ORIGINAL ARTICLE
Cardiopulmonary Exercise Testing Contributes to Accurate
Risk Assessment in Patients with Low-risk Pulmonary Hypertension
La prueba cardiopulmonar de ejercicio contribuye a determinar con precisión el riesgo con precisión en pacientes con hipertensión pulmonar
de bajo riesgo
Ignacio M. BluroMTSAC,1,
Leandro BarbagelataMTSAC, 1, María
Lorena Coronel2, Luciano Melatini3, Graciela Svetliza1,
Norberto Vulcano1, Andrés N. AtamañukMTSAC,4, Walter M.
MassonMTSAC,1, Rodolfo PizarroMTSAC,1
1 Hospital Italiano de Buenos Aires,
Buenos Aires, Argentina.
2 Instituto de Cardiología de Corrientes “Juana F. Cabral”,
Corrientes, Argentina
3 Instituto de Neumonología del Sur, Bahía Blanca,
Argentina
4 Hospital
Juan A. Fernández, Buenos
Aires, Argentina
Address for reprints:
Ignacio Martín Bluro. Servicio de Cardiología. Hospital
Italiano de Buenos Aires, Buenos Aires, Argentina. J. D. Perón 4190, Ciudad de Buenos Aires (C1181ACH), Argentina. E-mail: ignacio.bluro@hospitalitaliano.org.ar
Rev Argent Cardiol
2023;91:130-134. http://dx.doi.org/10.7775/rac.v91.i2.20613
ABSTRACT
Background: European guidelines for pulmonary arterial hypertension
(PAH) stratify the risk using clinical characteristics and complementary studies, including the
cardiopulmonary exercise test (CPET). This takes into account 3 parameters:
peak O2 consumption (peak VO2), its percentage with
respect to the predicted VO2, and the minute ventilation/carbon
dioxide production (VE/ VCO2) slope. However, none of the models that validated this way of stratifying risk included PCPE among their variables.
Objectives: To determine what proportion of patients with group I PAH
considered to be at low risk and who walk >440 meters in the 6-minute walk test (6MWT) have parameters
considered to be of moderate
or high risk in the PCPE.
Methods: Patients >18 years of age, diagnosed with group I PAH
at low risk of events, who walked >440 meters in the 6MWT and had NT-proBNP
value < 300 pg/dL
were included. A CPET was performed in which the peak
VO2, its percentage with respect to the predicted VO2, and the VE/VCO2 slope were recorded.
It was determined what proportion of patients presented
these parameters in a
higher than low risk stratum (peak VO2 consumption >15 ml/min/Kg,
its percentage with respect to the predicted VO2 65% and the VE/VCO2 slope > 36).
Results: Eighteen patients were included. Despite being low-risk
patients with a good functional class, all patients presented a peak VO2 less than 85% of predicted,
which determines a deterioration of functional capacity. A single patient (6%)
presented the three parameters
evaluated at low risk, 8 patients (44%) had at least one altered parameter, 7
patients (39%) presented 2 altered parameters
and in 2 patients (11%) all parameters were altered. The parameters that were most frequently altered
were the percentage
of predicted peak VO2 and the VE/VCO2 slope in 67%
of the cases. Only 4 patients presented a peak VO2 <15 ml/kg/m.
No patient presented peak VO2
values or percentage of predicted VO2 in the high-risk category.
However, 6 patients (33%) presented a high-risk VE/VCO2 slope.
Conclusion: Majority (92%) of the patients considered low risk and who
walk more than 440 meters in 6 minutes presented at least one altered variable in the CPET. The
VE/VCO2 slope and the percentage of predicted peak VO2
consumption were the most frequently altered variables. The VE/VCO2
slope was the only one that showed values considered high risk. CPET could have
a place in the precision stratification of low-risk patients.
The value of this finding should be evaluated in prospective studies.
Key words: Hypertension, Pulmonary - Risk Assessment
- Oxygen Consumption - Exercise Tolerance
- Exercise Test
RESUMEN
Introducción: Las guías europeas
de hipertensión arterial
pulmonar (HAP) estratifican el riesgo valiéndose de características clínicas
y estudios complementarios entre los
cuales está la prueba cardiopulmonar de ejercicio (PCPE), de la cual toma en
cuenta 3 pará- metros: el consumo de
O2 (VO2) pico, su porcentaje respecto del predicho y la
pendiente ventilación minuto/ producción de dióxido de carbono (VE/VCO2). Sin embargo, ninguno de los
modelos que validaron esta forma de estratificar el riesgo incluyeron
la PCPE entre sus variables.
