Open Journal of Respiratory Diseases, 2012, 2, 17-24
http://dx.doi.org/10.4236/ojrd.2012.22003 Published Online May 2012 (http://www.SciRP.org/journal/ojrd)
Mortality-Related Risk Factors in Patients with Pulmonary
Arterial Hypertension and Chronic Thromboembolic
Pulmonary Hypertension. The Importance of
Response to Treatment*
Manuel Lopez-Meseguer1,2, Río Aguilar3,4, Carles Bravo1,2, Víctor Monforte1,2, Laura Dos5,
Carmen P. Simeon6, Enric Domingo4,5, Antonio Roman1,2#
1Respiratory Department Hospital Universitari Vall d’Hebron, Institut de Recerca del Hospital Universitari Vall d’Hebron,
Universitat Autònoma de Barcelona, Barcelona, Spain
2Ciber Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
3Cardiology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain
4Department of Physiology, Universi tat Autonòma de Barcelona, Barcelona, Spain
5Cardiology Department, Hospital Universitari Vall d’Hebron, Institut de Recerca del Hospital Universitari Vall d’Hebron, Universitat
Autònoma de Barcelona, Barcelona, Spain
6Internal Medicine Department, Hospital Universitari Vall d’Hebron, Institut de Recerca del Hospital Universitari
Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
Received January 17, 2012; revised February 10, 2012; acce pted February 22, 2012
ABSTRACT
Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH)
are serious diseases with similar pathophysiologic aspects. The prognosis of patients with these conditions is highly
uncertain, particularly incident cases. Methods: A Cox proportional hazards model was applied to a group of 85 pa-
tients (81% women, mean age 52 (18 - 82) years) with PAH (80%) and non-surgical CTEPH (20%) to evaluate risk
factors for mortality. The following variables were included in the model: ag e, etiology, baseline 6-minute walk test (6
mWT), cardiac index, and improvement in the 6 mWT following initiation of first medical treatment. Results: In the
multivariate analysis, the response to treatment, assessed by an improvement on the 6 mWT, was the most relevant
prognostic factor in these patients ( RR, 4.832 (95% CI, 1.88 8 - 12.364); p = 0.00 1). The remaining variables studied in
this model had less influence on the pro gnosis: age > 50 years (RR, 0.744 (95% CI, 0.26 - 2.133); p = 0.5 82); etiology
of connective tissue disease-associated PAH (RR, 3.145 (95% CI, 0.995 - 9.946); p = 0.051) or CTEPH (RR, 0.654
(95% CI, 0.179 - 2.387); p = 0.521) with respect to idiopathic PAH; baseline 6 mWT (RR, 1.173 (95% CI, 0.599 -
4.895); p = 0.315); or cardiac index (RR, 2.295 (95% CI, 0.793 - 6.642); p = 0.125). Conclusions: There is a high de-
gree of uncertainty r egarding the prognosis of PAH and CTEPH at the start of appropriate treatment. Our results support
the idea that the initial treatment response is of paramount importance as prognostic factor in these patients.
Keywords: Pulmonary Arterial Hypertension; Chronic Thromboembolic Pulmonary Hypertension; Survival; Risk
Factors
1. Introduction
The incidence of pulmonary arterial hypertension (PAH)
is estimated to be 1.1 cases per million [1], and its natural
evolution leads to death at an average of 3 years from the
time of the diagnosis [2]. The incidence of chronic th-
romboembolic pulmonary hypertension (CTEPH), re-
mains to be defined, but is estimated to be less than 1%
to 4% of all cases of pulmonary embolism [3-5]. In non
operable CTEPH patients, natural course of the disease is
similar to that of PAH.
Because of these low incidences, it is difficult to as-
semble large groups of patients to better study their
prognoses. Classically, attempts to establish the progno-
sis are based on an analysis of the patients’ baseline
clinical, functional, and hemodynamic features [2,6].
Exercise capacity and cardiac index (CI) are well-recog-
*COI disclosure: None of the authors have any conflicts of interests to
disclose relating this study.
