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CIRCULATIONAHA.117.029254

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10.1161/CIRCULATIONAHA.117.029254
The Prognostic Value of Follow-up Hemodynamic Variables After Initial
Management in Pulmonary Arterial Hypertension
Running Title: Weatherald et al.; Hemodynamics and Prognosis in PAH
Jason Weatherald, MD1,2,3,4; Athénaïs Boucly, MD1,2,3; Denis Chemla, MD, PhD1,2,5;
Laurent Savale, MD, PhD1,2,3; Mingkai Peng, PhD6; Mitja Jevnikar, MD1,2,3;
Xavier Jaïs, MD1,2,3; Yu Taniguchi, MD, PhD1,2,3; Caroline O'Connell, MD1,2,3;
Florence Parent, MD1,2,3; Caroline Sattler, MD1,2,3; Philippe Hervé, MD1,2,3;
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Gérald Simonneau, MD1,2,3; David Montani, MD, PhD1,2,3; Marc Humbert, MD, PhD1,2,3;
Yochai Adir, MD7*; Olivier Sitbon, MD, PhD1,2,3*
1
Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre,
Krem
mlin
in-Bi
Biccêt
Bi
être
re,,
re
France; 2Service de Pneumologie, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre, France;
3
4
INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France;
University
Univ
Un
iveersi
iv
sity
si
ty of
of Calgary,
Ca
Department of Medicine,
Medicin
ne, Division of R
Respirology,
espiro
rology, Calgary, Alberta,
Canada; 5Serv
Service
rvicee de Physiologie,
Phy
hysi
siolog
log
ogie
i ,H
Hôpital
ôpitall B
Bicêtre,
iccêtree, AP
AP-HP
AP-HP,
HP, Le
HP
Le K
Kremlin-Bicêtre,
reemlin
in--Bi
in
Bicêt
être
êt
re, Fr
re
France;
ran
ance;;
6
Department
D
epartment
nt off Co
Com
Community
mmun
unnity Health S
Sciences
ciencees an
and
nd Li
Libi
Libin
binn Ca
bi
C
Cardiovascular
arrdio
ovascul
ularr IInstitute
nstitutee of
of Alberta,
Albertaa,
University
Calgary,
Calgary,
Alberta,
Canada;
Uniiverrsi
Un
sity
t ooff Ca
ty
Calg
gar
aryy, C
algaary
al
r , Al
Albe
bertta,
a C
an
nad
a a;; 7Lady
Lady D
Davis
av
vis C
Carmel
arrme
m l Me
Medi
Medical
dica
di
c l Ce
ca
C
Center,
nter
nt
er,
Pulmonary Division, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel
*Yochai Adir and Olivier Sitbon contributed equally and are both last authors.
Address for Correspondence:
Olivier Sitbon, MD, PhD
Service de Pneumologie et Soins Intensifs
CHU de Bicêtre
78 rue du General Leclerc, F-94275
Le Kremlin-Bicêtre, France
Tel: +33 1 45 21 79 72
Fax: +33 1 45 21 79 71
Email: olivier.sitbon@aphp.fr
Jason Weatherald, MD
Peter Lougheed Centre
3500 26 Ave NE
Calgary, Alberta, Canada
T1Y 6J4
Tel: +1 403 943 4779
Fax: +1 403 943 4017
Email: jcweathe@ucalgary.ca
1
10.1161/CIRCULATIONAHA.117.029254
Abstract
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Background—Hemodynamic variables, such as cardiac index and right atrial pressure (RAP),
have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the
time of diagnosis. Recent studies have suggested pulmonary arterial compliance (PCa) may also
predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after
treatment initiation is less well established.
Methods—Our objective was to evaluate the prognostic importance of clinical and
hemodynamic variables during follow-up, including PCa, after initial management in PAH. We
evaluated incident patients with idiopathic, drug and toxin-induced or heritable PAH enrolled in
the French pulmonary hypertension registry between 2006-2016 who had a follow-up right heart
catheterization (RHC). The primary outcome was death or lung transplantation. We used
stepwise Cox regression and receiver-operating characteristic analysis to assess variables
obtained at baseline and at first follow-up RHC.
Results—Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median
follow-up duration of 2.8 years (IQR25-75% 1.1-4.6). In a multivariable model considering only
baseline variables, no hemodynamic variables independently predicted prognosis. Median time
follow up RHC was 4.6 months (3.7-7.8).
(3.7 7.8). At first follow-up
follow up RHC (n=763),
(n 763), New
N w York
Ne
too first follow-up
tro
roke
ke vvolume
olum
ol
umee
um
Heart Association (NYHA) functional class, 6-minute walk distance (6MWD), st
stroke
ndex (SVI), and right atrial pressure (RAP) were independently associated with de
deat
a h or llung
at
ungg
un
index
death
transplantation,
ransplantation, adjusted for age, gender, and etiology of PAH. PCa did not independently
predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28
(95%CI
95%CI 1.11-1.49, p<0.01) per 10 mL/m2 decrease, and for RAP was 1.05 (95%CI 1.02-1.09,
p<0.01)
p<0.01
01)) pper
01
err mm
mmHgg increase. Among patients whoo hhad
ad 2 (n=355) oorr 3 ((n=193)
n=193) low-risk
prog
oggnostic features
feat
attures
e at fo
oll
llow
o -u
ow
-upp LQ
LQFO
F XG
GLQ
L JDFD
F UGLD
FD
LDFLQ
QGH
GH[
[ • 2.5
5 L/
L/mi
m n/
n/m2, 6M
6MWD
WD > 4440
40 m and
and
prognostic
follow-upLQFOXGLQJDFDUGLDFLQGH[•
L/min/m
either
eith
her NYHA I or III fun
functional
unnctio
ona
nal class
class,
s, low
lower
ower SV
SVI
VI wa
was st
still
till associated
asso
sociatted wi
so
with
ith
h hi
hig
higher
gher rates
rat
a es off deathh or
at
lung
ungg transplantation
transplan
nta
tati
t on (p<0.01).
(p<
p<0.011).
Conclusions—SVI
Conc
clu
lusi
s on
si
ns—SV
VI and
nd RAP
P were
w ree the
we
the hemodynamic
hem
e oddyn
y am
micc variables
var
a iaabl
bless independently
ind
nddep
e en
ndent
ntly
nt
ly associated
ass
ssoc
ss
ociate
oc
ted with
h
death or lung transplantation at first follow-up RH
RHC
C after initial PAH
PA
AH treatment. These findings
suggest that the SVI could be a more appropriate treatment target than the cardiac index in PAH.
Key Words: pulmonary hypertension; hemodynamics; primary pulmonary hypertension;
prognosis
2
10.1161/CIRCULATIONAHA.117.029254
Clinical Perspective
What is New?
x
Baseline hemodynamic variables did not predict the risk of death or transplantation in a
large cohort of incident patients with pulmonary arterial hypertension (PAH).
x
Following initial treatment of PAH, stroke volume index and right atrial pressure at first
follow-up right heart catheterization were the strongest independent hemodynamic
prognostic variables.
x
Stroke volume index had greater predictive value than cardiac index or pulmonary
arterial compliance, and low stroke volume index identified patients with a worse
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
prognosis even when cardiac index was within the low-risk range (•/PLQP2).
What are the clinical implications?
x
Hemodynamic variables remain central to a multidimensional assessment of prognosis
and treatment response in PAH.
x
While
Whil
Wh
ilee the
il
t e importance
th
i portance of right atrial pressu
im
pressure
uree was confirme
confirmed,
medd, stro
stroke
roke volume index could
tter hhemodynamic
emo
ody
dyna
naami
m c variable
vari
va
r ab
ble to monitor
monito
mo
tor inn prognostication
pro
rogn
gnosstica
gn
tii ati
tionn andd to
to consider
cons
co
nsider
ns
err as a P
A
AH
be a bet
better
PAH
treatmen
ent ta
en
target
et than
n tthe
he cardia
ac index,
indexx, which
whi
hich
ch is
is currently
curr
cu
rren
rentlyy recommended
recomm
mm
mended fo
or ri
iskk
treatment
cardiac
for
risk
assessment
a se
as
sess
ssme
ss
m nt iin
me
n ma
manyy iinternational
nter
nt
erna
er
nati
na
tional
ti
al guidelines.
gui
uide
deli
de
line
ness.
3
10.1161/CIRCULATIONAHA.117.029254
Pulmonary arterial hypertension (PAH) is a disease characterized by obliteration and remodeling
of the small pulmonary arteries, leading to progressively increased pulmonary vascular resistance
(PVR), right ventricular failure and death in most patients1,2. Right heart catheterization (RHC)
remains the gold standard for diagnosis and assessment of PAH severity1,2,3. Current guidelines
recommend a multidimensional approach using clinical, echocardiographic, exercise and
hemodynamic variables in the risk stratification of patients in order to inform prognosis and
guide treatment decisions1–5.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Numerous studies have evaluated the prognostic utility of hemodynamic variables at the
time of diagnosis. Most studies have suggested that cardiac output (CO) or cardiac index (CI)
and right atrial pressure (RAP) at baseline predict prognosis in PAH6–11. Other co
conventionally
onvven
enti
tiion
onal
ally
al
ly
measured variables such as mean pulmonary arterial pressure (mPAP) and PVR have
inconsistently
nconsistently been related to prognosis6,7,10–12. There has also been interest in the prognostic
util
lit
ityy of otherr calculated
calcu
culaate
cu
tedd hemodynamic
h mo
he
mody
dyna
dy
namiic variables,
na
variab
ble
l s, suc
ch as ppulmonary
u mo
ul
ona
n ry aarterial
r eria
rt
iall co
ia
omp
mplian
a ce ((PCa),
an
PCa),
PC
utility
such
compliance
8,13,14
,13,144
which
whic
ichh influenc
ic
influences
ces tthe
he ppulsatile
ulsatiilee compo
component
p neent of right
riight ventricular
ven
ntr
tric
icul
ic
ular
l r afterload
afteerload
d8,
. So far,
farr, fe
few
ew studie
studies
ies
14–18
18
have evaluated the prognostic utilit
utility
i y of hhemodynamic
emodynamic variables aft
after
f er treatment initiation
initiatio
i n14
.
