676 (0.623-0.728) NA 0.023 0.666 (0.614-0.719) NA
NSQIP MICA + NT-proBNP 0.023 0.732 (0.681-0.783) NA 0.027 0.715 (0.665-0.765) NA
NSQIP MICA + <4 METsb 0.023 0.690 (0.636-0.744) .14 0.028 0.668 (0.616-0.719) .10
NSQIP MICA + <1 floor stairs 0.023 0.684 (0.633-0.735) .07 0.028 0.671 (0.622-0.719) .09
NSQIP MICA + <20 min/wk 0.023 0.705 (0.655-0.754) .07 0.028 0.674 (0.626-0.721) .14
regular physical activityc

Abbreviations: ROC AUC, area under the receiver operating curve; MACE, major adverse in-hospital MACE, P = .40 for 30-day MACE; NSQIP MICA plus physical activity vs
cardiac events; METs, metabolic equivalents; NA, not applicable; NT-proBNP, N-terminal NSQIP MICA, P = .19 for in-hospital MACE, P = .38 for 30-day MACE.
pro–brain natriuretic peptide; NSQIP MICA, National Surgical Quality Improvement b
Six of 3597 patients had incomplete answers to the METs questions; the analyses on
Program, Risk Calculator for Myocardial Infarction and Cardiac Arrest. METs based on 86 in-hospital MACE in 3591 patients and 103 MACE in 3587 patients.
a
All models include a random intercept by country. DeLong tests for comparisons: c
Regular physical activity to brisk walking, jogging or running, cycling, swimming, or
NT-proBNP plus NSQIP MICA vs NSQIP MICA, P = .04 for in-hospital MACE, P = .19 for vigorous sports at a comfortable pace or other activities requiring similar levels of
30-day MACE; NSQIP MICA plus 4 METs vs NSQIP MICA, P = .35 for in-hospital MACE, exertion.
P = .48 for 30-day MACE; NSQIP MICA plus stair climbing vs NSQIP MICA, P = .48 for

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

for NSQIP-MICA-based models including NT-proBNP were marginal (depending on the model in the
order of 0 to 9 more true positive patients per 1000 patients) (eTable 7 in Supplement 1).

Discussion
Main Findings
After adjusting for RCRI and age, each of self-reported MET below 4, inability to climb 1 floor,
inactivity or limited regular physical activity, and NT-proBNP were independently associated with
30-day MACE. The same findings applied to adjustment using NSQIP MICA.
Albeit numerically larger, discrimination for either in-hospital or 30-day MACE of models using
NT-proBNP did not reach significant difference compared with models using self-reported measures
of functional capacity. This applied both for models using RCRI and age and those using NSQIP MICA
as the baseline. Discrimination for 30-day MACE significantly improved by the addition of NT-proBNP
to functional capacity measures (plus clinical risk score). A similar pattern was seen for in-hospital
MACE, but it did not consistently reach significance.
Decision analysis suggested that models using NT-proBNP provided a net benefit over models
using functional capacity measures at lower threshold probabilities, ie, if 20 or more false positives
were considered an acceptable trade-off per 1 true positive. At the predefined threshold of 10%
(trade-off at 10 false positives per 1 true positive), benefit by the use of NT-proBNP over self-reported
functional capacity measures for projection of perioperative MACE was marginal.
As such, there was no conclusive evidence of a difference between a NT-proBNP–based and a
self-reported functional capacity–based MACE projection. While a difference may still exist, its size
appears to be in an order of magnitude such as not to be conclusively detected within a sample of
near to 3600 patients at elevated cardiovascular risk. In our opinion, this raises concerns regarding
the clinical relevance of the potential difference and therefore regarding the clinical applicability of a
NT-proBNP–based preoperative risk assessment.