#Corresponding author.
C
opyright © 2012 SciRes. OJRD

M. LOPEZ-MESEGUER ET AL. 18
nized prognostic factors. Nonetheless, the course of each
individual patient remains highly uncertain at the time of
the diagnosis. There is some evidence that the response
to treatment with epoprostenol has an impact on survival
[7,8]. We hypothesized that the patient’s initial response
to the first specific treatment prescribed for PAH has an
important influence on prognosis. To investigate this idea,
a study of risk factors for mortality was carried out in a
group of PAH and CTEPH patients, all of whom re-
ceived medical treatment for their disease following a
similar scheme.
2. Patients and Methods
A retrospective study was performed including 85 adult
patients, (69 (81%) women, mean age at onset of symp-
toms: 52 (18 - 82) years) diagnosed with PAH classified
as group I (idiopathic PAH (IPAH) and connective tissue
disease-associated PAH (CTD-PAH)) and group IV
(CTEPH) according to the latest Pulmonary Hyperten-
sion Classification [9], and followed-up in Hospital Uni-
versitari Vall d’Hebron between April 1995 and Decem-
ber 2009 (minimum follow-up, 6 months). Fifty (58.8%)
patients had IPAH, 18 (21.2%) had CTD-PAH (17
scleroderma and 1 mixed connective tissue disease), and
17 (20%) had inoperable CTEPH treated with specific
medical treatment for PAH.
The diagnosis of both PAH and CTEPH was based on
hemodynamic criteria: mean resting pulmonary artery
pressure higher than 25 mmHg and mean pulmonary
capillary pressure lower than 15 mmHg on right heart
catheterization [9]. For the survival analysis, the date
when catheterization was performed was considered the
date of the diagnosis. All patients had received their first
specific treatment for PAH in our unit, which enabled us
to study their initial treatment response. The present
study has the approval of the IRB of our centre (CEIC
Hospital Universitari Vall d’Hebron. Approved in the
acta #190; July 29, 2011).
Statistical Analysis
Mortality risk factors were evaluated through a Cox pro-
portional hazards model designed to assess the predictive
capacity for mortality of 4 blocks of clinically differenti-
ated variables that were included in the model in succes-
sive steps. An attempt was made to reproduce the true
disease history from the time when patients first con-
sulted and their functional capacity and hemodynamic
status are determined, up to the time when treatment is
started and the patients’ respon se is evaluated. In the first
block of the analysis, age and etiology were included as
clinical variables. The second incorporated the baseline
functional capacity determined with the six-minute walk
test (6 mWT). The third added the CI obtained during
diagnostic catheterization, and the fourth included the
response to the first specific treatment patients received,
defined by the improvement on the 6 mWT in the first 6
to 8 weeks following the start of treatment. For the pur-
poses of the study, a positive treatment response was
established when there was any increase between the
baseline 6 mWT and the first follow up one after starting
treatment.
The variables age, distance walked, and CI were cate-
gorized into 2 groups, using the medians of the results
obtained as the cut-off value; the variable etiology was
categorized into 3 groups (IPAH, CTD-PAH, and CTEPH ),
with IPAH being the reference group (Table 2).
The data analysis was performed with SPSS, 17.0.
Descriptive data are presented as the mean and/or stan-
dard deviation. The Kaplan-Meier method was used to
calculate survival and Cox proportional hazards regres-
sion model to analyze risk factors for mortality. Relative
risk (RR) is expressed with the corresponding 95% con-
fidence interval (95% CI). Significance was set at p <
0.05 for all the tests used.
3. Results
Of the 85 patients, 69 (81%) were women, and the mean
age was 52 (18 - 82) years. The mean interval from the
onset of symptoms to the diagnosis was 20 (median 14)
months. Functional and hemodynamic status are shown
in Table 1.