Therefore, the optimal hemodynamic profile during follow-up is less established, with relatively
little evidencHVXSSRUWLQJWKHKHPRG\QDPLFWUHDWPHQWJRDOVRI5$3PP+JDQG&,•
L/min/m2 recommended by the most recent international guidelines1–3.
The main objective of this study was to determine the prognostic importance of measured
and calculated hemodynamic variables at diagnosis and at first follow-up right heart
catheterization (RHC) in PAH.
4
10.1161/CIRCULATIONAHA.117.029254
Methods
The data, analytic methods, and study materials will not be made available to other researchers
for purposes of reproducing the results or replicating the procedure. This study complied with the
Declaration of Helsinki. Although French law does not require ethics committee approval or
informed consent for retrospective data collection, the data collected in the French Pulmonary
Arterial Hypertension Network registry were anonymized and complied with the requirements of
the Commission Nationale Informatique et Liberté (CNIL). CNIL, the organization dedicated to
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
privacy, information technology and civil rights in France, approved the methods used to collect
and analyze data on May 24, 2003 (approval number 842063).
Patient Population
This was a retrospective study of incident patients from the French Pulmonary Arterial
HySHUWHQVLRQ1HWZRUNUHJLVWU\ZKRZHUHHQUROOHGEHWZHHQ-DQXDU\DQG0D\ZHUH•
y
HySHUWHQVLRQ1HWZRUNUHJLVWU\ZKRZHUHHQUROOHGEHWZHHQ-DQXDU\DQG0D\ZHUH•
18 years
years of agee an
andd di
iag
gno
nose
sedd wi
with
th idiop
opathic,, heritable
herritable
le oorr dr
drug
ug-iind
n uc
u ed PAH
AH.. Pa
AH
Pati
t en
nts were
werre
diagnosed
idiopathic,
drug-induced
PAH.
Patients
ncllud
uded if they
ey had
ad a ccalculable
alcu
ulable
laa follow
ow--up time
m , PA
me
PAH
H di
diag
agno
nosedd bby
yR
HC
C aand
nd at least
leeastt 1 followfollow
owincluded
follow-up
time,
diagnosed
RHC
up RHC
C afterr diagnosis. Diagnosis of PAH
A was according to current guid
i elines and def
fined as
guidelines
defined
P3$3•PP+JSXOPRQDU\DUWHU\ZHGJHSUHVVXUH”PP+JDQG395!:RRGXQLWVRQ
baseline RHC. "Incident" patients in the registry were defined as those meeting these
hemodynamic criteria at the time of their first RHC and follow-up time was calculated from this
date. Patients were excluded if there were incomplete hemodynamic data precluding the
calculation of stroke volume or PCa.
Measurements
Clinical measurements included New York Heart Association (NYHA) function class and 6minute walk distance (6MWD). For NYHA class IV patients with missing 6MWD values at
5
10.1161/CIRCULATIONAHA.117.029254
baseline (n=33) and at first follow-up (n=24) a value of 0 m was assumed. Hemodynamic
measurements included calculation of stroke volume index (SVI) from the cardiac index (CI)
divided by heart rate (HR), and PCa, calculated by stroke volume divided by pulse pressure (the
difference between systolic and diastolic pulmonary arterial pressure). Initial treatment strategy
was defined according to number of PAH-specific medications prescribed within 4 months of the
initial diagnostic RHC. The primary outcome for survival analysis was all-cause mortality or
lung transplantation.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) for normally distributed
or median (interquartile range 25%-75%) for non-normally distributed variables. No
orm
rmal
alit
al
ityy wa
it
w
Normality
wass
assessed using the Kolmogorov-Smirnov test. Categorical variables were expressed as absolute
and relative frequencies (%). The paired t-test, Wilcoxon signed-rank test, and Chi-square test
were
re used to ccompare
ompa
om
paree cchanges
pa
hang
ha
n es ffrom
rom
ro
m ba
ase
s line tto
o fo
olllow
w-u
-upp.
p.
baseline
follow-up.
Transpl
p ant-ffree surv
pl
vival time was
was defin
ned ffrom
rom
m th
thee date
d te of
da
of firstt RHC
RH
HC to date
t of
te
of death or
or
Transplant-free
survival
defined
ung transplantation for analysis off baseline
baselline factors, and from the date
d te of foll
da
low-up RH
RHC to date
date
lung
follow-up
of death or lung transplantation for analysis of follow-up variables. Surviving patients were
censored at date of last clinical contact. We examined the relationships between demographic
(age, gender, PAH etiology, body mass index), clinical (NYHA functional class, 6MWD) and
hemodynamic variables at baseline and at the time of first follow-up RHC using Cox
proportional hazards regression. Variables with a p-YDOXH”IURPXQLYDULDEOHDQDO\VLVZHUH
entered into a stepwise forward multivariable Cox proportional hazards regression model.
Stepwise addition of covariates was accepted if there was a significant (p<0.05) difference in log
likelihood between the models at each step using the likelihood ratio test. Variables with a p-
6
10.1161/CIRCULATIONAHA.117.029254
value >0.05 were removed from the multivariable model. One model assessed only baseline
variables and another model included only follow-up variables and demographic factors. To
assess the association between relative changes in hemodynamic variables from baseline to
follow-up and transplant-free survival, we derived Cox proportional hazards functions for each
hemodynamic variable at follow-up with age, gender, and PAH etiology as covariates. Based on
the beta coefficients from the predicted survival functions derived from the study population and
using the population mean or median values for each covariate, we estimated survival functions
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
for 20% incremental relative changes from baseline for a 'typical' or 'average' patient. To explore
the potential interaction between relative changes for each hemodynamic variable and their
baseline value, univariable Cox models were performed for the percent change fro
rom
m ba
base
s li
se
line
ne iinn
from
baseline
he overall population and within each baseline quartile for each hemodynamic variable.
the
Receiver ope
p rating characteristic analysis was used to determine the area under the curve (AUC)
operating
for co
ontinuouss vvariables
arriaablles iidentified
d nttif
de
ifie
iedd fr
ie
ffrom
om
m the m
u tiva
ul
variab
able
ab
le rregression,
egreesssio
eg
on,
n and
and
n opt
ptim
pt
imal
im
al cut points
poi
oint
n s were
nt
w re
we
continuous
multivariable
optimal
dete
erm
r ined byy th
he vvalue
alu
ue ma
aximizingg the
he sum of
o sensitivity
sen
ensiiti
tivi
vity
vi
ty and
and spe
pecifici
city
y199. Transplant-free
Transp
splaant-free
sp
determined
the
maximizing
specificity
survival
urvivall was estimatedd by the Kaplan-Meier
Kapla
l n-Meier meth
method
hod and compared
d across hemod
hemodynamic
dynamic groups
using the log-rank test. Proportional hazards assumptions were tested graphically using logminus-log versus log-time plots and observed-versus-predicted Kaplan-Meier plots. All tests
were two-sided with a p<0.05 considered statistically significant. Statistical analyses were
performed using SPSS version 17.0 (IBM, Armonk, New York, USA) and STATA version 13.1
for Mac (College Station, Texas, USA).
7
10.1161/CIRCULATIONAHA.117.029254
Results
Study Population
Patient selection is shown in Figure 1. The analysis cohort included 981 incident patients at
baseline and 763 patients who had a follow-up RHC with complete data. Baseline characteristics
are shown in Table 1. Median age was 64 years and 59.2% were female. The majority of patients
had idiopathic PAH (76.2%) and 12.5% had a positive vasoreactivity test at diagnostic RHC1,2.
Baseline 6MWD was 319 ± 135 meters, and 75.3% of patients presented in NYHA functional
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
class III or IV. Among the baseline cohort (n=981), a primary outcome occurred in 331 patients
(33.7%) over a median follow-up duration of 2.8 (1.1 - 4.6) years, of which 307 (92.7%) events
nd 33-years
-ye
year
ye
as
were deaths and 24 (7.3%) were due to lung transplantation. Overall survival at 1, 2, aand
y ((Supplemental
Supplemental Figure E1).
from diagnosis was 89.9%, 81.4% and 72.9%, respectively
Transplant-free survival at 1, 2, and 5-years was 89.3%, 80.7%, and 71.4%, respectively
Su
upp
pplemental
al Figure
Fig
igurre E2).
ig
E2)
(Supplemental
nittia
al Treatment
Treatm
ment S
tra
rategiies
Initial
Strategies
irst 4 months fo
ffollowing
llowing diagnostic
The most frequently used initial treatment strategy within the ffirst
RHC was oral monotherapy (46.0%) followed by dual oral combination therapy (29.7%) (Table
1). Upfront triple combination therapy with an endothelin receptor antagonist, phosphodiesterase
type-5 inhibitor and a prostacyclin analogue was used for 55 patients (5.6%).
Changes in Clinical and Hemodynamic Variables with Treatment
At the time of first follow-up RHC (n=763, median interval 4.6 months, IQR 3.7-7.8), there were
significant improvements in NYHA functional class and 6MWD (Table 2). A majority of
patients were in NYHA class III-IV at baseline, while a majority of patients (60.3%) were in
NYHA function class I-II at first follow-up RHC. Median 6MWD improved from 330 to 384
8
10.1161/CIRCULATIONAHA.117.029254
meters (p<0.001). Mean pulmonary arterial pressure decreased by 9% at first follow-up along
with a significant increase in CI, which was related to an increase in stroke volume index, while
heart rate slightly decreased (Table 2). As a result, median PVR decreased from 9.2 to 6.1 Wood
units (p<0.001) and PCa significantly increased (p<0.001).
