Results of the search
We identified 9,806 references from the databases, and three records from additional searches. A total of 2,919 records were excluded as duplicates. After screening for titles and abstracts, we selected 94 studies for full-text review. Finally, a total of eight studies (five RCTs and three NRSIs) with 364 patients were included (see Fig. 1) [22,31−37].
Study and patient characteristics
Characteristics of included studies and patients are illustrated in Table 1. These studies were published between 2005 and 2015 and the sample size ranged from 21 to 139, of which, sildenafil was all administered orally with 20mg/TID. Most studies recruited participants with WHO functional class II and III. The etiologies of majority were idiopathic PAH, PAH associated with CTD and CHD. Included studies were conducted for 20 weeks on average.
Table 1
Baseline characteristics of included studies
Study ID
|
Study Type
|
Etiology (%)
|
Sample
|
Age(T/C)*
|
WHO functional class (%)
|
Follow up
|
Outcomes †
|
I
|
II
|
III
|
IV
|
Galiè 2005[31]
|
RCT
|
IPAH (61.87)
CTD-PAH (30.94)
CHD-PAH (7.19)
|
139
|
47 ± 14/49 ± 17
|
0.72
|
40.29
|
53.24
|
5.76
|
12W
|
①②③④⑤⑦⑧⑨⑩
⑪⑫⑮⑯
|
Pepke-Zaba 2008[32]
|
RCT
|
NR
|
NR
|
NR
|
NR
|
12W
|
①⑬
|
Xu 2009[22]
|
NRSI
|
IPAH (66.67)
CHD-PAH (20.00)
CTD-PAH (13.33)
|
60
|
33.56 ± 14.12
|
0
|
43.33
|
53.34
|
3.33
|
16W
|
①②③④⑦⑧⑨⑩⑪⑫⑯
|
Zhang 2011[33]
|
NRSI
|
CHD-PAH (100.00)
|
84
|
28 ± 9
|
0
|
52
|
39
|
8
|
12M
|
①②③⑤⑥⑦⑧⑨⑫⑮⑯⑰⑱
|
Satoh 2011[34]
|
NRSI
|
IPAH (28.57)
FPAH (23.81)
APAH (47.62%)
|
21
|
47.1 ± 14.7
|
0
|
31.80
|
36.60
|
0
|
12W
|
①③④⑤⑥⑦⑪⑫⑯⑰⑱
|
Wirostko 2012[35]
|
RCT
|
IPAH (61.87)
CTD-PAH (30.94)
CHD-PAH (7.19)
|
139
|
47 ± 14/49 ± 17
|
0.72
|
40.29
|
53.24
|
5.76
|
12W
|
⑦
|
Xu 2013[36]
|
RCT
|
NR
|
42
|
33.7 ± 14.3
|
NR
|
3M
|
①④⑦
|
Webb 2015[37]
|
RCT
|
IPAH (61.87)
CTD-PAH (30.94)
CHD-PAH (7.19)
|
139
|
47 ± 14/49 ± 17
|
0.72
|
40.29
|
53.24
|
5.76
|
12W
|
⑭
|
* Ages were reported as mean ± standard deviation.
† Outcomes: ①Six-minute walk distance②Mean pulmonary artery pressure ③WHO functional class④Level of brain natriuretic peptide⑤Dyspnoea score on Borg scale ⑥Systemic arterial oxygen saturation ⑦Adverse events ⑧Mortality ⑨Clinical worsening ⑩Pulmonary vascular resistance ⑪Cardiac index ⑫ Right atrial pressure ⑬ Quality of life ⑭ Renal function ⑮ Hospitalization ⑯ Heart rate ⑰ Pulmonary capillary wedge pressure ⑱ Systemic vascular resistance index.