Specific PAH treatment was started in 65 incident pa-
tients (77%) and in 20 (23%) prevalent patients that were
diagnosed before 2002, when the first specific drugs for
this condition were approved. Seventy-six patients were
started on monotherapy: 44 (51.7%) with an endothelin
receptor antagonist, 17 (20%) with phosphodiesterase-5
inhibitor, 6 (7%) with epoprostenol, 2 (2.4%) with in-
haled iloprost and 1 (1.2%) with subcutaneous trepro-
stinil, and 6 (7%) with a positive vasorreactivity test,
with calcium channel blockers. Nine patients with severe
disease were initially treated with a combination of in-
haled iloprost plus sildenafil or bosentan.
At study end 22 (25.8%) patients had stopped fol-
low-up for the following reasons: 2 (2.3%) lung trans-
plant, 3 (3.5%) had withdrawn from follow-up, 17 (20%)
had died. The mean duration of follow-up was 45.8 (me-
dian: 37.5) months (Figure 1).
The analysis of risk factors for mortality is presented
in Table 2. In the univariate analysis neither of the ele-
ments in the first block had an effect on mortality.
Younger patients did not have a lower risk of death (RR,
0.738 (95% CI, 0.316 - 1.724); p = 0.482), and there
were no significant differences in survival according to
the etiology: CTD-PAH patients presented an RR of
2.329 (95% CI, 0.838 - 6.473) and those with CTEPH an

M. LOPEZ-MESEGUER ET AL. 19
Table 1. Baseline information.
All (n: 85) IPAH (n: 50) CTD-PAH (n: 18) CTPH (n: 17)
Gender ♀ (%) 81 72 100 82
Age at diagnosis (years) 51.4 (r: 18 - 82) 46.8 (r: 18 - 82) 55.6 (r: 18 - 78) 60.6 (r: 27 - 81)
Time to diagnosis (months) 20 ± 27 2 2 ± 32 15.3 ± 10 23 ± 24
BMI (Kg/cm2) 26.5 ± 5.9 26.5 ± 6 23.8 ± 4.2 29 ± 4.3
I (%) 2 4 0 0
II (%) 11 8 17 12
III (%) 76 72 78 82
NYHA
IV (%) 11 16 5 6
FVC (%) 75 ± 2 0 80 ± 19 72 ± 19 63 ± 16
FEV1 (%) 79 ± 19 8 3 ± 18 78 ± 20 71 ± 16 Lung function
DLCO (%) 59 ± 21 61 ± 22 48 ± 13 65 ± 18
Baseline 6 mWT (m) 273 ± 117 291 ± 127 247 ± 102 247 ± 91
Echocardiography PAPs (mmHg) 81 (r: 46 - 136) 82 (r: 53 - 136) 75 (r: 52 - 128) 83 (r: 46 - 113)
PAPm (mmHg) 49 ± 15 (r: 28 - 91) 52 ± 16.6 (r: 29 - 91)43 ± 9.8 (r: 28 - 64) 52 ±13.8 (r: 30 - 78)
CO (l/min) 3.6 ± 1.2 (r: 2.1 - 8.3)3.7 ± 1.2 (r: 2.1 - 7) 3.8 ± 1.5 (r: 2.2 - 8.3) 3.2 ± 0.9 (r: 2.3 - 5.2)
CI (l/min·m2) 2.2 ± 0.7 (r: 1.3 - 4.6)2.2 ± 0.6 (r: 1.3 - 3.9)2.5 ± 0.9 (r: 1.6 - 4.6) 2 ± 0.3 (r: 1.6 - 2.6)
Hemodinamics
PVR (WU) 13.5 ± 5.3 (r : 5 - 38) 14.2 ± 6 (r: 5 - 38) 12 ± 3.5 (r: 6 - 19) 12.9 ± 4.7 (r: 8 - 25)
BMI: body mass index; NYHA FC: New York Heart Association functional class; FVC: forced vital capacity; FEV1: forced expiratory volume in the first
second; DLCO: diffusion lung capacity for carbon mo noxide; PAPm: mean pulm o nary artery pressure; CO: cardiac output; PVR: pulmonary vascular resistance;
WU: wood units.