Baseline Variables Associated with Death or Transplantation
Predictors of death or transplantation at the time of diagnosis are shown in Table 3. Significant
predictors in univariable analysis were increasing age, male gender, idiopathic PAH etiology (vs.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
drug-induced), NYHA functional class, 6MWD, RAP, CO, CI, SV, SVI and PCa. Due to 359
missing baseline values for SvO2, this variable was not included in further multivariable analysis.
Independent
ndependent baseline predictors of death or lung transplantation in multivariable Cox
Co
ox regression
regr
re
gres
gr
e si
es
sioon
were: age, male gender, idiopathic PAH etiology, NYHA functional class and 6MWD. No
baseline hemodynamic variables were significant in multivariable analysis.
Association
Asso
socciation off Variables
so
Var
ariabl
b es from
fro
om First
Firs
Fi
r t Fo
rs
FollowFollow-Up
-Up
U R
Right
ight
ht Heart
Hea
eart
r Catheterization
Cat
a he
h te
teriza
ati
tion
on wi
w
with
th D
Death
eath
ea
th oorr
Lung
ng Transplantation
Transpl
pllanta
tation
on
Transplant-free
Transpla
l nt-fr
f ee survival according to the SV
SVI,
VI, R
RAP,
AP, CI, and HR
AP
R quartiles at follow-up
f llow-up RHC are
fo
shown in Figure 2. Lower SVI and CI quartiles, and higher RAP quartiles were associated with
higher rates of death or lung transplantation (p< 0.001 for each). There was no significant
difference across HR quartiles (p=0.13). Among 355 (46%) patients who had 2 "low-risk"
criteria according to current international guidelines1–3 1<+$,RU,,DQG&,•/PLQP2) at
the time of follow-up RHC, patients in lower SVI quartiles had significantly worse survival
(p<0.01) whereas the difference between RAP quartiles was of borderline significance in this
low-risk group (p=0.051) (Supplemental Figure E3). The association of SVI quartiles with
death or lung transplantation also remained when considering the subgroup of patients achieving
9
10.1161/CIRCULATIONAHA.117.029254
3 low risk criteria (n=193) at follow-XS1<+$,RU,,&,•/PLQP2 and 6MWD > 440m)
whereas prognosis did not differ according to RAP quartile in this subgroup (p=0.15)
(Supplemental Figure E3). There was no significant difference in outcome between HR
quartiles within these subgroups of patients with 2 (log-rank test p = 0.051) or 3 low-risk criteria
(p = 0.14) (Supplemental Figure E4). At the time of first follow-up RHC, NYHA functional
class, 6MWD, and all hemodynamic variables were associated with the risk of death or
transplantation in univariable Cox proportional hazards regression analysis considering each as a
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
continuous variable (Table 3). Due to 251 missing follow-up SvO2 values, it was not included in
multivariable analysis. Stroke volume index (adjusted hazard ratio 1.28 per 10 mL/m2 decrease,
95%CI 1.11-1.49, p=0.001) and RAP (adjusted hazard ratio 1.05 per mmHg increase,
increa
ease
se, 95
se
95%
% CI
1.02-1.09, p=0.001) at first follow-up RHC were the only hemodynamic variables associated
with death or transplantation. We performed sensitivity analyses by excluding the 79 patients
with
h a positivee vvasoreactivity
aso
soreeac
acti
tivi
ti
v ty
vi
y ttest
estt ((Supplemental
es
S pp
Su
pplement
n al Table
nt
Tab
blee E1)
E1) an
and
nd ex
eexcluding
c ud
cl
udingg th
thee 51 pat
patients
tieent
ntss who
wh
received
eceeiv
ived no PA
PAH-specific
AH-sppeccific the
therapy
herapy or wh
he
who rece
received
eiv
ved
d onl
only
nlyy ca
nl
ccalcium
lciu
lc
um ch
channe
channel
nel bl
blockers w
within
itthi
h n the fi
first
4 months
h off diagnosis (Supplemental
(Supplemental Table E2
E2),
2), which did not change
cha
h nge our results. As
A
hemodynamic variables were correlated (Supplemental Table E3), we also compared Cox
regression models by sequentially adding only hemodynamic variables that had correlation
coefficients (absolute value) < 0.6, and which resulted in significant improvement in log
likelihood compared to the previous model (Table 4). In these models RAP, CI, SVI, PVR and
PCa at follow-up RHC each were associated with the risk of death or transplantation when
adjusted for age, gender, PAH etiology, 6MWD at follow-up and NYHA functional class at
follow-up. The adjusted model for SVI (Model C) had a lower Akaike information criteria value
than the models for CI (Model B) or PCa (Model E), indicating a better model fit for SVI.
10
10.1161/CIRCULATIONAHA.117.029254
The percent change from baseline was also associated with the risk of death or
transplantation for most hemodynamic variables in univariable analysis (Supplemental Table
E4). Because the percent change does not account for variance in the baseline value of
hemodynamic variables20, hazard ratios for percent change are also provided according to the
highest and lowest quartiles of each hemodynamic variable at baseline. The percent changes in
RAP, CI and HR were not associated with mortality and lung transplantation in the most
favorable baseline quartile for each measure (i.e., lowest HR and RAP quartile and highest CI
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
quartile), but were associated with this outcome in the least favorable quartiles (highest HR and
RAP and lowest CI). In contrast, percent change in mPAP, SVI, PVR and PCa were
ignificantly associated with death or lung transplantation regardless of the baseli
inee qu
quar
arti
ar
tile
ti
l .
le
significantly
baseline
quartile.
Calculated predicted survival curves for percent change in hemodynamic variables for a 'typical'
g pa
ppatient
tient are shown in Figure 3.
or average
From rreceiver
eceiive
ec
v r operating
opper
erat
a in
ng characteristic
char
ch
a accte
ar
teristic analysis,
anaaly
lysis,
s, the
the optimal
opt
p im
mall cut
cutt point
point
nt ffor
or S
V at
VI
at follow-up
foll
fo
l ow
ll
ow-up
SVI
8 mL/m2 ((AUC:
A C:: 00.68,
AU
.68,, 95%CI
95%CI 0.6
0.64-0.72,
64-0.72,, pp<0.01)
<0.
0.011) and
and fo
ffor
orr RA
RAP
AP w
was
ass 9 m
mmHg
mHg ((AUC
AUC 0.62
AU
0.62,
2,
wass 338
95%CI 0.57-0.67, p<0
p<0.01).
0.01). The optimal cut point ffor CI at first fol
follow-up
llow-up RH
RHC
HC was 2.
22.7
7
L/min/m2 (AUC 0.64, 95%CI 0.60-0.67, p<0.01), for PVR at follow-up was 6.6 Wood units
(AUC 0.66, 95%CI 0.61-0.70, p<0.01), for HR was 81 bpm (AUC 0.57, 95%CI 0.53-0.62) and
for PCa at follow-up was 1.5 mL/mmHg (AUC 0.65, 95%CI 0.61-0.70, p<0.01) (Supplemental
Table E5).
Discussion
The main finding of this study was that SVI and RAP were the only hemodynamic variables
independently associated with death or lung transplantation at the time of first follow-up right
11
10.1161/CIRCULATIONAHA.117.029254
heart catheterization in a large cohort of incident patients with idiopathic, drug-induced and
heritable PAH. Furthermore, a low SVI still identified patients with poorer outcomes among
subgroups of patients who otherwise had 2 or 3 lower risk features (NYHA I or II, &,•
L/min/m2, 6MWD > 440 m). The prognostic value of SVI was maintained even when excluding
patients who did not receive PAH specific therapy in the first 4 months after diagnosis and when
excluding patients with an acute response during vasoreactivity testing.
Our analysis confirmed the known association between several baseline clinical
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
characteristics such as male gender, older age, PAH etiology, NYHA functional class and low
baseline 6MWD with a worse prognosis7,11,12,21. A recent study suggests that 6MWD
outperformed NYHA functional class at baseline in predicting survival across var
various
rio
ous ppulmonary
ulmo
ul
mona
mo
n ry
na
hypertension subgroups22. At the time of first follow-up, both 6MWD and persistent NYHA
functional class III or IV were associated with the risk of death or transplantation, confirming
previous
prev
vio
ious studies
es sho
showing
howi
ho
w ng tthat
wi
hatt th
ha
thes
these
esee clin
es
clinical
nic
i al variables
var
a ia
ar
i bl
bles pprovide
rovi
ro
vide
vi
de imp
important
mp
por
o ta
t nt prognostic
proogn
gnos
osti
os
ticc info
ti
information
form
fo
rmat
rm
atio
at
ion
io
14–16
4–16
during
duri
ring
ri
n followng
follow-up
-up14
.
While
While
l many studies have shown
sho
h wn the prognostic significance of bo
bboth
th C
CII and RA
RAP
AP at the
h
time of diagnosis, this was not observed in our study. This may reflect major changes in therapy
compared previously published prospective cohorts6,7,11,12. Indeed, 39% of patients in our cohort
were treated with upfront dual or triple therapy. More aggressive initial therapy resulted in more
pronounced hemodynamic improvements, as evidenced by not only a decrease in PVR and
improvement in CI but also a 9% decrease in mPAP at first follow-up in our cohort (Table 2).
Therefore, larger hemodynamic changes with more aggressive treatment in the most severe
patients could have obviated the association of baseline hemodynamic values with prognosis.
This hypothesis requires confirmation in prospective studies, however.
12
10.1161/CIRCULATIONAHA.117.029254
The importance of hemodynamic values during follow-up is less well established. The
prognostic importance of SVI during follow-up in our study extends, to a large population
(n=763), the results from van Wolferen et al., who found that cardiac magnetic resonance
imaging-derived measurements of SVI and right ventricular end-diastolic volume at follow-up
were independent predictors of survival in 54 patients with IPAH23. Nickel et al. found that
changes in cardiac index, but not SVI, at follow-up RHC were predictive of survival in IPAH16.