Comparison With Previous Studies

In line with previous studies,8-11 NT-proBNP was significantly associated with MACE after noncardiac
surgery. This confirms the well-established role of NT-proBNP as prognostic factor, ie, as factor
influencing the risk of adverse outcomes.
In terms of projection, the evidence appears more nuanced. In the largest sample to date,8 the
addition of NT-proBNP to the RCRI resulted in a ROC AUC of 0.73 (95% CI, 0.72-0.74) for a composite
of cardiovascular death and myocardial injury and of 0.75 (95% CI, 0.73-0.78) for all-cause mortality
and myocardial infarction. In addition to confirming the moderate ROC AUC (0.73; 95% CI,
0.68-0.79) for in-hospital MACE for RCRI plus NT-proBNP previously described by Duceppe et al,8 in
the present cohort we report discrimination in the same order of magnitude when NT-proBNP was
added to the NSQIP MICA, another commonly used clinical risk score.6,18 In the Measurement of
Exercise Tolerance before Surgery study (including 1347 participants),12 the discrimination (ROC
AUC) for a composite of 30-day mortality and myocardial infarction was 0.65 for the RCRI plus
NT-proBNP. NT-proBNP did not improve net reclassification. For the composite end point of 30-day
mortality and myocardial injury, ROC AUC amounted to 0.71 for the addition of NT-proBNP to age,
sex, and RCRI. While the assessment of model performance is not limited to discrimination, the body
of evidence including other measures is less conspicuous.11
Of note, the focus of this analysis was not the quantification of the predictive value of
NT-proBNP per se; rather, it specifically aimed at the direct comparison between NT-proBNP and self-
reported functional capacity measures, an easily implementable, low-cost approach commonly used
in clinical practice. The evidence in this regard is scarce. Duceppe at al8 did not report on functional
capacity. In the Measurement of Exercise Tolerance before Surgery study, 12 the discrimination for a
composite of 30-day mortality and myocardial infarction was 0.67 for the RCRI plus DASI, ie, a similar
order as for NT-proBNP (0.65). For the composite end point of 30-day mortality and myocardial

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

injury, ROC AUC amounted to 0.71 for the addition of DASI to age, sex, and RCRI, again in the same
order as for NT-proBNP (0.71). Formal testing for AUC difference between the baseline model with
DASI vs with continuous NT-proBNP was not reported.12 In the present cohort, while discrimination
was numerically higher for models using NT-proBNP added to the clinical risk score, it did not reach
a significant difference compared with self-reported functional capacity measures, as supported by
wide overlap in 95% CI intervals. Of note, the limited potential benefit of NT-proBNP measurement
over self-reported measured of functional capacity for MACE projection is supported by the findings
of benefit analysis suggesting that NT-proBNP–based assessment is preferable if 20 or more false
positives are acceptable to detect 1 additional true positive.
In a secondary analysis of the Measurement of Exercise Tolerance before Surgery study,31 the
ROC AUC for the model using both functional capacity (DASI) and NT-proBNP was 0.66.
Discrimination improvement compared with a model with DASI only was not reported. In our data,
the combined use of both functional capacity measures and NT-proBNP improved discrimination for
30-day MACE over clinical risk scores. As such self-reported functional measures and NT-proBNP
appear to provide complementary information. However, benefit analyses suggested that the
benefit of the combined use is limited (less than 10 additional true positives per 1000 patients
assuming a trade-off at 10%).

Strengths and Limitations

The analytical approach was strengthened first by the joint assessment of both self-reported
measures and NT-proBNP in a large prospective cohort. This allowed for the comparison of risk
assessment approaches endorsed by relevant guidelines, ie, the consideration (in addition to clinical
factors) of functional capacity in the American and European guidelines6,7 and of B-type natriuretic
peptide in the Canadian guidelines.5 We also assessed the combined use of self-reported functional
capacity measures and NT-proBNP. Second, the evaluation was not limited to RCRI-based models
but also included the evaluation of models based on the NSQIP MICA. Finally, in addition to the
quantification of independent associations and of measures of model performance, we applied a
decision analytical approach28-30 as recommended.32,33
This study had several limitations. First, the use of a composite end point (MACE) was mainly
driven by cardiac death and myocardial infarction. The preferred outcome according to the
Standardized Endpoints in Perioperative Medicine (StEP) initiative that was published after
conclusion of data collection, is all-cause death and myocardial infarction.34 While we did not
conduct a formal analysis, because less than 20% of the registered events were heart failures, we
consider that exclusion of heart failure from the MACE composite would not relevantly affect the
findings of the limited gain of NT-proBNP compared with functional capacity. If anything, considering
the closer link between NT-proBNP and heart failure than with death and myocardial infarction, one
would expect the discrimination gain using NT-proBNP for these end points to be even more limited.
Second, we did not conduct systematic postoperative troponin surveillance with the resulting risk
of misclassification. However, the discrimination we described for NT-proBNP (ROC AUC, 0.74) was
essentially the same as the discrimination described by Duceppe et al8 for vascular death and
myocardial injury (ROC AUC, 0.73) and for all-cause mortality at myocardial infarction (ROC AUC,
0.75).8
Third, while our primary end point was in-hospital MACE, our analysis applied an NT-proBNP
cut-off developed for vascular mortality and myocardial injury after noncardiac surgery.8 However,
those cut-offs demonstrated significant associations also for other end points in the publication by
Duceppe and colleagues.8 Fourth, the protocol did not mandate the masking of clinical care
professionals for NT-proBNP concentrations, so that we cannot exclude performance bias as a factor
to some extent. Fifth, we did not conduct correction for multiple testing. As such, we consider that
cautious appraisal of P values is warranted and we advise against the interpretation of De Long P
values slightly exceeding 0.05 as tendencies hinting at differences between NT-proBNP and self-
reported measures. Finally, while the sample included almost 3600 patients, the number of events