Objetivos: Determinar qué proporción de
pacientes con HAP del grupo I considerados de bajo riesgo y que caminan >440
metros en la prueba de caminata de 6 minutos (PC6M) tienen en la PCPE parámetros considerados de riesgo moderado o alto.
Material y métodos: Se incluyeron pacientes > 18 años con diagnóstico de HAP del
grupo I considerados de bajo riesgo con una PC6M
> 400 metros a los que se les
realizó una PCPE en la que se registró el VO2 pico, su porcentaje
respecto del VO2 predicho y la pendiente
VE/VCO2. Se determinó qué proporción de pacientes presentaban estos
parámetros en un estrato de riesgo mayor a bajo riesgo (VO2 pico < 15 ml/kg/min, su porcentaje
respecto del predicho
< 65% y la pendiente
VE/VCO2 >36).
Resultados: Se incluyeron 18 pacientes. A
pesar de ser pacientes de bajo riesgo y con buena clase funcional todos
presentaron un VO2 pico
menor al 85% del predicho, lo cual determina un deterioro al menos leve de la
capacidad funcional. Un único paciente (6%) presentó los tres parámetros evaluados en bajo riesgo, 8 pacientes (44%) tuvieron al menos un parámetro alterado,
7 pacientes (39%) presentaron 2 parámetros alterados y
en 2 pacientes (11%) todos los parámetros estuvieron alterados. Los parámetros
que más frecuentemente se vieron alterados fueron el porcentaje respecto del VO2
predicho y la pendiente VE/VCO2, en el 67% de los casos. Solo 4 pacientes presentaron un VO2
pico < 15 ml/k/m. Ningún paciente
presentó valores de VO2 pico o porcentaje respecto del predicho en la categoría
de alto riesgo. Sin embargo,
6 pacientes (33%) presentaron una pendiente VE/VCO2 considerada de alto riesgo.
Conclusión: El 94% de los pacientes
considerados de bajo riesgo presentaron al menos una variable en la PCPE que no
corresponde un perfil de riesgo bajo.
La pendiente VE/VCO2 y el porcentaje de VO2 pico respecto
del predicho fueron las variables más frecuentemente alteradas. La pendiente
VE/VCO2 fue la única que mostró valores considerados de alto riesgo.
La PCPE podría tener un lugar en la
estratificación de precisión de pacientes de bajo riesgo. El valor de este
hallazgo deberá ser evaluado en estudios prospectivos, al tiempo que genera las bases para el planteo de hipótesis
respecto de la estratificación de riesgo y la intensidad del tratamiento en pacientes
que aparentan estar en bajo riesgo.
Palabras clave: Hipertensión Pulmonar - Medición
de Riesgo - Consumo de Oxígeno - Prueba de Esfuerzo - Tolerancia al Ejercicio
Received: 12/12/2022
Accepted: 03/05/2022
INTRODUCTION
In 2015, the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS) guidelines proposed a multiparametric
tool of risk stratification to estimate the prognosis of patients with
pulmonary arterial hypertension (PAH) and guide treatment strategies. These
recommendations suggest classifying patientsas low
(mortality risk estimation <5% at 1 year), intermediate (mortality risk
estimation between 5-10% at 1 year) and high (>10% mortality risk estimation
at 1 year) risk, using clinical, imaging, and hemodynamic variables and
estimation of aerobic capacity, which are known to be associated with patient
prognosis. Among the latter, guidelines suggest using the World Health
Organization (WHO) functional capacity (FC), the sixminute
walking test (6MWT) and oxygen consumption (VO2) assessment in
cardiopulmonary exercise testing (CPET). (1) This risk evaluation tool in PAH was retrospectively
validated with different methods by three groups of investigators. The three
validation models demonstrated an adequate capacity to discriminate patient
prognosis. However, regardless of the method used, no group considered the use
of CPET or VO2 assessment, employing only the WHO FC and 6MWT, (2-4) which represents a limitation, as both the FC and 6MWT
present a prognostic performance inferior to CPET. (5,6) Firstly, there is no standardized way of assessing FC, a
subjective parameter which reflects in the high interobserver
variability in its evaluation, and the poor correlation between FC and maximum
VO2. (7,8) The 6MWT also presents several limitations: it is
influenced by age, body mass index, presence of comorbidities, (9) has little correlation with hemodynamic variables, (10) the changes in the distance walked are not translated
into modifications in the prognosis, (11,12) there is a “learning” effect, (13) and above all, it has a “ceiling” effect which
determines its poor sensitivity in low-risk patients. (14)
The objective of our study was to establish what
proportion of low-risk patients with PAH in FC I or II and who walk >440
meters in the 6MWT present moderate or high-risk parameters in CPET.