The discrepancy from our results could be explained by smaller numbers of patients in the
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Nickel et al. study (n=109), missing values for SVI in 25% of patients in that study, and the
observation that SVI significantly decreased between baseline and first follow-up, possibly
eflecting less aggressive or less effective treatment. The consideration of absolut
te values
valu
va
lues
lu
e ooff
es
reflecting
absolute
hemodynamic variables as treatment targets, as assessed in our study, is likely preferable to
changes from baseline. Absolute value cutoffs are applicable to all patients ffor treatment goals
d the
th changee iin
n a he
emo
mody
d naami
dy
m c va
vvariable
riab
able may
a dep
ay
epen
nd on iits
ts va
valu
luee at
lu
a bbaseline.
asellin
inee. In a rec
ecen
ec
entt
en
and
hemodynamic
depend
value
recent
hemo
modynamic su
mo
ub-sstu
udy off 1187
87 patients
ts from th
he S
ERA
RAPH
RA
PHIN
PH
IN ran
ndomizzedd controlled
controllled tr
rial of
hemodynamic
sub-study
the
SERAPHIN
randomized
trial
n PAH
H pati
ients, Galiè et al. ffound
ound tha
h t the absolute value off CI and RAP at 6
macitentan iin
patients,
that
months, but not the changes from baseline, predicted the risk of disease progression18.
Nevertheless, relative changes in mPAP, SVI, PVR and PCa in our study predicted outcomes
regardless of the baseline value, supporting the use of hemodynamics as an endpoint in early
phase studies.
A novel insight from our study was that lower SVI discriminated patients at a higher risk
RIGHDWKRUWUDQVSODQWDWLRQHYHQDPRQJWKRVHZKRZHUH1<+$,RU,,DQGZLWK&,•
L/min/m2 at follow-up, i.e. amongst patients who would otherwise be considered at lower risk
according to international guidelines (Supplemental Figure E3)1–3,5,24. We also found that
13
10.1161/CIRCULATIONAHA.117.029254
patients in the lower quartiles for CI had worse outcomes compared to those in the higher
quartiles (Figure 2). This observation, along with our result that the CI cut-point best predicting
the risk of death or lung transplantation was < 2.7 L/min/m2, provides some evidence to support
the suggestion that a higher CI treatment goal is warranted3. Interestingly, the follow-up SVI
threshold from ROC analysis of 38 mL/m2 obtained in our study approximated the worst
quartiles in these lower risk subgroups, and has strong physiological rationale, as this
corresponds to the lower range of normal25 and is at the limit of a low flow state in aortic valve
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
disease26–28. This suggests that the SVI, which is easily calculated from the CI and HR, is a better
reflection of right ventricular function and adaptation to treatment than the CI itself, and
consequently, long-term prognosis in PAH. The advantage of SVI can be understo
understood
tood
od by tthe
he ffact
act
KDW&,•/PLQP2 can be achieved or maintained by increasing HR without any
WKDW&,•/PLQP
improvement,
mprovement, or even worsening, in right ventricular function. Nevertheless, it is clear that the
HR
R at follow-u
follow-up
up wa
was no
nnott th
tthee ma
main
in
n vvariable
ariaabl
b e driv
driving
i ingg prog
iv
prognosis
ogno
og
nosi
no
siss in
si
n oour
u m
ur
multivariable
ultivaari
ul
riab
able
ab
le analysis
anaaly
lysi
siss and
si
and
didd no
nnott discrimi
discriminate
mina
mi
n tee ooutcomes
na
utcome
mes in ROC aanalysis
me
nalysiis ass well
wel
elll as
a S
SVI
VI orr CI
VI
CI (Supplemental
(Su
Supp
pp
plementtal
a Table
Table E5).
E5).
theVHSDWLHQWVZLWK&,•
Furthermore, there was no difference between HR quartiles in theVHSDWLH
L QWVZLWK
K&,•
L/min/m2 (Supplemental Figure E4). These results suggest that a maladaptive right ventricular
response to treatment could go unrecognized if only the CI is considered in risk assessment and
not the value of SVI, consistent with prior cardiac magnetic resonance studies23,29.
Right atrial pressure at follow-up was also an independent predictor of death or lung
transplantation in our study, confirming recent findings by Gerges et al.17 and Galiè et al18.
Patients with RAP in the lower quartiles at follow-up had better survival than those in the higher
quartiles. The optimal RAP threshold at follow-up of < 9 mmHg in our study was consistent with
the current international guideline recommendations of < 8 mmHg as an indicator of lower
14
10.1161/CIRCULATIONAHA.117.029254
risk1,2,3. Pulmonary arterial compliance is decreased in PAH30,31 and arterial stiffening
contributes to an increase in pulsatile pulmonary arterial pressure and right ventricular afterload.
Based on previous studies showing the prognostic importance of PCa in idiopathic PAH13, we
had hypothesized that PCa, both at baseline and after treatment initiation, would also be a strong
predictor of survival. However, we found that neither baseline nor follow-up PCa provided
additional prognostic information beyond SVI. Several previous studies have reported the
prognostic importance of PCa in PAH due to various etiologies8,13,14,32. However, the two largest
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
studies to assess PCa at baseline and follow-up, our current study (n=763) and that of Gerges et
al. (n=978)17, did not find that PCa independently predicted outcomes. The study by Nickel et al.
also did not find PCa to be a significant predictor16. Our results favor the hypothesis
hypothes
esis
iss that
tha
hatt the
the
predictive value of PCa in some studies was related predominantly to the information provided
by stroke volume in the calculation of PCa (PCa = SV/pulse pressure), whereas the incorporation
of ppulse
ulse pressur
ul
uree do
ur
doess nnot
ot aadd
ddd further
fur
urth
ther
th
e pprognostic
r gnossti
ro
tic in
inform
rmat
rm
atio
at
ionn bu
io
ut do
ddoes
e increases
es
inc
n reeas
ases
ess tthe
h nnumber
he
umbe
um
berr of
be
o
pressure
information
but
independent
nde
deependent variables.
vaari
riab
bless. The parsimony
parsimony principle
princip
ple
l would
would
ld favor
fav
a orr uusing
sing
ng the simplest
sim
mplest and
an
nd fe
fewest
ewest
variables possible unless the additional
additiional information provided is sub
substantial.
bstantial. Furthermore,
F rthe
Fu
h rmore, as
compared to SVI, PCa calculation includes an additional source of measurement error. Indeed,
there may be inaccuracies in measuring pulse pressure using fluid-filled pressure catheters, with
whip artefacts sometimes leading to underestimation of the diastolic pulmonary arterial pressure
or overestimation of systolic pulmonary artery pressure. Finally, the results apply strictly to the
PAH population under study and we cannot exclude the possibility that PCa independently
predicts outcome in other PH subgroups
The major strengths of our multi-center study were the inclusion of a large cohort of
patients restricted to incident idiopathic, heritable and drug and toxin-induced PAH, since
15
10.1161/CIRCULATIONAHA.117.029254
survival is better in cohorts of prevalent patients and survival in PAH due to other associated
conditions (systemic sclerosis, congenital heart disease, and portopulmonary hypertension) may
be substantially different and related to the underling etiology21,22,33–35. Another strength of our
study was that a relatively high proportion received initial combination therapy (39%) compared
with other studies that assessed the prognostic value of hemodynamics during follow-up, which
better reflects PAH management in the modern era. We recognize some limitations given the
retrospective nature of the study and that we excluded patients from the analysis due to missing
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
hemodynamic data or lack of a follow-up RHC. However, these excluded patients' baseline
clinical and hemodynamic characteristics were broadly similar to our analysis cohort, suggesting
hey were representative of the overall population. The extent of missing data for SvO
SvO2 an
aand
d it
itss
they
exclusion from the multivariate models is also a potential limitation of the study since it has
known prognostic
p oggnostic significance. Selection bias could have been introduced as some patients died
pr
or w
ere transpla
lantted before
la
beffor
oree ha
havi
ving
vi
ng a fol
ollow-upp RHC
RH
HC performed
perf
pe
rfor
rf
orme
or
m d an
andd we
were nnot
ot iincluded
nclu
nc
l dedd in tthe
lu
he
were
transplanted
having
follow-up
analysis,
anal
alys
al
y is, howe
ys
however
eve
v r th
this
hiss is
is unavoidable
unnav
avoidable when
wh studying
stu
udyin
ing follow-up
foll
fo
llow
ll
ow--up parameters
parramet
eterrs and reflects
refflects
ts the
serious
erious nature of PA
PAH
H in
i a real-world setting.
Conclusions
Although hemodynamic variables at diagnosis did not predict long-term transplant-free survival,
SVI and RAP at the time of first follow-up right heart catheterization, after treatment initiation,
were independently associated with long-term outcomes in PAH. Even when CI was within the
WDUJHWUDQJHRI•/PLQP2, patients with lower SVI had a worse prognosis. Our results
reinforce the importance of clinical and hemodynamic variables, particularly the RAP and SVI,
during follow-up in predicting prognosis in PAH. If validated in prospective studies, and in PAH
16
10.1161/CIRCULATIONAHA.117.029254
cohorts of different etiologies, attention to the SVI could refine treatment targets beyond the
current recommendation of a CI •/PLQP2.
Sources of Funding
Jason Weatherald is the recipient of a joint European Respiratory Society/Canadian Thoracic
Society Long-Term Research Fellowship (LTRF 2015 – 4780)
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Acknowledgements
We wish to acknowledge Laurence Rottat for her help in obtaining the data for this study and her
hard work in managing data in the French PAH Registry.