Figure 1. Survival of a group of 85 patients (68 PAH and 17 CTPH).
RR of 1.168 (95% CI, 0.375 - 3.644), with p values of
0.105 and 0.789, respectively, relative to those with a
diagnosis of IPAH. Univariate analysis of the second
block, involving functional capacity at baseline measured
by the 6 mWT, showed no d ifferences in mortality risk in
patients who walked a shortr distance than the median e

M. LOPEZ-MESEGUER ET AL. 20
Table 2. Cox proportional hazards regression model.
Cox Proportional Hazards Regression Model
Cumulative probability of survival (Kaplan-Meier)
2 years 4 years 6 years 8 years
Variables Cut-off
(median) n Death- transplant
% SE % SE % SE % SE
Log rank
Breslow
(p)
Cross HR
crude
mortality rates
(95% CI)
Cross HR
adjusted mor-
tality rates
(95% CI)
>50 42 11 88.1 0.05771.40.08965.50.09940.90.1531 1
Age, y <50 43 11 87.6 0.05269.50.08469.50.08469.50.084
LR: 0.481
B: 0.869 0.738
(0.316 - 1.724)
p 0.482
0.744
(0.26 - 2.133)
p 0.582
IPAH 50 12 91.1 0.04372.10.07872.10.07866.50.0891 1
CTD-PAH 18 6 75.5 0.10767.10.12444.70.2- - 2.329 (0.838 - 6.473)
p 0.105
3.145
(0.995 - 9.946)
p 0.051
Etiology
CTEPH 17 4 93.8 0.06174.60.13274.60.13249.70.221
LR: 0.243
B: 0.26 1.168
(0.375 - 3.644)
p 0.789
0.654
(0.179 - 2.387)
p 0.521
>288 42 12 92.4 0.04276.50.08271.40.09163.40.111 1
6 mWT, m <288 43 10 83.3 0.06362.70.09354.90.1154.90.11
LR: 0.207
B: 0.063 1.708
(0.736 - 3.967)
p 0.213
1.173
(0.599 - 4.895)
p 0.315
>2 42 12 90.2 0.04680.80.06776.30.07769.40.0961 1
Cardiac
index,
L/min/m2 <2 43 10 86 0.05955.60.10955.60.10944.50.132
LR: 0.068
B: 0.097 2.207
(0.924 - 5.273)
p 0.075
2.295 (0.793 -
6.642)
p 0.125
Si 51 8 97.9 0.02178.80.07378.80.07378.80.0731 1
Improvement
6 mWT with
specific
therapy No 34 14 72.1 0.085570.10449.90.11329.90.129
LR: 0.003
B: 0.003 3.438
(1.439 - 8.214)
p 0.005
4.832
(1.888 - 12.364)
p 0.001
6 mWT: 6-minute walk test; CTD-PAH: connective tissue disease-associated pulmonary artery hypertension; CTEPH: chronic thromboembolic pulmonary
hypertension; SE: standard error; HR: hazard ratio; IPAH: idiopathic pulmonary artery hypertension.
(RR, 1.708 (95% CI, 0.736 - 3.967); p = 0.213). In the
third block, containing information on hemodynamic
status provided by the CI, patients with an index lower
than 2 L/min/m2 did not have a significative higher risk
of mortality (RR, 2.207 (95% CI, 0.924 - 5.273); p =
0.075). The last block, which assessed the influence on
survival of the treatment response as determined by any
increase in the distance covered in the 6 mWT, showed
that patients did not improve their 6 mWT following the
start of specific treatment had a much higher risk of
mortality than those who were able to walk a longer dis-
tance than at baseline (RR, 3.438 (95% CI, 1.439 - 8.214) ;
p = 0.005).