METHODS
Variable design and definition
A multicenter cross-sectional study was carried out including patients
>18 years with PAH, in agreement with the 2015
ESC/ERS guideline definition, (1) who were at low-risk
acaccording to the
simplified risk evaluation method of the French registry: FC I-II, NT-proBNP <300 pg/mL and 6MWT
>440meters. (4) Patients with congenital diseases were excluded
from the study.
The
CPET was performed in a treadmill (H/P Cosmos, Mercury Med, Germany)
within 90 days following risk stratification and the respiratory gas exchange
was continuously analyzed (Cosmed Quark CPET OMNIA
1.6/7 software). A Bruce or modified Bruce protocol was used, selected by the
operator according to the clinical conditions of the patient.
Dynamic
electrocardiographic changes (ST depression >1 mm) and arrhythmia occurrence
were reported. The recorded variables included heart rate (HR), blood pressure,
peripheral arterial oxygen saturation (SaO2), VO2, rate
of carbon dioxide production (VCO2) and minute ventilation (VE). The
respiratory quotient or respiratory exchange ratio (RER=VCO2/ VO2)
was used as indicator of maximum exercise. Maximum exertion was considered for
RER >1.1. Peak VO2 was definedas
average VO2 during the last minute of exercise and was expressed as
milliliters/minute/kilogram of body weight (ml/min/kg), and was also reported
as percentage of the predicted VO2 value (according to prespecified tables which take into account sex, age and
body surface area). Functional capacity was defined as normal when peak VO2/predicted
VO2 was ≥85%. The three variables considered for PAH risk
evaluation in the ESC guideline were: (1) peak
VO2, its percentage with respect to predicted VO2 and the
VE/VCO2 slope. The proportion of patients presenting these
parameters in a risk category above low was established (peak VO2
≤15 ml/min/ kg, percentage with respect to predicted VO2
≤65% and a VE/ VCO2 slope ≥36.
Statistical analysis
Categorical variables were expressed as frequency and percentage, and were analyzed
using the chi-square test or Fisher´s
exact test, as appropriate. Continuous variables were
expressed as mean and standard deviation, or median an interquartile range (IQR), according to their distribution. Student´s t test or the Wilkinson rank sum
test was used to compare two groups,
as appropriate. Statistical significance was
considered for p <0.05. Stata 13.0 software
package was used for statistical analyses.
Ethical considerations
The study was performed following the recommendations for medical
research stated in the Declaration of Helsinki, Good Clinical Practice standards and current ethical regulations. The protocol was reviewed and approved by the Ethical
Committees of the participating centers.
RESULTS
A total of 18 patients were included in the study and 16 (89%) were women. Median
age was 43.5 years
(IQR 33-51 years) and median time
from diagnosis to evaluation was 4.7 years (IQR 1.8-8.6 years). In half
of the cases (n=9) the etiology of HAP was idiopathic, in 6 cases it was
associated with connective tissue
disease, in 2 cases it was secondary to human
immunodeficiency virus (HIV) and in one case to portal hypertension.
Baseline population characteristics are described
in Table 1.
