Vardenafil treatment for patients with pulmonary

arterial hypertension: a multicentre, open-label study

Z-C Jing,
1
X Jiang,
1
B-X Wu,
2
X-Q Xu,
3
Y Wu,
4
C-R, Ma,
1
Y Wang,
5
Y-J Yang,
4
J-L Pu,
4
W Gao
6
1
Department of Pulmonary
Circulation, Shanghai Pulmonary
Hospital, Tongji University
School of Medicine, Shanghai,
China;
2
Department of
Cardiology, First Affiliated
Hospital, Haerbin Medical
University, Haerbin, China;
3
Department of Internal
Medicine, Aviation Industry
Central Hospital, Beijing, China;
4
Department of Cardiovascular
Medicine, Cardiovascular
Institute and Fu Wai Hospital,
Peking Union Medical College,
Beijing, China;
5
Department of
Respiratory Medicine, Beijing
Shijitan Hospital, Peking
University, Beijing, China;
6
Department of Thoracic
Surgery, Shanghai Pulmonary
Hospital, Tongji University
School of Medicine, Shanghai,
China
Correspondence to:
Professor Z-C Jing, Department
of Pulmonary Circulation,
Shanghai Pulmonary Hospital,
Tongji University School of
Medicine, 507 Zhengmin Road,
Shanghai 200433, China;
jingzhicheng@gmail.com
Accepted 4 June 2009
Published Online First
22 June 2009
ABSTRACT
Background: Vardenafil is a new phosphodiesterase-5
inhibitor that has shown some efficacy in the treatment of
pulmonary arterial hypertension (PAH).
Objective: To examine the long-term effects of vardenafil
in patients with PAH.
Methods: A multicentre, open-label study of 1-years
duration was undertaken in 45 patients with PAH to
determine the long-term safety and efficacy of vardenafil
(5 mg once daily for the first 4 weeks, then 5 mg twice
daily) and make a preliminary assessment of its monthly
acquisition cost compared with other PAH-active treat-
ments. The patients clinical features, exercise capacity,
WHO functional class and haemodynamic variables were
measured at baseline and at 3 and at least 9 months after
initiating vardenafil treatment.
Results: At the 3 months and a mean (SD) of 14
(3) months (range 918) follow-up assessments, the
6 min walking distance was significantly increased from
baseline by 70.7 (78.4) m (p,0.001) and 83.4 (91.8) m
(p,0.001), respectively. Furthermore, long-term treat-
ment with vardenafil for a mean duration of .1 year was
also associated with improvements in haemodynamic
parameters, WHO functional class and serum uric acid
concentrations. Overall, vardenafil treatment was well
tolerated. No patients were withdrawn owing to adverse
events and none died during the course of the study.
Conclusion: Long-term treatment with vardenafil is well
tolerated and has sustained beneficial effects on PAH, as
measured by patients exercise capacity, WHO functional
class and haemodynamic parameters.
Pulmonary arterial hypertension (PAH) is a pro-
gressive disease characterised by an elevation of
pulmonary artery pressure and pulmonary vascular
resistance, ultimately leading to right ventricular
failure and death. Currently, the efficacy of several
drugs in PAH has been established. These treat-
ments include prostanoids,
13
endothelin receptor
inhibitors,
46
and phosphodiesterase-5 (PDE5) inhi-
bitors.
7 8
PDE5 is a phosphodiesterase isoenzyme
that degrades cyclic guanosine monophosphate
(cGMP) causing constriction of blood vessel
walls.
9 10
Sildenafil, a widely used PDE5 inhibitor,
has gained recognition as a useful oral treatment
option for PAH.
7 8 11 12
Based on its favourable
effects in patients with PAH, sildenafil was
approved by the FDA and the EMEA in 2005 for
the treatment of symptomatic PAH.
Recently, a new PDE5 inhibitor, vardenafil was
approved for the treatment of erectile dysfunction.
Vardenafil is significantly more potent than
sildenafil in inhibiting PDE5 and may therefore
have a more favourable clinical profile.
13
Ghofrani
et al
14
reported that with short-term use in patients
with PAH, vardenafil appeared to lack specificity
for the pulmonary circulation despite inducing
significant pulmonary vasorelaxation. Currently,
the efficacy and safety of mid- to long-term
vardenafil treatment in patients with PAH has
only been examined in case reports,
15
which had
insufficient power and sample size. Consequently,
it is still unclear whether vardenafil is an effective
and well-tolerated treatment for PAH.
