Respiratory Medicine (2014) 108, 531e537

Available online at www.sciencedirect.com

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journal homepage: www.elsevier.com/locate/rmed

Efficacy and safety of sildenafil treatment

in pulmonary arterial hypertension:
A systematic review
Rong-chun Wang, Fa-ming Jiang, Qiao-ling Zheng, Chun-tao Li,
Xia-ying Peng, Chen-yun He, Jian Luo, Zong-an Liang*

Department of Respiratory Medicine, West China Medical School and West China Hospital,
Sichuan University, No. 3, Guo Xie Xiang, Chengdu, Sichuan 610000, China

Received 6 June 2013; accepted 6 January 2014

Available online 15 January 2014

KEYWORDS Summary
Pulmonary arterial Background: To evaluate the safety and efficacy of using sildenafil for
12 weeks to treat pul-
hypertension; monary arterial hypertension (PAH).
Pulmonary Methods: Randomized controlled trials (RCTs) of sildenafil therapy in patients with PAH pub-
hypertension; lished through May 2013 were identified by searching PubMed, the Cochrane Library, Embase,
Sildenafil; relevant websites, and reference lists of relevant studies. Two reviewers independently as-
Systematic review sessed the quality of the trials and extracted information.
Results: Meta-analysis was carried out with subsets of 4 trials involving 545 patients. Sildenafil
therapy significantly reduced clinical worsening of PAH compared to placebo (RR 0.39, 95% CI
0.21e0.69) and improved the 6-min walk distance (MD 31.3 m, 95% CI 18.01e44.67), WHO func-
tional class, hemodynamic variables and health-related quality of life (HRQoL). Sildenafil did
not, however, improve all-cause mortality (RR 0.29, 95% CI 0.02e4.94) or Borg dyspnea score
relative to placebo, nor did it significantly affect the incidence of serious adverse events. In
fact, sildenafil was associated with higher total incidence of adverse events, but these addi-
tional events were mild to moderate in severity and were tolerable.
Conclusions: Sildenafil therapy lasting
12 weeks improves multiple clinical and hemodynamic
outcomes in patients with PAH, but it appears to have no effect on mortality or serious adverse
events. The long-term efficacy and safety of sildenafil therapy in PAH requires further study
based on large and well-designed RCTs.
ª 2014 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel./fax: þ86 28 85423036.

E-mail addresses: liangzongan@hotmail.com, springxy@gmail.com (Z.-a. Liang).