In the multivariate analysis, the block 1 variables again
showed no effect, with younger patients presenting an
RR of 0.744 (95% CI, 0.26 - 2.133) (p = 0.582) and the
etiologies as follows: CTD-PAH yielded an RR of 3.145
(95% CI, 0.995 - 9.946) (p = 0.051) and CTEPH an RR
of 0.654 (95% CI, 0.179 - 2.387) (p = 0.521) with respect
to patients with IPAH. Neither the baseline 6 mWT re-
sults (RR, 1.173 (95 % CI, 0.599 - 4.895); p = 0.315) nor
the CI results (RR, 2.295 (95% CI, 0.793 - 6.642); p =
0.125) showed prognostic power in the multivariate
model. The variable response to treatment, maintained a
strong predictive capacity for mortality (RR, 4.832 (95%
CI, 1.888 - 12.364); p = 0.001) (Figure 2). Among the 51
(60%) patients who improved their 6 mWT after onset of
treatment, the mean increase in the 6-min walk distance
was 110 m from baseline (259 ± 123 m) to the first fol-
low up visit (369 ± 87 m). The mean increase in the dis-
tance walked was greater for patients who were initially
in NYHA functional class IV (199 m) than for patients in
class III (26 m), but the absolute distance walked re-
mained lower (272 ± 120 m vs. 307 ± 138 m). Among
the 34 (40%) patients that didn’t improve after being
treated they experienced a mean decrease in the distance
walked of 64m from baseline (293 ± 106 m) to the first
follow up visit (229 ± 149 m).
The chi-square value for the incremental predictive
capacity of each block of variables based on the log like-
lihood ratio is shown in Figure 3. At the initial visit, in
which only the clinical information is available, repre-
sented here by the age and diagnosis, a very high degree
of uncertainty is evident (χ2, 2.94; p = 0.401). There was

M. LOPEZ-MESEGUER ET AL. 21
Figure 2. Compared survival in patients with PAH and CTPH according to their response to therapy measured by improve-
ment in 6 mWT.
Figure 3. Progressive incremental predictive value of this model.

M. LOPEZ-MESEGUER ET AL. 22
only a slight improvement when additional information
on the functional status (6 mWT) (χ2, 4.648; p = 0.325)
and hemodynamic status (CI) (χ2, 7.49; p = 0.187) was
provided. The predictive power significantly increased,
however, when the last block with information on the
disease follow-up and response to treatment was intro-
duced (χ2, 20.8 73; p = 0.002).
4. Discussion
This study attempts to clarify the factors pr edictive of th e
prognosis in PAH and in a subgroup of CTEPH patients
who had an indication for medical treatment similar to
those with PAH. The model was designed to define the
reliability with which the prognosis of PAH can be esti-
mated according to the information available at each
phase of the disease management. The most striking
finding is the prognostic v alue of the response to the first
specific treatment, measured by an increase in the dis-
tance walked in the 6 mWT. Patients who showed no
improvement in the 6 mWT had an almost 5-fold higher
risk of death (RR, 4.8) than those who showed any in-
crease. The development of specific therapies for PAH
over the last decade has surely improved the prognosis of
patients with this condition [10,11]. Nonetheless, uncer-
tainty regarding the prognosis remains high, and the
baseline clinical and hemodynamic parameters do not
suffice as reliable predictive factors.
When a patient is seen for the first time and the clini-
cal data are analyzed, the physician may consider that
advanced age or a diagnosis of CTD-PAH would indicate
a poorer prognosis. It is known the PAH presents a
poorer prognosis at both extreme ages of life [12,13]. A
poorer prognosis has also been described in CTD-PAH
with respect to IPAH [14,15]. In our model these factors
had no impact on risk, although in the case of CTD-PAH,
the RR may have reached significance if the sample size
were larger. However, the results obtained allow reason-
able speculation that these factors carry less weight for
the prognosis than the response to treatment.
Baseline functional status was measured by the dis-
tance covered in the 6 mWT, as it is a well-recognized
prognostic factor in PAH, reported in several articles
published in the 1990s [7,8,16]. New York Health Asso-
ciation functional class was not analised in order to avoid
interferences with distan ce walked in the Cox model due
to the clear and well known correlation of these two pa-
rameters. Based on this information, the regulatory agen-
cies have considered changes in the patients’ exercise
capacity as a surrogate endpoint for survival, and this has
enabled clinical development of specific drugs for PAH.