Disclosures
Jasoon Weatherald
Weathera
ralld hhas
ra
as rreceived
ecei
ec
e veed a si
ei
sign
g iffic
gn
icant research
reese
searrch ffellowship
ello
el
lows
lo
wshi
ws
h p gr
gran
ant fr
from the
the Canadian
Can
a ad
diaan
Jason
significant
grant
Vasc
scul
sc
u ar Netwo
work
wo
rk/B
Bay
yer and
nd a significa
cant resea
e rcch fellowship
ea
feell
llow
owsh
ow
ship
hip gr
rannt from
m th
he Euro
opean
Vascular
Network/Bayer
significant
research
grant
the
European
Respiratory Society/Canadian
Society/Ca
C nadian Thoracic Society;
S ciiety; A
So
Athénaïs
thénaïs Boucly received modest travel grants
for scientific meetings from Actelion, Bayer, GSK and MSD; Denis Chemla - none ; Laurent
Savale reports modest honoraria in the field of pulmonary hypertension (outside from the
submitted work) from Actelion Pharmaceuticals Ltd, Bayer, GSK, Merck, Pfizer, and significant
research grants in the field of pulmonary hypertension (outside from the submitted work) from
Actelion, Bayer and GSK; Mingkai Peng - none; Mitja Jevnikar - none; Xavier Jaïs reports
modest honoraria in the field of pulmonary hypertension (outside from the submitted work) from
Actelion Pharmaceuticals Ltd, Bayer, GSK, Merck, Pfizer, and significant research grants in the
field of pulmonary hypertension (outside from the submitted work) from Actelion, Bayer and
17
10.1161/CIRCULATIONAHA.117.029254
GSK; Yu Taniguchi - none; Caroline O'Connell - none; Florence Parent - none; Caroline Sattler none; Philippe Hervé - none; Gérald Simonneau reports modest honoraria in the field of
pulmonary hypertension (outside from the submitted work) from Actelion Pharmaceuticals Ltd,
Bayer, MSD, GSK, Merck, Pfizer, and significant research grant in the field of pulmonary
hypertension (outside from the submitted work) from Actelion, Bayer and GSK; David Montani
reports modest research grants and honororia from Actelion, modest grants and personal fees
from Bayer,modest personal fees from BMS, modest personal fees from GSK, modest personal
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
fees from Novartis, and modest personal fees from Pfizer, outside the submitted work; Marc
Humbert reports modest honoraria in the field of pulmonary hypertension (outside from the
ubmitted work) from Actelion Pharmaceuticals Ltd, Bayer, GSK, Merck, Pfizer,, an
nd Un
Unit
ited
it
ed
submitted
and
United
Therapeutics, and significant research grants in the field of pulmonary hypertension (outside
from the submitted work) from Actelion, Bayer and GSK; Yochai Adir - none; Olivier Sitbon
has received
re
con
onsuult
on
l an
ncy and
and lecture
lec
ectu
ture
tu
r fee
re
ees from
m Act
ctelio
on Ph
Phar
arma
ar
mace
ceut
ce
utical
als Lt
td (m
(mod
o erat
od
a e)
at
e),, Ba
Baye
y r
consultancy
fees
Actelion
Pharmaceuticals
Ltd
(moderate),
Bayer
Hea
alt
lthcare (m
mod
oderrate)), Glax
xoSmithKlin
ine (mo
oderat
ate),, an
andd Me
M
erckk ((moderate),
modderaate), and si
ssignificant
gnificant
gn
Healthcare
(moderate),
GlaxoSmithKline
(moderate),
Merck
esearch
h grant in the field
f eld of pulmonary hypertension
fi
hypertension (outside ffrom
rom the submitted work
k) from
research
work)
Actelion, Bayer and GSK.
References
1. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A,
Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko
W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper
M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo
Badano L, Albert Barberà J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol Ç,
Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P,
Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GYH, Orfanos SE, Park MH, Piepoli
MF, Ponikowski P, Revel M-P, Rigau D, Rosenkranz S, Völler H, Luis Zamorano J. 2015
ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint
Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European
18
10.1161/CIRCULATIONAHA.117.029254
2.
3.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
4.
5.
6.
7.
8.
9.
Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by:
Association for European Paediatric and Congenital Cardiology (AEPC), International
Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.
Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A,
Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko
W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper
M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension:
The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the
European Society of Cardiology (ESC) and the European Respiratory Society (ERS):
Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC),
International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J.
2015;46:903–975.
McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, Palazzini M,
Park MH, Tapson VF, Sitbon O. Treatment goals of pulmonary hypertension. J Am Coll
Cardiol. 2013;62:D73-81.
Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, Palevsky HI, Rich S,
Sood N, Rosenzweig EB, Trow TK, Yung R, Elliott CG, Badesch DB. Pharmacologic
therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert
expper
e t panel
report. Chest. 2014;146:449–475.
athi
at
hier
hi
er M
A
A,
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, M
Mathier
MA,
McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA,
Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA,
Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM,
Rosenson
RS,
Stein
CM,
Rose
Ro
sensson R
se
S, Schofield
Schofield RS, Shubrooks SJ, Ste
tein JH, Tracy C
M Weitz
M,
Weitz HH, Wesley DJ,
ACCF/AHA.
A
CCF/AHA
HA. ACCF/AHA
HA
A CF
AC
CF/A
/AHA
/A
HA
A 2009
200
0099 expert
ex
xpe
p rt consensus
connsens
nsus document
doc
ocum
umen
um
nt on ppulmonary
ulmo
ul
m na
nary
ry hhypertension:
yperte
yp
t ns
te
nsio
ion:
io
n: a
American
College
Cardiology
Foundation
Expert
Consensus
rreport
eport of the Am
Ame
eric
ican C
ic
ollege ooff Ca
C
rdiollogyy F
ouundatio
on Task
Taaskk Force
Foorcce oon
n Expe
ert C
onsenssus
Documents
Association:
D
ocumentts and
and the
th
he American
Am
mer
erican Heart
rt Assoc
ciatiion: developed
deve
de
v lo
ve
lope
p d in collaboration
colla
labooration with
witth the
th
he
American
College
Chest
Physicians,
Thoracic
Society,
Inc.,
Pulmonary
Amer
Am
e iccan C
ollleegee ooff Ch
hes
estt Ph
hys
ysicia
ians
ia
n , American
Americ
Am
ican
nT
hoora
raci
cicc So
ci
oci
c et
e y, Inc
nc.,, and
nc
nd tthe
he P
ulmona
nary
Association.
2009;119:2250–2294.
Hypertension A
ssociation. Circulation. 20
2009
0 ;119:2250–
0 22
2294.
D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP,
Goldring RM, Groves BM, Kernis JT. Survival in patients with primary pulmonary
hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–
349.
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum
E, Cordier J-F, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M,
Hachulla E, Cottin V, Degano B, Jaïs X, Montani D, Souza R, Simonneau G. Survival in
patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension
in the modern management era. Circulation. 2010;122:156–163.
Campo A, Mathai SC, Le Pavec J, Zaiman AL, Hummers LK, Boyce D, Housten T,
Champion HC, Lechtzin N, Wigley FM, Girgis RE, Hassoun PM. Hemodynamic predictors
of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care
Med. 2010;182:252–260.
Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JSR, Vrapi F, Das C, Elliot CA,
Johnson M, DeSoyza J, Torpy C, Goldsmith K, Hodgkins D, Hughes RJ, Pepke-Zaba J,
Coghlan JG. Connective tissue disease-associated pulmonary arterial hypertension in the
modern treatment era. Am J Respir Crit Care Med. 2009;179:151–157.
19
10.1161/CIRCULATIONAHA.117.029254
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
10. Saggar R, Sitbon O. Hemodynamics in Pulmonary Arterial Hypertension: Current and Future
Perspectives. Am J Cardiol. 2012;110:S9–S15.
11. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the
impact of epoprostenol therapy. Circulation. 2002;106:1477–1482.
12. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A,
Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary
arterial hypertension: insights from the Registry to Evaluate Early and Long-Term
Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation.
2010;122:164–172.
13. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of Pulmonary
Arterial Capacitance and Mortality in Idiopathic Pulmonary Arterial Hypertension. J Am
Coll Cardiol. 2006;47:799–803.
14. Ghio S, D’Alto M, Badagliacca R, Vitulo P, Argiento P, Mulè M, Tuzzolino F, Scelsi L,
Romeo E, Raineri C, Martino L, Tamburino C, Poscia R, Vizza CD. Prognostic relevance of
pulmonary arterial compliance after therapy initiation or escalation in patients with
pulmonary arterial hypertension. Int J Cardiol. 2017;230:53–58.
15. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, Rainisio M, Simonneau G.
Long
term intravenous epoprostenol infusion in primary pulmonary hypertension:
n prognostic
Long-term
factors and survival. J Am Coll Cardiol. 2002;40:780–788.
16. Nickel N, Golpon H, Greer M, Knudsen L, Olsson K, Westerkamp V, Welte T
H
eper
ep
er M
M
M.
T,, Ho
Hoeper
MM.
The prognostic impact of follow-up assessments in patients with idiopathic pulmonary
arterial hypertension. Eur Respir J.
J 2012;39:589–596.
17. Gerges
Gerg
ges C, Gerges M, Skoro-Sajer N, Zhou Y, Zhang L, Sadushi-Kolici R, Jakowitsch J,
MB,
Precapillary
Pulmonary
Lang
La
ng M
B, Lang
Lan
ng IM. Hemodynamic Thresholds
ds for Precapillar
ary Pu
ulm
lmonary Hypertension.
Chest.
2016;149:1061–1073.
C
hest. 2016
16;149
16
49:1
49
10661–
1 10
073
73..
P,, P
Pulido
H-A,
Lee Brun
F-O,
Mehta
18. Galiè
Galiè N, Jansaa P
u idoo T,
ul
T, Channick
Chaannic
ick RN, Delcroix
Delc
lcroix
ix M, Ghofrani
Ghofra
Gh
rani H
-A,, L
unn F-O, Meh
hta
S,, Perchenet
L,, Ru
Rubin
Sitbon
Souza
S
Perchen
net L
ubin LJ
LJ, Sastry
y BKS,
BKS, Simonneau
Simo
m nn
nneaau G,
G, S
i bon O,
it
O, Sou
ouzaa R, Torbicki
Torbbicki
ki A.
SERAPHIN
receptor
antagonist
SERA
SE
R PH
RA
PHIN
IN haemodynamic
haeemo
modynaami
micc substudy:
suubs
b tu
udy
dy: the
th
he effect
effeect of
of thee du
dual
a eendothelin
ndot
nd
o he
helinn re
recept
ptor
pt
o ant
or
ntagonistt
NT-proBNP
macitentan on ha
hhaemodynamic
emodynamic parameters and
d NT
N
-proBNP
P levels and their association withh
disease progression in patients with pulmonary arterial hypertension. Eur Heart J.