0954-6111/$ - see front matter ª 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.rmed.2014.01.003
532
Introduction
Pulmonary arterial hypertension (PAH), characterized by
vascular proliferation and remodeling of small pulmonary
vessels, leads to progressive increase in pulmonary vascular
resistance (PVR) and, ultimately, to right ventricular failure
and death [1]. Several factors contribute to PAH patho-
genesis, and one of the signaling pathways participating in
PAH pathogenesis is the nitric oxide (NO) pathway [2,3].
This pathway is targed by inhibitors of phosphodiesterase
type 5 (PDE-5), an enzyme that degrades cyclic guanosine
monophosphate (cGMP) and thereby causes vasoconstric-
tion. PDE-5 inhibitors induce vasodilation by inhibiting the
hydrolytic breakdown of cGMP [4].
The PDE-5 inhibitor sildenafil has been advocated as a
first-line drug for treating PAH. It is a potent, orally active,
and selective inhibitor that has been widely used in mon-
otherapy and combination therapy for adults with PAH
[5,6]. Several meta-analyses of drug therapies to treat PAH
[7e10] have been carried out, and they suggest that sil-
denafil is safe and effective. However, these meta-analyses
feature relatively small sample sizes, treatment durations
of fewer than 12 weeks, and lack of blinding or randomi-
zation. Furthermore, they do not take into account two
recently published randomized controlled trials (RCTs) of
sildenafil therapy lasting 12 weeks [11,12]. In particular, we
are unaware of meta-analyses of RCTs assessing the safety
and efficacy of the drug when given to adults for periods of
12 weeks or more.
To address some of these gaps in previous meta-
analyses, we systematically reviewed the literature on sil-
denafil safety and efficacy for treating PAH over periods of
at least 12 weeks.
Materials and methods
Search strategy
We systematically searched for randomized controlled tri-
als (RCTs) involving sildenafil published in English through
May 2013 in PubMed, the Cochrane Library, and Embase
databases, as well as in review articles and reference lists
of relevant studies. We used the following search terms:
“sildenafil” and “PAH” or “pulmonary arterial hyperten-
sion” and “randomized controlled”. We also searched
Clinicaltrials.gov to identify ongoing but still unpublished
studies.
Study inclusion criteria
Studies were included if they satisfied all the following
conditions: (1) the study is an RCT that compares PAH with
placebo or other vasodilators (2) administered for
12
weeks to (3) adult patients who were (4) definitively diag-
nosed with group 1 PAH according to a standard clinical
classification [13].
Efficacy and safety outcomes
Two investigators independently extracted the following
data from included studies using a standardized form: first
author, year of publication, study design, patient charac-
teristics, interventions, and major outcomes, such as
R.-chun Wang et al.
clinical worsening, all-cause mortality, 6-min walk distance
(6MWD), WHO functional class (WHO FC), health-related
quality of life (HRQoL) score, Borg dyspnea score, hemo-
dynamic measures such as mean pulmonary arterial pres-
sure (mPAP), PVR and cardiac index. Data on adverse
events were also recorded to allow safety evaluation.
Quality assessment
Studies were assessed for quality of randomization, blind-
ing, reporting of withdrawals, generation of random
numbers and concealment of allocation according to the
Cochrane systematic review software, RevMan 5.2.
Statistical analysis
Statistical analyses were performed using RevMan 5.2
software. The statistical heterogeneity of treatment ef-
fects between studies was tested using the chi-squared
test, with a significance threshold of P < 0.1. Statistical
heterogeneity was considered to be significant when
I2 > 50%. Regardless of whether statistical heterogeneity
was present, meta-analyses were performed using a
random-effects model. We calculated risk ratios (RR) for
dichotomous data and weighted mean differences (WMD)
for continuous data; these estimates were reported
together with 95% confidence intervals (CI). When studies
failed to report the standard error of the mean (SEM) to
allow calculation of effect size, it was estimated from
published data [14]. If a study failed to report outcome
values at the end of follow-up and the associated SEM, we
calculated these values manually from figures if available.
Results
Study identification and inclusion
Our literature searches initially identified 941 articles, six
of which satisfied the inclusion criteria [11,12,15e18]. We
excluded the study by Wilkins et al. [17] because it involved
only 26 patients, and we excluded the study by Iversen
et al. [18] because most patients had Eisenmenger’s syn-
drome. In the end, four multicenter, double-blind RCTs
[11,12,15,16] were included in the meta-analysis (Fig. 1).
The studies involved 545 patients, comprising 342 who
received sildenafil and 203 who received placebo. Three of
the four included trials [11,12,16] involved the same 278
patients, but they reported on different outcomes related
to safety and efficacy, so duplicate counting of the same
patients among the studies was not an issue.
Key characteristics of the four trials are shown in
Tables 1 and 2. Of the 545 patients, 387 (71%) were
diagnosed with idiopathic PAH, while the remainder was
diagnosed with associated PAH; 500 of the 540 patients
(92.6%) were in WHO FC II or III. (Data on WHO FC were
missing for 5 patients.) One RCT investigated the effect of
adding oral sildenafil to long-term intravenous epopros-
tenol therapy for patients with PAH over periods of 12e16
weeks [15]. The three other studies, involving the same
278 patients, examined the efficacy and safety of 12-week
sildenafil monotherapy [11,12,16]. Primary endpoints
were 6MWD [15,16], HRQoL [11], and ocular safety of
sildenafil [12].
Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension 533

Efficacy

Clinical worsening
Clinical worsening refers to death, hospitalization, symp-
tomatic deterioration, lack of improvement and the need
for treatment escalation, for example, additional drugs, or
lung transplantation [19].
Among the total 545 subjects, 49 (9.0%) developed
clinical worsening: 31 (5.7%) in the placebo group and
18 (3.3%) in the sildenafil group. Clinical worsening was
enafil group than in the placebo group (RR 0.39, 95% CI
0.21 to 0.69; Fig. 3(a)).