The aim of this study was to investigate
whether vardenafil can safely improve the func-
tional capacity and haemodynamic parameters of
patients with PAH over the course of about 1 year.
As PAH-active treatments such as bosentan and
iloprost are quite expensive in China and patients
are not reimbursed for such treatment, a secondary
objective of the study was to compare the monthly
acquisition cost of vardenafil with that of com-
parator drugs to make a preliminary assessment of
whether it might prove a more affordable treat-
ment option in China and other developing
countries.
METHODS
A long-term, open-label study was conducted at
five pulmonary vascular or cardiovascular centres
in China during October 2006 to January 2008. The
study protocol was reviewed and approved by
ethics committees at local centres, and written
informed consent was obtained from all patients
who were enrolled.
Patient selection
The study included patients with PAH who were
admitted for diagnosis and treatment to the
participating study centres. To make the patient
population as homogeneous as possible, only those
with idiopathic PAH (sporadic or familial),
advanced pulmonary vasculopathy associated with
connective tissue disease and congenital heart
disease, or portopulmonary hypertension were
included. Patients with chronic pulmonary
obstruction, chronic pulmonary thromboembolism
and pulmonary hypertension associated with left
heart disease were excluded. A mean pulmonary
artery pressure (mPAP) .30 mm Hg and pulmon-
ary vascular resistance (PVR) .5 Wood units at
rest in the presence of a normal pulmonary
capillary wedge pressure (PCWP; ,15 mm Hg)
measured during cardiac catheterisation before the
study were criteria for inclusion. Patients with
WHO functional class IIIV were permitted to
enter the study if their disease was stable. Patients
Pulmonary hypertension
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were enrolled if they were able to walk a maximum of 550 m
during a 6 min walk test, but we did not establish any lower
limit for inclusion.
During the study, patients continued to receive conventional
treatment (including diuretics, warfarin, digoxin or supplemen-
tal oxygen) if necessary. However, no vasodilators other than
vardenafil were permitted at least 3 months before or during the
study. In particular, prostacyclin analogues, bosentan and
sildenafil were not given to any patient.
Study procedures
Patients who met the inclusion criteria were hospitalised in one
of the study centres for pretreatment (baseline) evaluation,
which consisted of history, physical examination, echocardio-
graphy, ECG, chest x-ray examination, nuclear ventilation-
perfusion scan, chest computed tomography scan and a 6 min
walk test. All patients underwent diagnostic cardiac catheter-
isation. Patients were given vardenafil 5 mg orally daily for
1 month after which the dosage was increased to 5 mg orally
twice daily if no significant adverse events occurred. Subsequent
evaluations included assessment of the WHO functional class
and exercise capacity at 3 months and a complete re-evaluation
at 918 months. All patients continued to receive vardenafil
after the end of the study period.
Outcome measures
WHO functional class and exercise capacity
The 6 min walk test was performed according to a standardised
protocol at baseline and after 3 and at least 9 months of
vardenafil treatment. Subjects were asked to walk and cover as
much ground as possible in 6 min. The patients WHO
functional class was also evaluated at baseline and at 3 months
and at least 9 months.
Haemodynamic parameters
To characterise the baseline haemodynamic profile and the
haemodynamic response to oral vardenafil treatment, all
patients underwent right heart catheterisation and were
scheduled to repeat the procedure after 9 months. This was
performed via the right internal jugular or left antebrachial veins
using a 7F Swan-Ganz catheter (7F, 131HF7P; Edwards
Lifesciences World Trade, USA). Measurement of systemic
blood pressure and arterial blood gases was performed via an
arterial line inserted into the radial artery. Cardiac output (CO;
which was measured in triplicate by the thermodilution
technique with ice-cold isotonic sodium chloride solution),
cardiac index (calculated by dividing CO by body surface area),
systemic blood pressure, mPAP, right atrial pressure and PCWP
were also measured at baseline and after vardenafil treatment.
Aerosolised iloprost or infused adenosine was administered as a
screening agent to assess pulmonary vasoreactivity in all
patients. As recommended in recent guidelines,
1619
a positive
vasodilator response was defined as a fall of mPAP of at least
10 mm Hg to (40 mm Hg, with an increased or unchanged
CO. Only non-responders were selected as candidates to receive
vardenafil treatment.