2017;38:1147–1155.
19. Perkins NJ, Schisterman EF. The Youden Index and the optimal cut-point corrected for
measurement error. Biom J. 2005;47:428–441.
20. Vickers AJ. The use of percentage change from baseline as an outcome in a controlled trial is
statistically inefficient: a simulation study. BMC Med Res Methodol. 2001;1:6.
21. Humbert M, Sitbon O, Yaïci A, Montani D, O’Callaghan DS, Jaïs X, Parent F, Savale L,
Natali D, Günther S, Chaouat A, Chabot F, Cordier J-F, Habib G, Gressin V, Jing Z-C,
Souza R, Simonneau G, French Pulmonary Arterial Hypertension Network. Survival in
incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir
J. 2010;36:549–555.
22. Gall H, Felix JF, Schneck FK, Milger K, Sommer N, Voswinckel R, Franco OH, Hofman A,
Schermuly RT, Weissmann N, Grimminger F, Seeger W, Ghofrani HA. The Giessen
Pulmonary Hypertension Registry: Survival in pulmonary hypertension subgroups. J Heart
Lung Transplant. 2017;36:957-967.
23. van Wolferen SA, Marcus JT, Boonstra A, Marques KMJ, Bronzwaer JGF, Spreeuwenberg
MD, Postmus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume,
20
10.1161/CIRCULATIONAHA.117.029254
24.
25.
26.
27.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
28.
29.
30.
31.
32.
33.
34.
35.
and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–
1257.
Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, Picard F, de Groote P,
Jevnikar M, Bergot E, Chaouat A, Chabanne C, Bourdin A, Parent F, Montani D, Simonneau
G, Humbert M, Sitbon O. Risk assessment, prognosis and guideline implementation in
pulmonary arterial hypertension. Eur Respir J 2017; 50: 1700889.
Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and
diastolic function normalized to age, gender and body surface area from steady-state free
precession cardiovascular magnetic resonance. Eur Heart J. 2006;27:2879–2888.
Clavel M-A, Berthelot-Richer M, Le Ven F, Capoulade R, Dahou A, Dumesnil JG, Mathieu
P, Pibarot P. Impact of classic and paradoxical low flow on survival after aortic valve
replacement for severe aortic stenosis. J Am Coll Cardiol. 2015;65:645–653.
Dumesnil JG, Pibarot P, Carabello B. Paradoxical low flow and/or low gradient severe aortic
stenosis despite preserved left ventricular ejection fraction: implications for diagnosis and
treatment. Eur Heart J. 2010;31:281–289.
Lønnebakken MT, De Simone G, Saeed S, Boman K, Rossebø AB, Bahlmann E, GohlkeBärwolf C, Gerdts E. Impact of stroke volume on cardiovascular risk during progression of
aortic valve stenosis. Heart. 2017;103:1443
1448.
2017;103:1443-1448.
Bogaa
aard
rd H
-J,,
-J
van de Veerdonk MC, Kind T, Marcus JT, Mauritz G-J, Heymans MW, Bogaard
H-J,
Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A. Progressive ri
righ
ghtt
gh
right
ventricular dysfunction in patients with pulmonary arterial hypertension responding to
therapy. J Am Coll Cardiol. 2011;58:2511–2519.
Thenappan
Thenapp
p an T, Prins KW, Pritzker MR, Scandurra J, Volmers K, Weir EK. The Critical Role
pp
Pulmonary
Pulmonary
Hypertension.
Ann
of P
ulmo
ul
mona
mo
nary Arterial
na
Arterial Compliance in Pulmon
narry Hypertension
on. An
nn Am Thorac Soc.
22016;13:276–284.
20
16;13:2776–
6–28
284..
28
Vonk
A,, W
Westerhof
BE,
Westerhof
N.. The R
Relationship
Vonk Noordegraaf
Noordegr
graaaf A
esterhof
of B
E, Wes
steerhhof N
elaatiionshhip Between
Between
n tthe
hee
Right
Pulmonary
Coll
R
ight Ventricle
Ven
ntr
tric
i le and
nd its Load
Load in Pul
lmonary
y Hypertension.
Hyp
yperrte
tens
nsio
ns
ionn. J Am Co
olll Ca
Cardiol. 20
22017;69:236–
17;;69:23
36–
243.
24
3.
Takatsuki
Saji
Tak
katsuki
k S, Nakayama
N kayama T, Ikehara
Na
Ikeh
hara S,
S Matsuura H, Ivy DD, Saj
ji T. Pulmonary Arterial
Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic
and Heritable Pulmonary Arterial Hypertension. J Pediatr. 2017;180:75–79.e2.
Rubenfire M, Huffman MD, Krishnan S, Seibold JR, Schiopu E, McLaughlin VV. Survival
in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern
era. Chest. 2013;144:1282–1290.
Hascoët S, Baruteau A-E, Humbert M, Simonneau G, Jais X, Petit J, Laux D, Sitbon O,
Lambert V, Capderou A. Long-term outcomes of pulmonary arterial hypertension under
specific drug therapy in Eisenmenger syndrome. J Heart Lung Transplant. 2017;36:386–
398.
Sithamparanathan S, Nair A, Thirugnanasothy L, Coghlan JG, Condliffe R, Dimopoulos K,
Elliot CA, Fisher AJ, Gaine S, Gibbs JSR, Gatzoulis MA, E Handler C, Howard LS, Johnson
M, Kiely DG, Lordan JL, Peacock AJ, Pepke-Zaba J, Schreiber BE, Sheares KKK, Wort SJ,
Corris PA, National Pulmonary Hypertension Service Research Collaboration of the United
Kingdom and Ireland. Survival in portopulmonary hypertension: Outcomes of the United
Kingdom National Pulmonary Arterial Hypertension Registry. J Heart Lung Transplant.
2016;36:770-779
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10.1161/CIRCULATIONAHA.117.029254
Table 1. Baseline characteristics (n=981)
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Variable
Age (y)
64
(48-74)
Male Gender
400
(40.8%)
Body Mass Index (kg/m2)
27.8
± 6.7
Body Surface Area (m2)
1.79
(1.65-1.95)
Follow-Up Time (y)
2.8
(1.1-4.6)
Death
307
(31.2%)
Lung Transplant
24
(2.4%)
Etiology of PAH
Idiopathic
748
(76.2%)
Drugs and Toxins
152
(15.5%)
Heritable
81
(8.3%)
Positive vasoreactivity test (n=807)
101
(12.5%)
NYHA FC (n=967)
I
25
(2.6%)
II
214
(22.1%)
III
578
(59.8%)
IV
150
(15.5%)
6MWD (m) (n=707)
319
± 135
Initial Treatment Strategy
Monotherapy (n=451)
PDE5i
155
(15.8%)
ERA
ER
A
276
(18.1%)
PCA
P
CA
2
20
(2
(2.0%)
.00%)
Dual
Du
ual therapy (n=323)
(n=32
23)
ERA+PCA
A
221
1
(2.1
(2
(2.1%)
1%)
PDE5i+PCA
P
PD
E5i+
+PC
PCA
1
11
((1.1%)
1.1%)
%)
ERA+PDE5i
ERA+PD
ER
PDE5
PD
E5ii orr R
Riociguat
io
oci
cigu
guat
at
2291
91
((29.7%)
29.77%)
Triple therapy (n=55)
ERA+PDE5i+PCA
55
(5.6%)
CCB only
59
(6.0%)
None
93
(9.5%)
Variables are expressed as number (%), median (Interquartile range 25-75%) or mean ± standard
deviation
PAH - pulmonary arterial hypertension; NYHA FC - New York Heart Association functional class;
6MWD - 6-minute walk distance; PDE5i - phosphodiesterase type-5 inhibitor; ERA - endothelin receptor
antagonist; PCA - prostacyclin analogue; CCB - calcium channel blocker
22
10.1161/CIRCULATIONAHA.117.029254
Table 2. Clinical and hemodynamic variables at baseline and first follow-up right heart
catheterization
Clinical Variables
NYHA FC (n=755)
I
II
III
IV
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Baseline
Follow-Up
p-value
n (%)
n (%)
<0.001
18 (2.4)
74 (9.8)
176 (23.3)
380 (50.5)
463 (61.3)
251 (33.4)
98 (13.0)
47 (6.3)
Median (IQR)
Median (IQR)
6MWD (m) (n=707)
330 (220-420)
384 (265-470)
<0.001
Hemodynamic Variables (n=763)
Median (IQR)
Median (IQR)
RAP (mmHg)
8 (5-12)
7 (4-10)
<0.001
PAPs (mmHg)
76 (64-89)
69 (54-84)
<0.001
PAPd (mmHg)
31 (25-38)
26 (20-32)
<0.001
mPAP (mmHg)
47 (40-56)
43 (35-51)
<0.001
PAWP (mmHg)
9 (7-12)
9 (7-12)
0.01