Mortality
Two studies reported data on mortality [15,16]. Among the
545 subjects in the two trials, 11 (2.0%) died: 8 (3.9%) in the
control group and 4 (0.9%) in the sildenafil group. The
likelihood of mortality did not differ significantly between
the sildenafil and placebo groups (RR 0.29, 95% CI 0.02 to
4.94; Fig. 3(b)).

6MWD
A widely used indicator of exercise capacity, 6MWD was the
primary endpoint in two trials involving 545 patients
[15,16]. Both trials reported significantly greater improve-
ment in 6MWD in the sildenafil group than in the placebo
group, with no significant heterogeneity between the two
studies (I2 Z 40%, P Z 0.19). Meta-analysis showed that
sildenafil improved 6MWD by 31.34 m relative to placebo
(95% CI 18.01 to 44.67; Fig. 3(c)) after 12e16 weeks of
treatment.

Figure 1 Flow diagram of systematic review.
The four trials showed low risk of bias related to random
sequence generation, allocation concealment, blinding,
incomplete collection of outcome data, or selective
reporting (Fig. 2). However, all trials were sponsored by the
manufacturer of sildenafil, so all other potential risks were
assessed as high.
WHO FC
One study reported data on changes in WHO FC after 12
weeks of sildenafil or placebo treatment [16]. Sildenafil
improved functional class significantly more than did pla-
cebo. While 7% of patients receiving placebo improved in at
least one functional class, 28% of patients receiving 20 mg
sildenafil improved in at least one functional class. This
corresponded to a placebo-corrected difference of 21%

Table 1 Key details of the studies in this meta-analysis.a

Study Patients Loss of Interventions Intervention Outcomesb
follow-up Experimental group Control duration
(%) group
Simonneau 2008.15 267 4.2 Sildenafil 20 mg tid (4w); 40 mg placebo 16w 1/2/3/5/6/8/9/10
tid(4w); 80 mg tid (8w)
Galiè 2005.16 278 4.7 Sildenafil 20 mg tid Sildenafil 40 mg Placebo 12w 1/2/3/4/5/6/7/8/9
tid Sildenafil 80 mg tid
Pepke-Zaba 2008.11 278 4.7 Sildenafil 20 mg tid Sildenafil 40 mg Placebo 12w 10
tid Sildenafil 80 mg tid
Wirostko 2012. 12 278 4.7 Sildenafil 20 mg tid Sildenafil 40 mg Placebo 12w 11
tid Sildenafil 80 mg tid
bid: twice daily; tid: three times daily.
a
All studies were multicenter, double-blind randomized controlled trials.
b
Outcomes that can be entered in the systematic review; 1: clinical worsening; 2: mortalily; 3: 6-min walk distance; 4: World Health
Organization functional class; 5: mean pulmonary arterial pressure; 6: pulmonary vascular resistance; 7: cardiac index; 8: Borg dyspnea
score; 9: Adverse events 10: health-related quality of life (HRQoL) score; 11: ocular safety.
534 R.-chun Wang et al.

Table 2 Patient demographics and baseline clinical characteristics.

Study Age Female Weight IPAH/ WHO FC 6MWD mPAP PVR (dyn RAP CI Concomitant
(years) (%) (kg) PAH (%) (m) (mmHg) sec cm5) (mmHg) (L/min/m2) medicationsa
Simonneau 200813 47.65 79.8 71.4 79.4 Mainly II,III 345.2 51.6 805.8 8.4 NR Epoprostenol
Galiè 200514 48.8 74.4 72.7 63.1 Mainly II,III 343.7 52.7 956.2 8.75 2.35 Conventional
Pepke-Zaba 200815 48.8 74.4 72.7 63.1 Mainly II,III 343.7 52.7 956.2 8.75 2.35 Conventional
Wirostko 201216 48.8 74.4 72.7 63.1 Mainly II,III 343.7 52.7 956.2 8.75 2.35 Conventional
Data are means.
APAH: associated pulmonary arterial hypertension; CI: cardiac index; IPAH: idiopathic pulmonary arterial hypertension; mPAP: mean
pulmonary arterial pressure; NR: not reported; PVR: pulmonary vascular resistance; RAP: right atrial pressure; WHO FC: World Health
Organization functional class; 6MWD: 6-min walk distance.
a
Conventional medication refers to calcium channel blockers, digitalis, diuretics, and anticoagulants.