Clinical parameters
Standard clinical assessments for PAH recommended in several
recent guidelines were performed in all patients, including
blood gas analysis, measurement of pulmonary function,
an ECG, echocardiography, chest x-ray examination and a
ventilationperfusion scan. All parameters were reassessed
after 3 and at least 9 months of treatment with vardenafil.
Tolerability
Laboratory tests, including evaluation of hepatic and renal
function and routine blood tests, were performed at baseline
and every 3 months in all subjects who received vardenafil. To
detect any adverse effects or changes in clinical status, patients
underwent medical evaluations every 3 months.
Statistical analysis
Haemodynamic parameters were expressed as mean (SD)
values. SPSS 13.0 software (SPSS Chicago, Illinois, USA) was
used for statistical analysis. A paired t test was applied to
compare differences in clinical characteristics and haemo-
dynamic variables between baseline and the post-treatment
assessments. A x
2
test was used to compare differences in
WHO functional class distribution between baseline and the
post-treatment assessments. Significance was set at p,0.05.
RESULTS
Patient disposition
A total of 45 patients (36 women, nine men; mean (SD) age 32.5
(10.3) years) with PAH were evaluated and treatment started
with vardenafil. Diagnoses were idiopathic PAH in 10 and
secondary PAH in 35 patients (associated with connective tissue
disease in 11, congenital heart disease in 23 and portopulmonary
hypertension in one). Among the patients with congenital heart
disease, three had defects repaired by interventional or surgical
treatment and 20 had Eisenmenger syndrome (12 with
ventricular septal defect, four with atrial septal defect and four
with patent ductus arteriosus). At the beginning of the study,
all participants were in WHO functional classes II through IV.
None of the patients had been treated with other PAH-active
drugs, including bosentan, prostanoids and sildenafil, in the
previous 3 months. Vardenafil was given for a mean (SD) of 14
(3) months (range 918). Table 1 shows the baseline character-
istics of the patient population enrolled in the study.
Changes in clinical characteristics during vardenafil treatment
During vardenafil treatment, the mean (SD) 6 min walking
distance was increased by 70.7 (78.4) m at 3 months and 83.4
(91.8) m at 14 (3) months (fig 1). The improvement in 6 min
walking distance was statistically significant between baseline
and the 3 month assessment (p,0.001), but the increase
between 3 and 14 (3) months did not reach statistical
significance (p=0.36). The serum uric acid (UA) concentration
was significantly decreased after 1-years treatment with
vardenafil treatment (p=0.038). A slight decrease was also
seen in right ventricular end-diastolic diameter by echocardio-
graphy after 14 (3) months, but the change from baseline did
not reach statistical significance.
At the beginning of the study, 12% of patients were in WHO
functional class IV, 64% in class III, 24% in class II and none in
class I. After 3 months, there was a substantial improvement in
WHO functional class (p,0.001) and a further improvement
was seen at 14 (3) months (p,0.001 compared with baseline;
p,0.05 compared with month 3). At the end of the study, 11%
of patients were in WHO functional class I, 69% in class II, 18%
in class III and 2% in class IV (fig 2).
Pulmonary hypertension
1532 Heart 2009;95:15311536. doi:10.1136/hrt.2009.169417
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Changes in cardiopulmonary haemodynamic and blood gas
variables
Twenty patients underwent repeated right heart catheterisation
and blood gas analysis after a mean follow-up time of 14
(3) months (range 1018 months; table 2 and fig 3). In these
patients there were significant decreases from the baseline value
in mPAP (from 67.4 (16.1) to 59.7 (16.0) mm Hg; p =0.001), in
PVR (from 17.5 (9.7) to 11.4 (5.1) Wood units; p,0.001) and in
heart rate (from 86.5 (11.3) to 80.8 (11.2) bpm; p=0.009), along
with significant increases in cardiac index (from 2.7 (1.0) to 3.3
(1.2) l/min/m
2
; p =0.001) and in SvO
2
(from 66.2 (15.0)% to
68.8 (14.0)%; p =0.009). Additionally, the PVR/systemic
vascular resistance (SVR) ratio was also significantly decreased
after vardenafil treatment (from 0.76 (0.24) to 0.66 (0.22);
p =0.006). Although treatment with vardenafil had a slight
beneficial effect on right atrial pressure and arterial oxygen
saturation (table 2), these changes did not reach statistical
significance.