CO (L/min)
4.20 (3.40-5.20)
5.21 (4.26-6.20)
<0.001
CI (L/min/m2)
2.36 (1.92-2.83)
2.89 (2.38-3.42)
<0.001
<0.0
. 01
.0
0
SvO2 (%), n=507
63 (57-69)
67 (61-72)
<0.001
< .0
<0
.0001
PVR (WU)
9.2 (6.3-12.9)
6.1 (4.2-8.5)
<0.001
<0
0.0
.0001
HR (bpm)
80 (69-90)
78 (68-88)
0.008
SV (mL)
55 (41-70)
68 (55-84)
<0.001
SVI (mL/m2)
31 (24-38)
39 (31-46)
<0.001
PCaa (m
(mL/
(mL/mmHg)
L mm
L/
mmHg
Hg)
Hg
1.19 (0.85(0.85-1.74)
-1.74)
1.599 ((1.14-2.45)
1.144-22.45)
<0.001
RAP
P - right atri
atrial
ial pre
pressure;
ressur
re
u e; P
ur
PAPs
AP
Ps - sy
syst
systolic
s olicc pulmona
st
pulmonary
n ry
na
y aarterial
rterriaal pr
pres
pressure;
e suuree; PA
es
PAPd
Pd - dias
diastolic
asto
as
toli
to
licc pu
li
ppulmonary
lm
mon
onar
ay
ar
arterial
mean
pulmonary
wedge
arte
eriial pressure; mPAP
mPA
PAP
P-m
ean
n ppulmonary
ulmo
ona
nary
y aarterial
rteriall pressure;
preesssure
re;; PAWP
WP - pu
pulmon
naryy ar
artery w
edgee ppressure;
ed
ressuure;
saturation;
CO
O - cardiac output;
ou
utp
tputt; CI - cardiac
card
diac index; SvO2
SvvO2 - mixed
mix
ixed
d venous
ven
nou
ouss oxygen
oxyg
ox
ygen sa
aturaationn; PVR - ppulmonary
ulmo
monary
vascular
resistance;
HR
vascul
ular
ul
a resista
tanc
ta
nce; H
nc
R - heartt ra
rate; SV
V - stroke
stroke vvolume;
olum
me; SVI
SVI - stroke
str
trokke volume
tr
vo
olumee index;
inddex
e ; PCaa - pulmonary
puulm
monaryy
arterial
walk
distance;
FC
arte
ar
teri
rial
all ccompliance;
ompl
pllia
ianc
nce;
e;; 66MWD
MWD
MW
D - 66-minute
-mi
minu
mi
ute
t w
allk di
dist
stan
st
ance
c ; NY
ce
NYHA
HA F
C - New
N w York
Ne
York
k Heart
Heaart
r Association
Assoc
sssocia
iattion
tion
functional class
23
10.1161/CIRCULATIONAHA.117.029254
Table 3. Univariable and multivariable Cox proportional-hazards regression for transplant-free survival.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Baseline (n= 981)
Univariable analysis
Variable
Age at diagnosis (per year)
Male gender
IPAH Etiology
NYHA III (vs I/II)
NYHA
HA IV (vs. I/II)
6MWD
WD (per 10 meters)
RAP (per mmHg)
mPAP
AP (per mmHg)
CO (per
per L/min)
CI (per
per L/min/m2)
SvO2 (per 1% increase)
PVR (per Wood
Woo
ood
d unit)
un
unit
nit
it))
PVRII (per
er Wood
Wood unit
m2)
HR (per
per 100 bpm)
SV (per
per 100 mL decrease)
SVI (perr 110
0 mL/m2 decrea
decrease)
ease
ea
s )
PCa (per m
mL/mmHg)
L mmHg)
L/
Firstt follow
follow-up
w-up (n=763)
(n=
n=76
763)
76
3)
Univariable
ariable analysis
Variable
NYHA III (vs I/II)
NYHA IV (vs I/II)
6MWD (per 10 meters)
RAP (per mmHg)
mPAP (per mmHg)
CO (per L/min)
CI (per L/min/m2)
SvO2 (per 1% increase)
Multivariable Analysis*
Hazard
Ratio
1.04
1.88
2.15
1.66
3.17
0.95
1.04
0.99
0.91
0.81
0.97
1.0
1.0
1.00
1.11
1.1
11
1.22
1.2
22
0.81
0.8
81
95% CI
p-value
Variable
1.03-1.05
1.51-2.33
1.59-2.90
1.21-2.27
2.21-4.55
0.94-0.96
1.01-1.06
0.99-1.00
0.84-0.98
0.70-0.94
0.96-0.98
0.98-1.02
0.99-1.01
0.97-1.10
0.97
0.
97-11.110
97
1.02-1.14
1..02-1.14
1.11-1.36
1.11-1.36
00.70-0.95
0.
.70-0.95
<0.001
<0.001
<0.001
0.002
<0.001
<0.001
0.001
0.198
0.016
0.007
<0.001
0.826
0.75
0.228
0.2228
0.006
0.0006
0.003
0.0003
0.
0.008
.0008
Age at diagnosis (per year)
Male Gender
IPAH Etiology
6MWD (per 10 meters)
NYHA III (vs. I/II)
NYHA IV (vs. I/II)
Adjusted
Hazard Ratio
1.03
1.95
1.70
0.97
1.32
2.22
95% CI
p-value
1.02-1.04
1.49-2.53
1.19-2.44
0.96-0.99
0.93
0.93-1.85
93--1.
1 85
8
1.
1.40-3.51
.40--3.
3 511
<0.001
<0.001
0.004
0.001
00.11
0.
11
0.001
0.00
0.
001
00
95% CI
p-value
1.01-1.03
1.27-2.48
1.12-2.67
0.96-0.99
1.05-2.24
1.79-6.48
1.02-1.09
1.11-1.49
0.008
0.001
0.013
0.001
0.027
<0.001
0.001
0.001
Multivariable Analysis †
Hazard
Ratio
1.66
3.17
0.95
1.09
1.02
0.81
0.59
0.924
95% CI
p-value
Variable
1.21-2.27
2.21-4.55
0.94-0.96
1.06-1.12
1.01-1.03
0.73-0.89
0.49-0.71
0.908-0.94
0.002
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
Age at diagnosis (per year)
Male Gender
IPAH Etiology
6MWD (per 10 meters)
NYHA III (vs. I/II)
NYHA IV (vs. I/II)
RAP (per mmHg)
SVI (per 10 mL/m2 decrease)
24
Adjusted
Hazard Ratio
1.02
1.77
1.73
0.97
1.54
3.4
1.05
1.28
10.1161/CIRCULATIONAHA.117.029254
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
PVR (per Wood unit)
1.08
1.05-1.12
<0.001
PVRI (per Wood unitm2)
1.06
1.04-1.08
<0.001
HR (per 10 bpm)
1.10
1.01-1.21
0.016
SV (per 10 mL decrease)
1.22
1.11-1.86
<0.001
SVI (per 10 mL/m2 decrease) 1.50
1.36-1.85
<0.001
PCa (per mL/mmHg)
0.64
0.54-0.77
<0.001
IPAH - idiopathic pulmonary arterial hypertension; NYHA FC - New York Heart Association functional class RAP - right atrial pressure; 6MWD
- 6-minute walk distance; RAP - right atrial pressure; mPAP - mean pulmonary arterial pressure; PAWP - pulmonary artery wedge pressure; CO cardiac output; CI - cardiac index; SvO2 - mixed venous oxygen saturation; PVR - pulmonary vascular resistance; PVRI - pulmonary vascular
resistance index; HR - heart rate; SV - stroke volume; SVI - stroke volume index; PCa - pulmonary arterial compliance.
* Variables
SVI,
PCa
iables entered in model: Age at diagnosis, Gender, Etiology, 6MWD, NYHA functional class (3 levels), RAP, CI, SVI
VII, PC
Ca
† Variables
levels:
I/II,
IV),
iables entered in forward stepwise model: Age at diagnosis, Gender, Etiology, 6MWD, NYHA functional class (33 le
eve
vels:: I/
I/II
I , II
II
IIII an
aand
d IV
RAP, mPAP, CI, HR, SVI, PVR, PCa
25
10.1161/CIRCULATIONAHA.117.029254
Table 4. Comparison of multivariable Cox regression models for hemodynamic variables at follow-up.
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Model A
Model B
Model C
Model D
Model E
Hazard
Hazard
Hazard
Hazard
Hazard
Ratio 95% CI p
Ratio
95% CI
p
Ratio
95% CI
p
Ratio
95% CI
p
Ratio
95% CI
p
Age (per year)
1.02
1.004-1.03 0.008 1.02
1.003-1.029 0.016 1.02
1.006-1.003 0.005 1.02
1.004-1.03 0.009 1.02
1.004-1.03 0.009
Male Gender
1.77
1.28-2.46 0.001 1.67
1.20-2.32
0.002 1.77
1.27-2.45 0.001 1.87
1.34-2.62 <0.001 1.88
1.36-2.61 <0.001
IPAH Etiology
1.94
1.26-2.98 0.003 1.86
1.20-2.86
0.005 1.78
1.15-2.74 0.009 1.64
1.06-2.56 0.03
1.81
1.17-2.78 0.007
NYHA at Follow-Up (per class) 1.71
1.29-2.27 <0.001 1.69
1.28-2.24
<0.001 1.72
1.30-2.28 <0.001 1.61
1.21-2.15 0.001 1.68
1.27-2.22 <0.001
6MWD at Follow-Up (per 10m) 0.97
0.96-0.99 <0.001 0.97
0.96-0.99
<0.001 0.97
0.96-0.99 <0.001 0.97
0.96-0.99 <0.001 0.97
0.96-0.99 <0.001
RAP (per mmHg)
1.06
1.03-1.09
1.03 1.09 <0.001
0.001 1.05
1.02
1.02-1.08
1.08
0.001 1.05
1.02
1.02-1.08
1.08 0.001 1.05
1.02
1.02-1.09
1.09 0.
0.001
.001 1.05
11.02-1.08 0.001
CI (per L/min)
0.76
0.612-0.933 0.009
SVI (per mL/m2 decrease)
ecrease)
1.29
1.12-1.47 0.001
PVR (per Wood unit)
nit)
1.06
1.02-1.100 0.
00.003
.0
003
3
PCa (per mL/mmHg)
Hg)
0.77
00.64-0.92 0.004
Log Likelihood
-864.6
-860.73
-857.68
-825.83
-859.58
Akaike Information
on Criteria 1741.21
1735.46
1729.36
1665.67
1733.16
p-value*
0.005
<0.001
<0.001
0.002
*p-value obtained from the li
likelihood
ikeli
l ho
hood
o ratio test
od
tesst compared to Model A.