(95% CI 9%e33%, P Z 0.003). The placebo-corrected dif- three times daily than it did in groups receiving placebo.
ference for those receiving 40 mg sildenafil was 29% (95% CI However, the group receiving sildenafil 20 mg three times
16% to 42%, P < 0.001); for those receiving 80 mg, it was daily showed an increase in cardiac index from baseline
35% (95% CI 22%e48%, P < 0.001). that was similar to that observed in the placebo group.

Quality of life
Safety
HRQoL score. Two trials [11,15] reported changes in
HRQoL score based on the Short Form-36 questionnaire
Serious adverse events and total adverse events
(SF-36). Subgroup analysis indicated that the sildenafil
Two studies [15,16] reported information on serious
group showed greater adjusted improvement from
adverse events and total adverse events. In one trial [15],
baseline than did the placebo group in the domains of
68 serious adverse events occurred among 267 patients, but
physical functioning (MD 8.76, 95% CI 4.81 to 12.80;
among them, only 2 in the placebo group and 3 in the sil-
I2 Z 0%; P Z 0.78), general health (MD 7.84, 95% CI 4.55
denafil group were considered to be treatment-related. A
to 11.12; I2 Z 0%; P Z 0.93), vitality (MD 8.76, 95% CI
total of 138 treatment-related adverse events were re-
3.80 to 11.53; I2 Z 0%; P Z 0.42), social heath (MD 7.15,
ported by 61 patients (47%) in the placebo group, signifi-
95% CI 2.15 to 11.56; I2 Z 0%; P Z 0.83), and mental
cantly fewer than the 290 reported by 92 patients (69%) in
health (MD 5.38, 95% CI 2.05 to 8.72; I2 Z 0%; P Z 0.43).
the sildenafil group (difference of 22%, 95% CI 11%e34%).
The sildenafil and placebo groups did not differ
Most adverse events were mild or moderate in nature. In
significantly in bodily pain (MD 3.54, 95% CI 1.13 to 8.22;
another trial [16], 42 of 278 patients (15%) reported 68
I2 Z 0%; P Z 0.52).
serious adverse events, of which only 2 were considered to
be related to sildenafil. Most adverse events in either
Borg dyspnea score
treatment group were of mild or moderate severity. Many
Two studies [15,16] reported change in Borg dyspnea score
of the adverse events were attributed to the vasodilatory
from baseline. The change was similar between the sil-
effect of sildenafil; these events included headache,
denafil group and the placebo group.
flushing, body pain (back, extremity pain or myalgia) and
blurred vision.
Hemodynamic parameters
Two studies reported data on mPAP and PVR [15,16]. The
Ocular safety
WMD between sildenafil patients and placebo patients was
One trial [12] specifically assessed the ocular safety of sil-
3.84 mm Hg (95% CI 5.17 to 2.50; Fig. 4(a)) for mPAP
denafil in patients with PAH. The results suggest that 80 mg
and 190.16 dyne s cm5 (95% CI 260.08 to 120.25;
of the drug delivered three times daily for 12 weeks was
Fig. 4(b)) for PVR.
safe for ocular function and well-tolerated. No significant
One study involving 278 patients reported data on car-
detrimental effects were observed on best corrected visual
diac index [16]. Cardiac index increased from baseline
acuity, contrast sensitivity, color vision, visual field, or
significantly more in groups receiving 40 or 80 mg sildenafil
intraocular pressure, as measured by slit lamp examina-
tions or funduscopy.

Publication bias

This meta-analysis involved only four studies, preventing

reliable assessment of potential publication bias.