The results from clinical trials also confirmed that pa-
tients who can walk farther, live longer, and this fact was
used to evaluate the optimal response to treatment in
clinical practice guidelines. Thus, it has been established
that patients able to walk less than 300 m in the 6 mWT
have a poor prognosis, and those able to walk more than
500 m have a good prognosis [9]. We found no differ-
ences in the prognosis related to the baseline 6 mWT,
possibly because our model contained other factors that
were more important.
Other available data at the time of the diagnosis is the
baseline hemodynamic study. The CI, one of the meas-
ures recorded in this study, was first described to be an
important prognostic factor in PAH at the beginning of
the 1990s [2] and later studies supported its value [7-9].
The fact that we did not observe differences in survival
according to the CI may be due to an insufficient sample
size and because of the lower weight of this factor in
comparison to the improvement following treatment ini-
tiation.
The most relevant result from this study is that the
predictive factor with the greatest influence on survival
of PAH is the patients’ response to the first specific
treatment received, established as any improvement in
the distance walked in the first 6 mWT performed fol-
lowing treatment initiation. A key related question that
currently remains unresolved is what would be the
minimum improvement on the 6 mWT that has an impact
on survival. In this sense, Sitbon et al. [7] evaluated
treatment response as measured by improvements in the
NYHA functiona l class and th e 6 mW T in a grou p of 178
patients diagnosed with IPAH in functional class III or
IV, treated with epoprostenol and evaluated at 3 months.
The authors reported better survival in patients who
walked a greater distance than the group mean (380 m) in
the 6 mWT at 3 months after starting treatment. There
were, however, no differences in survival related to the
magnitude of the increase in distance walked: patients
who improved to a great degree (>112 m) and those who
improved less (<112 m) presented similar survival. One
of the objectives at the start of treatment in these patients
is to achieve the greatest possible increase in the distance
covered in the 6 mWT. Nonetheless, based on the avail-
able information, it is not clear that there is a correlation
between the magnitude of the improvement and survival;
hence, we can assume that any increase in the distance
walked has a positive impact on survival. Our results
support this concept. Patients who showed no improve-
ment in exercise capacity after starting treatment had a
nearly 5-fold higher risk of mortality on average, than
those who did. Our model illustrates how the uncertainty
regarding the prognosis of PAH decreases as additional
information about the patient is obtained. However, the
initial response to treatment seems to carry a great deal
of weight for establishing the prognosis in this patient
population.
The decision to include patients from groups I and IV

M. LOPEZ-MESEGUER ET AL. 23
of the Pulmonary Hypertension Classification was made
for two reasons. First, CTEPH shares certain pathophysi-
ologic characteristics with PAH in terms of pulmonary
vasculature remodeling, which is known to occur even in
patients who show macroscopic resolution of the clot
[17]. Furthermore, some patients with CTEPH in whom
endarterectomy is not indicated respond to specific PAH
therapy, an alternative treatment for CTEPH that has
been tested in clinical trials [18,19]. Lastly, according to
our data, survival in CTEPH is similar to that in PAH.
The main limitations of this study are its retrospective
nature, a relatively small sample size, and the fact that it
was carried out in a single center. Furthermore, we can-
not know whether other variables related to treatment
response such as hemodynamic parameters or biomarkers
are also relevant to the prognosis. Validation of this
model of risk predictors in a larger sample would be ad-
visable. Future prospective studies particularly multicen-
ter studies, in which substantial patient groups can be
assembled, will be important to determine the value of
these results.
In conclusion, the prop ortional risks model u sed in this
study demonstrated the high degree of uncertainly re-
garding the prognosis of PAH and CTEPH at the start of
medical treatment, and showed that the data related to
treatment response are of value in estimating the progno-
sis of the disease.
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