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

(86 in-hospital and 103 30-day MACE) was not sufficient to provide conclusive evidence of any
difference between a NT-proBNP–based and a self-reported functional capacity-based MACE
projection. In our opinion, this suggests that the size of the potential difference between the 2
approaches may not be of clinical relevance.

Conclusions
In this cohort study of approximately 3600 patients with elevated cardiovascular risk undergoing
noncardiac surgery, there was no conclusive evidence of a difference between a NT-proBNP–based
and a self-reported functional capacity–based MACE projection. Our results suggest that caution
about the clinical applicability of a NT-proBNP–based preoperative assessment is warranted.

ARTICLE INFORMATION
Accepted for Publication: September 13, 2023.
Published: November 8, 2023. doi:10.1001/jamanetworkopen.2023.42527
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Lurati Buse
G et al. JAMA Network Open.
Corresponding Author: Giovanna Lurati Buse, Anaesthesiology Department, University Hospital Düsseldorf,
Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany ([email protected]
duesseldorf.de).
Author Affiliations: Anesthesiology Department University Hospital Düsseldorf, Heinrich Heine University,
Düsseldorf, Germany (Lurati Buse); Department of Anesthesiology, Heidelberg University Hospital, Heidelberg,
Germany (Larmann); Department of Anaesthesiology and Intensive Care Medicine, Hannover Medical School,
Hannover, Germany (Gillmann); Department of Anesthesiology, Intensive Therapy and Acute Intoxications,
Pomeranian Medical University, Szczecin, Poland (Kotfis); Department of Anesthesiology, Kantonsspital
Winterthur, Winterthur, Switzerland (Ganter); Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency
Medicine and Pain Therapy, University Hospital Basel, Basel, Switzerland (Bolliger); Division of Anesthesiology,
Intensive Care, Rescue and Pain Medicine, Kantonsspital St Gallen, St Gallen, Switzerland (Filipovic); Anesthesia
and Intensive Care Department, University Hospital, Varese, Italy (Guzzetti); Division of Clinical Epidemiology,
Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland (Chammartin);
Department of Anesthesiology, Zurich City Hospital, Zurich, Switzerland (Mauermann); Department of
Anaesthesia and Intensive Care I, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
(Ionescu); Center for Intensive Care and Perioperative Medicine Jagiellonian University Medical College, Kraków,
Poland (Szczeklik); Department of Anaesthesiology and Peri-operative Medicine, Ghent University Hospital, Ghent
University, Ghent, Belgium (De Hert); Institute of Anaesthesiology, University Hospital Zurich, University of Zurich,
Zurich, Switzerland (Beck-Schimmer); Leeds Institute of Medical Research at St James’s, University of Leeds,
Leeds, United Kingdom (Howell).
Author Contributions: Dr Lurati Buse had full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: Lurati Buse, Gillmann, Filipovic, Mauermann, Szczeklik, de Hert, Beck-Schimmer, Howell.
Acquisition, analysis, or interpretation of data: Lurati Buse, Larmann, Gillmann, Kotfis, Ganter, Bolliger, Filipovic,
Guzzetti, Chammartin, Ionescu, Mauermann, Szczeklik, de Hert, Howell.
Drafting of the manuscript: Lurati Buse, Bolliger, de Hert, Howell.
Critical review of the manuscript for important intellectual content: Larmann, Gillmann, Kotfis, Ganter, Bolliger,
Filipovic, Guzzetti, Chammartin, Ionescu, Mauermann, Szczeklik, de Hert, Beck-Schimmer, Howell.
Statistical analysis: Chammartin.
Obtained funding: Lurati Buse, Mauermann.
Administrative, technical, or material support: Kotfis, Bolliger, Guzzetti, Ionescu, Mauermann, Szczeklik, de Hert.
Supervision: Gillmann, Ganter, Ionescu, Mauermann, Szczeklik, de Hert.
Conflict of Interest Disclosures: Dr Lurati Buse reported service on an advisory board by Roche Diagnostics. Dr
Larmann reported grants from Philips and personal fees from Philips outside the submitted work. Dr Filipovic
reported receiving grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the