Discussion

Figure 2 Risk of bias graph: review authors’ judgements Previous studies showed the safety and efficacy of sildenafil
about each risk of bias item as percentages across all. for treating PAH but were limited by relatively small sample
Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension 535

Figure 3 (a) Incidence of clinical worsening for sildenafil versus placebo. (b) All-cause mortality for sildenafil versus placebo. (c)
Mean checnge from baseline in 6-min walk distance(6MWD) for sildenafil versus placebo.

size, short treatment duration or lack of blinding or
randomization. We show in this meta-analysis of RCTs that
sildenafil appears to be safe and effective when used for as
long as 12e16 weeks. This evidence supports the wide-
spread practice of clinicians to prescribe the drug for longer
periods.
The present study suggests that sildenafil therapy for
12e16 weeks significantly reduces the likelihood of clinical
worsening and improves 6MWD, WHO FC, HRQoL, mPAP,
PVR, and cardiac index. However, the drug was associated
with similar mortality, incidence of serious adverse events,
and Borg dyspnea scores as placebo. Although sildenafil was
associated with a larger number of total adverse events
than was placebo, most of these additional events were
mild or moderate in intensity.
Our meta-analysis found that clinical worsening
occurred in 15.2% of patients in the placebo group but in
only 5.3% of patients in the sildenafil group. Clinical wors-
ening is a composite endpoint widely used to assess the
clinical status and disease progression in patients
[11,20e24]. While our findings suggest that sildenafil ther-
apy can delay disease progression, it is possible that other
drugs, either in use or under development, may slow pro-
gression better or work more effectively against refractory
forms of the disease [25].
We meta-analyzed 6MWD as a measure of exercise ca-
pacity and found that sildenafil was associated with a WMD
of 31.3 m compared to placebo. This, coupled with the fact
that the sildenafil and placebo groups had similar Borg
dyspnea scores, indicates that patients receiving sildenafil

Figure 4 (a) Change from baseline in mean pulmonary arterial pressure (mPAP) for sildenafil versus placebo. (b) Change from
baseline in Pulmonary Vascular Resistance(PVR) for sildenafil versus placebo.
536
therapy could walk farther than those receiving placebo for
the same perceived exertion.
Our study of adverse events showed that sildenafil was
associated with a higher total number of adverse events
than placebo, most of which were mild or moderate. The
number of serious adverse events was similar in the two
groups. The drug also appears to be safe and well-tolerated
for ocular function even at doses up to 80 mg three times
daily [12]. These findings strongly suggest that sildenafil is
safe and well-tolerated, but patients receiving it should
nevertheless be carefully monitored.
We found that sildenafil therapy for 12e16 weeks did not
significantly improve the risk of all-cause mortality in 545
patients (RR 0.29, 95% CI 0.02e4.94). The fact that the RR was
much closer to 0 than 1 may mean that sildenafil treatment
might have decreased the mortality rate if we had sampled a
larger population. We recommend exploring this question
with larger, higher-quality studies involving longer follow-up.
Some long-term data on sildenafil safety and efficacy are
already available. The open-label, non-controlled SUPER-2
trial suggests that 3-year sildenafil monotherapy of PAH is
generally well-tolerated [26]. In contrast, the STARTS-2
study suggests that, among pediatric patients, high-dose
sildenafil monotherapy is associated with greater risk of
mortality than is low-dose monotherapy [27]. Together,
these studies suggest that sildafenil dose may have a sig-
nificant effect on patient outcomes. Although we cannot
test this rigorously because of the small number of trials
and the variety of doses used, we did find that sildenafil
therapy three times daily at doses of 40 or 80 mg, but not at
a dose of 20 mg, caused a much larger increase in cardiac
index than did placebo. These results suggest the need to
reassess the guideline of 20 mg sildenafil three times daily
for PAH [28]. Future studies should examine different drug
doses in parallel treatment arms in order to determine the
optimal dose for adults.
Our meta-analysis has several limitations. The small
sample sizes and different methodologies of the four
studies prevented us from performing subgroup analysis to
assess the efficacy and safety of different sildenafil doses,
or from comparing sildenafil outcomes with those of other
vasodilators such as prostanoids, endothelin receptor an-
tagonists and other PDE-5 inhibitors. Only four studies were
enrolled, increasing the risk of publication bias, and all four
trials were sponsored by the manufacturer of sildenafil,
increasing the risk of various kinds of bias, including se-
lective reporting.
In conclusion, our study suggests that sildenafil therapy
over 12e16 weeks is effective in improving the symptoms of
PAH and delaying disease progression in adults. These
findings should be verified in large, well-designed RCTs,
which should also aim to determine optimal therapeutic
doses.
Financial disclosure
None of the authors received any financial support.
Conflicts of interest
The authors have no conflicts of interest to disclose.
R.-chun Wang et al.
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