IPAH - idiopathic pulmo
pulmonary
hypertension;
functional
walk
pressure; CI - cardiac
onary
nary arteriall hy
hype
p rten
pe
nsi
sion; NYHA - New York Heart Association func
ctio
onal class; 6MWD - 66-minute
-m
minute w
alk distance; RAP - right atrial pressure
index; SVI - stroke volume
compliance
volum
umee index; PVR
um
R - pulmonary
pulm
mon
o aryy vascular
v sccul
va
u ar
a resistance;
ressis
ista
t nc
ta
nce;
e PCa - pulmonary
p lmonarry arterial
pu
a terriaal compl
ar
p ia
pl
ianc
ncce
26
10.1161/CIRCULATIONAHA.117.029254
Figure Legends
Figure 1. Study Profile
Figure 2. Transplant-free survival stratified by hemodynamic quartiles at first follow-up
right heart catheterization. A) stroke volume index (SVI), B) right atrial pressure (RAP), C)
cardiac index (CI) and D) heart rate (HR)
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Figure 3. Predicted survival estimates according to percent change from baseline for
RAP
AP),
), C
hemodynamic variables. A) stroke volume index (SVI), B) right atrial pressure (R
(RAP),
C))
cardiac index (CI), D) heart rate (HR), E) pulmonary vascular resistance (PVR) and F)
pulmonaryy arterial compliance (PCa). Based on the coefficients from our predicted survival
equa
uati
ua
t ons derive
ti
ved fr
ve
from
m tthe
he stu
tu
udy ppopulation
o ullat
op
a ion and
and th
the me
mean
an oorr me
medi
dian
di
an vvalues
a uess in Table
al
Ta
1 aand
nd
equations
derived
study
median
Tabl
blee 2, a 'typical'
bl
'typpiccall' ppatient
attieent co
correspondss to
to a 60-year-old
600-year
ar-ol
oldd fe
ol
fema
malle w
itth id
dio
opaathic PAH
A , in NYHA
AH
NYH
HA
Table
female
with
idiopathic
PAH,
class IIII at ddiagnosis
iagnosis
i with
wit
i h baseline values for 6M
MWD
W of 314 m, SVI of 32
3 mL/
L m2, RA
AP of 8
6MWD
mL/m2,
RAP
mmHg, HR of 80 bpm, CI of 2.36 L/min/m2, PVR of 9.2 WU, and PCa of 1.19 mL/mmHg. The
predicted survival curves for each variable represent 20% increments from the median or mean
baseline value in the population (the 0% change curve) while holding other variables fixed.
27
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The Prognostic Value of Follow-up Hemodynamic Variables After Initial Management in
Pulmonary Arterial Hypertension
Jason Weatherald, Athénaïs Boucly, Denis Chemla, Laurent Savale, Mingkai Peng, Mitja Jevnikar,
Xavier Jaïs, Yu Taniguchi, Caroline O'Connell, Florence Parent, Caroline Sattler, Philippe Hervé,
Gérald Simonneau, David Montani, Marc Humbert, Yochai Adir and Olivier Sitbon
Downloaded from http://circ.ahajournals.org/ by guest on October 25, 2017
Circulation. published online October 25, 2017;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2017 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/early/2017/10/24/CIRCULATIONAHA.117.029254
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2017/10/24/CIRCULATIONAHA.117.029254.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in
Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
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Permissions in the middle column of the Web page under Services. Further information about this process is
available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL
The prognostic value of follow-up hemodynamic variables after initial management in
pulmonary arterial hypertension
Jason Weatherald, MD; Athénaïs Boucly, MD; Denis Chemla, MD, PhD; Laurent Savale,
MD, PhD; Mingkai Peng, PhD; Mitja Jevnikar, MD; Xavier Jaïs, MD; Yu Taniguchi,
MD, PhD; Caroline O'Connell, MD; Florence Parent, MD; Caroline Sattler, MD;
Philippe Hervé, MD; Gérald Simonneau, MD; David Montani, MD, PhD; Marc Humbert,
MD, PhD; Yochai Adir, MD; Olivier Sitbon, MD, PhD
Table of Contents
Supplemental Table E1
Supplemental Table E2
Supplemental Table E3
Supplemental Table E4
Supplemental Table E5
Supplemental Figure E1
Supplemental Figure E2
Supplemental Figure E3
Supplemental Figure E4
p2
p3
p4
p5
p6
p7
p8
p9
p10
1
Supplemental Table E1 - Multivariable Cox regression excluding patients with positive
vasoreactivity testing (n=684)
Multivariable analysis
Variable
Age at diagnosis
Male Gender
IPAH Etiology
NYHA III (vs I/II)
NYHA IV (vs I/II)
6MWD (per meter)
RAP (per mmHg)
SVI (per mL/m2)
Hazard
Ratio
1.02
1.66
1.75
1.45
3.42
0.998
1.05
0.974
95% CI
1.003-1.031
1.18-2.34
1.13-2.70
0.986-2.236
1.76-6.63
0.996-0.999
1.02-1.09
0.959-0.988
p
0.014
0.004
0.013
0.059
<0.001
0.004
0.001
<0.001
2
Supplemental Table E2 - Multivariable Cox regression excluding patients who received
no PAH-specific treatment or calcium channel blocker therapy between diagnosis and
first follow-up right heart catheterization (n=712)
Multivariable analysis
Variable
Age at diagnosis
Male Gender
IPAH Etiology
NYHA III (vs I/II)
NYHA IV (vs I/II)
6MWD (per meter)
RAP (per mmHg)
SVI (per mL/m2)
Hazard
Ratio
1.02
1.68
1.75
1.59
3.55
0.998
1.05
0.974
95% CI
1.004-1.03
1.19-2.36
1.12-2.72
1.08-2.35
1.84-6.84
0.996-0.999
1.02-1.08
0.96-0.99
p
0.009
0.003
0.013
0.019
<0.001
0.002
0.002
<0.001
3
Supplemental Table E3 - Correlation matrix of hemodynamic variables at first follow-up
right heart catheterization
RAP
RAP mPAP CI PVR SVI PCa
.406 -.202 .195 -.226 -.176
Pearson Correlation 1.00
mPAP Pearson Correlation
.406
1.00 -.160
CI
Pearson Correlation -.202
PVR
Pearson Correlation
SVI
Pearson Correlation -.226
-.311
.771 -.602
1.00
.596
PCa
Pearson Correlation -.176
-.617
.451 -.658
.596
1.00
.195
-.160
.710 -.311 -.617
1.00 -.594
.710 -.594
.771
.451
1.00 -.602 -.658
All correlations significant at the 0.01 level (2-tailed).
4
Supplemental Table E4 - Univariable and adjusted analysis of the association between percent change for hemodynamic variables and
transplant-free survival.
Variable
RAP (per 10% decrease)
mPAP (per 10% decrease)
CI (per 10% increase)
HR (per 10% decrease)
SVI (per 10% increase)
PVR (per 10% decrease)
PCa (per 10% increase)
Univariable
Hazard 95% CI
Ratio
0.99
0.981.04
0.81
0.770.86
0.92
0.880.95
0.95
0.891.01
0.92
0.900.95
0.89
0.860.92
0.92
0.900.95
p
0.18
<0.001
<0.001
0.09
<0.001
<0.001
<0.001
Least Favourable Quartile at Baseline
Quartile
Hazard 95% CI p
median value Ratio
14 mmHg
0.89
0.83<0.001
0.94
63 mmHg
0.75
0.640.001
0.88
1.7 L/min/m2 0.92
0.860.01
0.98
96 bpm
0.76
0.630.005
0.92
20.0 mL/m2
0.90
0.85<0.001
0.95
15.7 WU
0.87
0.790.002
0.94
0.69
0.84
0.770.001
mL/mmHg
0.91
Most Favourable Quartile at Baseline
Quartile
Hazard 95% CI p
median value Ratio
3 mmHg
0.99
0.970.26
1.01
35 mmHg
0.89
0.790.04
0.99
3.3 L/min/m2 0.91
0.790.15
1.04
63 bpm
0.97
0.870.64
1.09
44.4 mL/m2
0.79
0.690.001
0.91
4.8 WU
0.89
0.850.001
0.93
2.27
0.93
0.890.001
mL/mmHg
0.97
5
Supplemental Table E5 - Receiver operating characteristic analysis for hemodynamic
variables at follow-up right heart catheterization and risk of death or transplantation.
Variable
SVI
RAP
PVR
CI
PCa
Heart Rate
AUC
0.68
0.62
0.66
0.64
0.65
0.57
95% CI
0.64-0.72
0.57-0.67
0.61-0.70
0.60-0.67
0.61-0.70
0.53-0.62
Optimal Cut point
38
9
6.6
2.7
1.5
81
Sn
0.69
0.43
0.62
0.56
0.64
0.51
Sp
0.58
0.76
0.63
0.67
0.65
0.62
6
Supplemental Figure E1 - Overall survival from the time of diagnosis.
7
Supplemental Figure E2 - Transplant-free survival from the time of diagnosis.
8
Supplemental Figure E3 - Transplant-free survival in patients with low-risk features
at follow-up. Patients who had 2 low-risk criteria (NYHA I or II and Cardiac Index ≥ 2.5
L/min/m2) at the time of first follow-up right heart catheterization (n=355) stratified by
within-group quartiles at follow-up A) stroke volume index (SVI), B) right atrial pressure
(RAP). For patients with three low-risk features at follow-up (NYHA I or II, CI ≥ 2.5
L/min/m2 and 6MWD > 440 m) at first follow-up right heart catheterization (n=193)
survival differed according to within-group C) SVI quartile (log-rank test p=0.003) but
not D) RAP quartile (log-rank test p=0.15)
9
Supplemental Figure E4 - Transplant-free survival in patients with low-risk features
at follow-up according to heart rate quartiles. A) Patients who had 2 low-risk criteria
(NYHA I or II and Cardiac Index ≥ 2.5 L/min/m2) at the time of first follow-up right
heart catheterization (n=355) and B) patients with three low-risk features at follow-up
(NYHA I or II, CI ≥ 2.5 L/min/m2 and 6MWD > 440 m) at first follow-up right heart
catheterization (n=193).
10
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