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 JAMA Network Open | Anesthesiology NT-proBNP vs Functional Capacity to Estimate Cardiovascular Events After Noncardiac Surgery

Cantonal Hospital St. Gallen, Switzerland outside the submitted work. Dr Beck-Schimmer reported grants from
Uniscientia Foundation, Vontobel Foundation, and Swiss National Science Foundation outside the submitted work.
Dr Howell reported grants from University of Leeds Research Grant from Association of Anaesthetists of Great
Britain and Ireland during the conduct of the study; he reported service on an advisory board for Edwards
Lifesciences. No other disclosures were reported.
Funding/Support: MET-REPAIR and its NT-proBNP subcohort were sponsored by a grant from the European
Society of Anaesthesiology Clinical Trial Network (ESAIC CTN) and by a grant from the Swiss Society of
Anaesthesiology and Resuscitation. The conduct in the UK was supported by a grant from the National Institute of
Academic Anaesthesia.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Group Information: The METREPAIR NTproBNP Subcohort Investigators appear in Supplement 2.
Data Sharing Statement: See Supplement 3.

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SUPPLEMENT 1.
eMethods.
eTable 1. Baseline Characteristics of Patients Included and Excluded From the NT-proBNP Substudy
eTable 2. Adjusted Odds Ratios (OR) for In-Hospital and 30-day MACE for RCRI-Based Models Including
NT-proBNP or Each of the Assessed Self-Reported Functional Capacity Measures
eTable 3. Brier Score and ROC AUC for In-Hospital and 30-day MACE From Mixed Effect Logistic Regression
Models Based the Addition of NT-proBNP to Models Including RCRI, Age, and Functional Capacity Measures
eTable 4. Weighted Comparison and Benefit Equivalent for MACE for the Addition of NT-proBNP to Models
Including RCRI, Age, Functional Capacity Measures
eTable 5. Adjusted Odds Ratios (OR) for In-Hospital and 30-day MACE for NSQIP MICA-Based Models Including
NT-proBNP or Each of the Assessed Self-Reported Functional Capacity Measures
eTable 6. Brier Score and ROC AUC for MACE From Mixed Effect Logistic Regression Models Based on for the
Addition of NT-proBNP to Models Including NSQIP MICA Plus Functional Capacity Measures
eTable 7. Weighted Comparison and Benefit Equivalent for In-Hospital and for 30-day MACE for NSQIP-MICA-
Based Models
eFigure 1. Decision Curves of Various RCRI-Based Models for In-Hospital MACE
eFigure 2. Decision Curves of Various RCRI-Based Models Combining NT-proBNP and Self-Reported Functional
Capacity Measures for In-Hospital MACE
eFigure 3. Decision Curves of Various NSQIP MICA-Based Models for In-Hospital MACE
eFigure 4. Decision Curves of Various NSQIP MICA-Based Models Combining NT-proBNP and Self-Reported
Functional Capacity Measures for In-Hospital MACE

SUPPLEMENT 2.
Nonauthor Collaborators

SUPPLEMENT 3.
Data Sharing Statement

JAMA Network Open. 2023;6(11):e2342527. doi:10.1001/jamanetworkopen.2023.42527 (Reprinted) November 8, 2023 13/13

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