Safety and tolerability
No patients died during the course of the study. Overall,
vardenafil treatment was well tolerated. Although the majority
of patients experienced an adverse event (table 3), most events
were mild and transient. No patient discontinued treatment
prematurely owing to adverse events. However, two patients
were admitted to hospital because of progressive shortening of
breath and deterioration in right heart function at 6 months and
11 months, respectively. Both patients were treated with addi-
tional PAH-active drugs (bosentan and iloprost, respectively).
DISCUSSION
This multicentre, open-label study has demonstrated that
vardenafil may improve both exercise tolerance and pulmonary
vascular haemodynamic parameters in patients with PAH. The
6 min walking distance increased during the first 3 months of
Table 1 Demographic and clinical characteristics of the
patients at baseline
Characteristics All patients (n =45)
Gender:
Male, n (%) 9 (20)
Female, n (%) 36 (80)
Age (years) 32.5 (10.3)
Weight (kg) 53.1 (12.5)
BSA (m
2
) 1.5 (0.2)
Aetiology of PAH:
IPAH, n (%) 10 (22)
CHD-PAH, n (%) 23 (51)
Repaired defects 3 (7)
Unrepaired defects* 20 (44)
CTD-PAH, n (%) 11 (24)
Porto-PAH, n (%) 1 (2)
WHO functional class:
II, n (%) 11 (24)
III, n (%) 29 (64)
IV, n (%) 5 (12)
mPAP (mm Hg) 69.2 (14.9)
RAP (mm Hg) 5.6 (5.0)
PCWP{ (mm Hg) 6.8 (3.6)
PVR (Wood units) 18.1 (9.3)
CI (l/min/m
2
) 2.7 (1.2)
6MWD (m) 409 (103)
Borg dyspnoea score 3.1 (1.6)
Oral digoxin, n (%) 21 (47)
Oral warfarin, n (%) 15 (33)
Oral diuretics, n (%) 31 (69)
*Data are presented as mean (SD) unless stated otherwise;
{ventricular septal defect (12), atrial septal defect (4) and patent
ductus arteriosus (4); {the PCWP could not be successfully
measured in eight patients at the first evaluation because of a
markedly enlarged right atrium and severe tricuspid regurgitation,
but these eight patients were identified as having a PCWP ,15 mm
Hg on repeated right heart catheterisation with the aid of a guidewire
with a diameter of 0.025 inches (Cordis, Johnson & Johnson, USA)
14 (3) months later.
BSA, body surface area; CHD, congenital heart disease; CI, cardiac
index; CTD, connective tissue disease; IPAH, idiopathic pulmonary
arterial hypertension; mPAP, mean pulmonary artery pressure;
6MWD, 6 min walking distance; PAH, pulmonary arterial
hypertension; PCWP, pulmonary capillary wedge pressure; Porto-
PAH, portopulmonary hypertension; PVR, pulmonary vascular
resistance; RAP, right atrial pressure; WHO, World Health
Organization.
Figure 1 The 6 min walking distance (6MWD) at baseline and after
3 months and 14 (3) months of vardenafil treatment in patients with
pulmonary arterial hypertension (n =45).
Figure 2 WHO functional class at baseline and after 3 months and 14
(3) months of vardenafil treatment in patients with pulmonary arterial
hypertension (n =45).
Pulmonary hypertension
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vardenafil treatment and this improvement was maintained for
more than 1 year. In addition, long-term treatment was not
associated with any major adverse sequelae attributable to
vardenafil.
Vardenafil has been reported to exhibit both more potent and
more selective inhibition of PDE5 than sildenafil.
20
Several
previous studies have shown that short-term treatment with
sildenafil significantly reduces mPAP and PVR.
2123
In a
comparison of the short-term effects of three different PDE5
inhibitors on pulmonary and systemic haemodynamic para-
meters in patients with PAH, Ghofrani et al
14
found that
sildenafil and tadalafil caused a significant reduction in the
PVR/SVR ratio, while vardenafil caused an almost equipotent
reduction of PVR and SVR, suggesting that it lacks selectivity
for the pulmonary circulation, even at high doses. Similar
findings for the acute effects of oral vardenafil were also
reported in another study by Aizawa et al.