Table 1. Baseline variables
(n=18)
|
Female
sex, n (%) |
|
|
16 (89) |
|
Age,
years, median (IQR) |
|
|
43.5 (33-51) |
|
Functional class, n (%) |
|
|
|
|
I |
|
|
4 (22) |
|
II |
|
|
14 (78) |
|
Etiology,
n(%) |
|
|
|
|
Idiopathic |
|
|
9(50) |
|
CTD |
|
|
6(33) |
|
HIV |
|
|
2 (11) |
|
Portopulmonary |
|
1(6) |
|
|
6MWT,
m. median (IQR) |
|
|
484 (465-510) |
|
NT-proBNP, pg./mL, median (IQR) |
|
|
116 (59-272) |
|
MPAP,
mmHg, median (IQR) |
|
|
41 (33-50) |
|
RAP,
mmHg, median (IQR) |
|
|
6 (4-8) |
|
PVR,
Wood units, median (IQR) |
|
|
7,6 (4,7-8,9) |
|
CI,
L/m/m2, median (IQR) |
|
|
2,85 (2,4-3,2) |
|
N° drugs, n (%) |
|
|
|
|
1 2 3 |
|
|
1(11) 12 (67) 4 (22) |
|
|
|
|
|
6MWT:
6-minute walking test; CI: Cardiac
index; CTD; Connective tissue disease; HIV: Human immunodeficiency virus;
IQR: Interquartile range;
MPAP: Mean pulmonary artery
pressure, PVR: Pulmonary vascular resistance; RAP: Right atrial
pressure.
All patients evaluated presented an exercise functional
capacity below 85% of the predicted value (Table 2). Only one female patient presented the three parameters assessed in the low-risk level.
Eight patients (44%) had at least one abnormal parameter, 7 patients (39%) presented 2 altered
parameters and in 2 patients
all the parameters were anomalous. The most frequently
altered parameters were the percent- age with respect to predicted VO2 and the VE/VCO2 slope in 67% of cases. Only 4 patients
presented VO2 <15 ml/kg/min. No patient evidenced
peak VO2 or percentage
of predicted VO2 values in the high risk category. However, 6 patients (33%) presented a VE/ VCO2 slope considered as high risk (Figure 1).
Table 2. Cardiopulmonary exercise
testing results
|
O2 consumption, ml/kg/min, median (IQR) |
17,5 |
(15.5-20) |
|
|
% predicted O2 consumption, median (IQR) |
|
60 |
(56-66) |
|
MV/VCO2 slope, median (IQR) |
|
39 |
(33-49) |
|
O2 consumption <15
ml/kg/min, n (%) |
|
4 |
(22%) |
|
Predicted O2 consumption <65%, n (%) |
|
12 |
(67%) |
|
MV/VCO2 slope >36,
n (%) |
|
12 |
(67%) |
|
MV/VCO2 slope >45,
n (%) |
|
6 |
(33%) |
|
N° of abnormal parameters |
|
|
|
|
|
0 |
1 |
(6%) |
|
|
1 |
8 |
(44%) |
|
|
2 |
7 |
(39%) |
|
|
3 |
2 |
(11%) |
IQR: Interquartile range; VO2: oxygen consumption; VE/VCO2: Minute ventilation/carbon dioxide
production.
Fig. 1. Graphic distribution of variables
considered in cardiopulmonary exercise testing
according to the risk category
of the 2015 ESC/ERS guidelines. (1)
Red: high risk; Yellow: intermediate risk; Green: low risk; VO2: O2 consumption; VE: Minute ventilation; VCO2: CO2 production
DISCUSSION
Despite having included a population of patients who at the time of CPET were at a low-risk
level and with preserved functional
capacity, all the patients evaluated presented a peak VO2 <85% of
the predicted value, which indicates
at least mild impairment of functional capacity.
(15) Only one patient presented all the parameters evaluated within
the low-risk profile.
Surprisingly, this patient was a woman treated with three drugs: phosphodiesterase-5 inhibitor, endothelin receptor antagonist,
and intravenous prostanoid, which were started simultaneously in the context of
cardiogenic shock 30 months prior to this evaluation. Although
this evolution would seem unexpected, it is consistent with the results
recently published by Boucly et al., who report a
5-year survival of 91% in 76 high-risk patients who were treated with initial triple therapy, including a parenterally administered prostanoid.
(16)
The rest of the patients (92%) presented at least one altered parameter in CPET. This may be due to the
inherent limitations of FC assessment and the diagnostic sensitivity of the 6MWT. The population of our study was significantly younger than the low-risk
population of the European registries in which the risk stratification proposed by the ESC/ERS guidelines was validated: median
age of 43.5 years vs. mean of 52±17 years in the German registry; mean of 57±17
years in the French registry
and median of 57 (IQR 39-68) years in the Swedish registry.
(2-4) The fact that the patients
are younger may affect the sensitivity of the 6MWT to detect FC impairment. (14) In the same
sense, the fact that patients
have several years
of disease evolution and therefore have performed the 6MWT on repeated
occasions can generate
a "learning" effect that conditions
its diagnostic capacity.
(13) Recent publications have sought to subdivide the moderate-risk population into two strata:
moderate- low and moderate-high risk. (17) Even Badagliacca et al. demonstrated and validated the value of CPET in the substratification of moderate-risk patients.
(18) This substratification has important implications when making therapeutic decisions, both pharmacological as in time of inclusion
on the lung transplantation list. (19) However, and despite the fact that low- risk patients
present a non-negligible rate of events,
as the 5-year mortality in the Swedish,
French, and German
registries was 8%, 9% and 31.9% respectively, (2-4) little has been done to identify which patients considered to be at low risk are more likely of disease
progression and even of suffering fatal events. Similarly, the lowest
mortality, 8% at 5 years, reported by the
Swedish registry, does not seem at all auspicious if we consider that our population had an average age of 43 years. The CPET is then seen as a very useful tool to better identify those patients at
higher risk who require a more aggressive treatment strategy with triple therapy
and/or parenteral drug administration.
A recent study analyzed the mortality of incident patients
diagnosed with PAH according to whether they started treatment before or after the
publication of the 2015 ESC/ERS
guidelines, which advocate the initiation
of treatment with two drugs. (20) Although the
investigators found that as of 2015 the percentage of patients who started
combination treatments had significantly increased, this did not translate
into a reduction of mortality;
nevertheless, what was associated with lower mortality was reaching a low-risk stratum. In this same sense, although our
work does not allow us to draw definitive
conclusions, it can hypothesize about the importance of reaching a state of "absolute low
risk". We understand as such, an exhaustive
risk assessment strategy based on a method that allows FC to be estimated in an objective, measurable, reproducible manner that is correlated with hemodynamic parameters and whose variations correlate with the prognosis
of the disease, such as CPET. (5,6) Another
clinical scenario of potential value for CPET concerns
those patients who, thanks to treatment, have reached a low-risk state and for some reason the possibility of de-escalating treatment
is being considered. Although, in principle, we do not believe that there is any valid situation that warrants de-escalating treatment when the objective, that is so difficult to achieve, has been reached, it is not unusual for this possibility to be raised, both in the literature and in daily
practice. (21,22). In this sense, CPET could establish if the patient really has a preserved
FC prior to the start of medication reduction and could detect a possible deterioration of the FC before it is clinically manifest. However, and mindful of the presence
of studies that show that patients who worsened their
condition by reducing
the intensity of treatment do not recover
the lost well-being when a rescue
treatment is administered, we strongly advise against venturing
to reduce the intensity of treatment if no serious
adverse effects occur.
(23).
Our work has multiple limitations. In the first place, it is a small sample due to the
fact that we are analyzing a disease considered rare, where
most of the patients present at
moderate or high-risk levels, and less than 30% are in FC I or II. (2-4) Secondly, although these are all patients
who have been diagnosed a while ago, there is a great dispersion
regarding the time of disease
development. Another point that deserves to be mentioned is the heterogeneity
that exists in terms of treatment. Although 12 patients (67%) are being treated with 2 drugs (an endothelin receptor antagonist and a 5-phosphodiesterase inhibitor), 2 are
treated with 1 alone, and 4 with 3 drugs: 2 with selexipag, 1 with intravenous epoprostenol and 1 with
subcutaneous treprostinil. This treatment
heterogeneity suggests that, although they are patients with different evolutionary stages, it does not
rule out the hypothesis underlying
this study, which does not intend to compare
one patient with another directly, but rather the possibility of disease
progression with the consequent need
to eventually require a more aggressive treatment, either pharmacological or a
transplant, according to the baseline treatment.
CONCLUSIONS
All except one of the patients considered as low risk and who walk more than 440 meters in 6
minutes, presented at least one
altered variable in CPET. The VE/VCO2 slope and the percentage of predicted O2 consumption were the most frequently altered variables. The VE/VCO2 slope was the only one that showed
values considered as high risk. The CPET could have a place in the substratification of
low-risk patients and thus allow the
identification of a stratum of "absolute low risk". The importance of
reaching this level of "absolute
low risk" in terms of prognosis and patient survival should be evaluated in prospective studies.
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©Revista Argentina de Cardiología
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