15
However, in the
latter study, the PVR/SVR ratio was significantly decreased by
20.7% after vardenafil administration for 3 months. In our
study, selectivity for the pulmonary vasculature was evident
with long-term vardenafil administration, as reflected by a
decrease in the PVR/SVR ratio of 13.2% after 14 (3) months of
treatment. Therefore, the long-term effects of vardenafil may
differ from its short-term effects, as has been observed with
epoprostenol.
2426
In addition to pulmonary vasodilatation, other effects of
PDE5 inhibition such as an anti-smooth muscle proliferative
effect on pulmonary artery cells
27
and a direct effect on the right
ventricle to enhance contractility and CO
28
may be involved in
the long-term effect of vardenafil. Vardenafil may also influence
bone marrow-derived endothelial progenitor cells, the migration
of which into the peripheral circulation promotes endothelial
repair and neovascularisation.
29
Foresta et al have reported a
significant increase in the number of circulating endothelial
progenitor cells in humans after vardenafil administration,
30
suggesting that this phenomenon may have a role in the drugs
long-term effects.
In the study of Ghofrani et al,
14
sildenafil, but not vardenafil
or tadalafil, improved arterial oxygenation after short-term
administration. The authors attributed this difference to an
additional effect of sildenafil in amplifying local cGMP-based
vasoregulatory loops. As alveolar oxygenation is an important
determinant of local nitric oxide (NO) production and cGMP
levels, poorly ventilated areas of the lung would be expected to
have lower NO and cGMP levels and therefore the local effect of
PDE5 inhibition would be expected to be less than in well-
ventilated lungs.
31
Consequently, PDE5 inhibition may improve
rather than disturb the ratio of perfusion to ventilation
distribution. In this study, arterial oxygen saturation was
slightly improved after oral vardenafil treatment had been given
for 14 (3) months, but the change from baseline did not reach
statistical significance. This long-term effect was similar to that
reported in previous short-term studies.
15
In comparison with
sildenafil, vardenafil has different selectivities for PDE iso-
enzymes.
32
Further studies are needed to examine the question
of whether this different profile is related to differences in the
pattern of PDE inhibition or to other, currently unknown
mechanisms.
Pulmonary hypertension characterised by extensive remodel-
ling of the pulmonary vasculature increases right ventricular
after load. Subsequently, the balance of oxygen supply and
consumption deteriorates owing to a decrease in CO. A feature
of PAH and one that was evident in the patients we studied, is
an elevated baseline serum UA concentration which (as a
marker of impaired oxidative metabolism) is positively corre-
lated with total pulmonary resistance and negatively correlated
with CO and has been shown to be independently related to
mortality.
33
In this study, long-term treatment with vardenafil
caused a significant reduction of both the serum UA concentra-
tion and mPAP. The decrease in mPAP may ameliorate the
increased wall stress in the right ventricle and the impaired left
ventricular diastolic function due to the enlarged right ventricle
of these patients and improve the balance of oxygen supply and
consumption owing to a significant increase of CO.
Table 2 Mean changes (95% confidence intervals) in haemodynamic parameters measured during cardiac
catheterisation, and clinical characteristics from baseline to the mean follow-up time of 14 (3) months in 20
patients
Variables Baseline
After treatment (14
(3) months)
Change with vardenafil*
(n =20) p Value{
Haemodynamic parameters
HR (bpm) 86.5 (11.3) 80.8 (11.2) 25.7 (211.6 to 20.3) 0.009
RAP (mm Hg) 5.3 (4.6) 6.5 (4.7) 1.3 (20.8 to 3.4) 0.218
PCWP (mm Hg) 7.0 (3.4) 6.8 (2.2) 0.4 (21.6 to 2.3) 0.713
mPAP (mm Hg) 67.4 (16.1) 59.7 (16.0) 27.7 (211.6 to 23.6) 0.001
mSAP (mm Hg) 86.9 (9.8) 87.4 (8.0) 0.3 (21.9 to 2.6) 0.781
CI (l/min/m
2
) 2.7 (1.0) 3.3 (1.2) 0.7 (20.3 to 1.1) 0.001
PVR (Wood units) 17.5 (9.7) 11.4 (5.1) 26.1 (28.6 to 23.6) ,0.001
SVR (Wood units) 23.2 (10.8) 17.4 (6.1) 25.8 (28.7 to 22.9) 0.001
PVR/SVR ratio 0.76 (0.24) 0.67 (0.22) 20.1 (20.16 to 20.03) 0.006
SaO
2
(%) 90.7 (5.1) 91.8 (4.9) 1.22 (0.02 to 2.41) 0.058
SvO
2
(%) 66.2 (15.0) 68.8 (14.0) 2.56 (0.70 to 4.41) 0.009
Clinical characteristics
UA (mmol/l) 364.6 (117.3) 317.2 (74.7) 247.5 (291.9 to 22.7) 0.039
RVEDD (mm) 31.5 (9.1) 28.2 (6.8) 23.4 (27.4 to 0.7) 0.097
*Values shown represent the mean change (with 95% confidence intervals); {p values are for the comparison of vardenafil with
baseline.
CI, cardiac index; HR, heart rate; mPAP, mean pulmonary arterial pressure; mSAP, mean systemic arterial pressure; PCWP,
pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RVEDD, right ventricular end-
diastolic diameter; SaO
2
, arterial oxygen saturation; SvO
2
, mixed-venous oxygen saturation; SVR, systemic vascular resistance;
UA, uric acid.
Pulmonary hypertension
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Oral vardenafil treatment proved to be well tolerated. No
patient died during the course of our study and none was
withdrawn owing to intolerable adverse effects. As with
sildenafil,
8
the most common adverse effects with vardenafil
were flushing and headache. Most adverse events were transient
and of mild severity and only two patients needed to be
admitted to hospital during the study (at 6 months and
11 months, respectively) owing to clinical worsening of PAH.
In both these patients, additional PAH-active drugs were given
and a combination therapeutic regimen was established.
In China and in many other developing countries, expensive
PAH-active drugs are not covered by government medical
insurance. Although we did not conduct a full pharmaco-
economic analysis, a comparison of 2008 drug acquisition costs
showed that vardenafil at a dose of 5 mg twice daily costs
US$212 a month, which is considerably cheaper than bosentan
125 mg twice daily (US$4234 a month) and also cheaper than
sildenafil 20 mg three times daily (US$255 a month). Thus,
vardenafil could make PAH treatment more affordable to
patients in many developing countries.
Our study has some limitations. First, it was a non-
randomised, open-label study and confirmation of its findings
in a randomised, controlled clinical trial is necessary to verify
the efficacy and tolerability of vardenafil in patients with PAH.
Second, it was not a dose-titrated study and only one dose was
investigated. As the response to higher doses of vardenafil
beyond 10 mg daily has not been investigated, the ideal
maintenance dose is not yet known.
In conclusion, the results of this 1-year, open-label study
indicate that long-term vardenafil treatment is well tolerated
and significantly improves the haemodynamic parameters,
WHO functional class and exercise capacity of patients with
PAH. Oral vardenafil may therefore be beneficial as a selective
pulmonary vasodilator to treat patients with this condition.
Funding: This study was supported by Shanghai Pujiang Programme (08PJ14086) and
China National 973 Project (2007CB512008).
Competing interests: None.
Ethics approval: Approval from the ethics committee of the PI institute, Shanghai
Pulmonary Hospital, Tongji University.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Figure 3 Mean ( SD) (A) cardiac index (CI) and (B) pulmonary vascular
resistance (PVR; bottom) at baseline and at the mean follow-up time of
14 (3) months in 20 patients who completed haemodynamic evaluations.
The statistical significance of the changes with vardenafil treatment was
evaluated with the paired t test.
Table 3 Incidence of clinical worsening and the most
common adverse events during vardenafil treatment
Adverse events No (%)
Clinical worsening
Death 0
Hospitalisation for PAH; or 2 (4.4)
Initiation of other PAH-active treatment 2 (4.4)
Adverse events
Flushing 27 (60.0)
Headache 12 (26.7)
Diarrhoea 1 (2.2)
Skin rash 2 (4.4)
Gastritis 1 (2.2)
Gingival ulcer 1 (2.2)
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doi: 10.1136/hrt.2009.169417
2009 95: 1531-1536 originally published online June 22, 2009 Heart

Z-C Jing, X Jiang, B-X Wu, et al.

multicentre, open-label study

pulmonary arterial hypertension: a
Vardenafil treatment for patients with
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