Abbreviation: RCT: Randomized Controlled Trial; NRSI: Non randomized Studies of Interventions; IPAH: Idiopathic Pulmonary Arterial Hypertension; CTD-PAH: Connective-Tissue Disease-Pulmonary Arterial Hypertension; CHD-PAH: Congenital Heart Disease- Pulmonary Arterial Hypertension; FPAH: Familial Pulmonary Arterial Hypertension; APAH: Associated with Pulmonary Arterial Hypertension; NR: Not Reported; W: Week; M: Month; T: Treatment; C: Control.
|
Risk of bias in included studies
For the five RCTs, we assessed random sequence generation, allocation concealment, blinding of participants and personnel and blinding of outcomes as low risk for only one study [35]. Galiè 2005[31], Pepke-Zaba 2008 [32], Xu 2013 [36] and Webb 2015[37] were at unclear risk, as they did not report the relevant methods. As for incomplete outcome data and selective reporting, all studies were assessed as low risk [31–32,35−37]. In the domain of other potential sources of bias, four studies [31–32, 35, 37] received funding from Pfizer and one contained error in data [36], so we rated all of them at high risk. For the three NRSIs, two [22, 33] were assessed as moderate risk and one [34] was serious risk. Details can be found in Additional file 3.
Clinical outcomes
6MWD
Five studies [22,31−34] (two RCTs and three NRSIs) evaluated 6MWD. Two studies [31–32] which reported only P values and 99% CI with significant improvement in 6MWD were excluded from the pooled analysis. In comparison with symptomatic treatment, sildenafil yielded greater improvement in 6MWD (MD = 68.3 meters, 95% CI 48.85 to 87.76). There was no heterogeneity between trials (I2 = 0%, Fig. 2).
Dyspnoea score
Three studies [31,33−34] (one RCT and two NRSIs) evaluated dyspnoea score based on Borg scale. One study [31] only reported the change from baseline did not differ significantly from that in the placebo group with no other data available was excluded from the pooled analysis. When comparing to symptomatic treatment, sildenafil was associated with a significant decrease (reflecting improvement) in dyspnoea score (MD=-0.99 points, 95% CI -1.45 to -0.53). There was no heterogeneity between trials (I2 = 0%, Fig. 3).
WHO functional class
Four studies [22,31,33−34] (one RCT and three NRSIs) evaluated WHO functional class. We described them in narrative form because most data were missing for Meta-analysis (Table 2). In general, when compared to placebo or symptomatic treatment, the total number of patients with WHO class III and IV in group of sildenafil showed an overall trend of decline (reflecting improvement).
Table 2
Improvement in WHO functional class
Study ID
|
Study Type
|
Placebo/Before
|
Sildenafil /After
|
P
|
Galiè 2005[31]
|
RCT
|
patients with an improvement of at least one functional class were 7 percent
|
patients with an improvement of at least one functional class were 28 percent
|
0.003
|
Xu 2009[22]
|
NRSI
|
I: 0
II: 26
III: 32
IV: 2
|
I: 6
II: 42
III: 12
IV: 0
|
NR*
|
Zhang 2011[33]
|
NRSI
|
I: 0
II: 44
III: 33
IV: 7
|
I: 7
II: 68
III: 8
IV: 1
|
< 0.001
|
Satoh 2011[34]
|
NRSI
|
I: 0
II: 7
III: 14
IV: 0
|
I: 1
II: 11
III: 9
IV: 0
|
NR
|
Abbreviation: RCT: Randomized Controlled Trial; NRSI: Non randomized Studies of Interventions; NR: Not Reported.
|
Level of BNP
Three studies [22, 34, 36] (one RCT and two NRSIs) evaluated the level of BNP. One study [34] that only reported plasma BNP decreased from baseline was excluded from the pooled analysis. When compared to placebo or symptomatic treatment, sildenafil was associated with a decrease in level of BNP (MD=-86.16 pg /mL, 95% CI -103.39 to -68.93). There was not important heterogeneity between trials (I2 = 14%, Fig. 4).
Mean PAP
Four studies [22, 31, 33, 36] (two RCTs and two NRSIs) evaluated the mean PAP. When compared to placebo, sildenafil was associated with a greater reduction in mean PAP (MD=-4.13 mmHg, 95% CI -6.52 to -1.74). There was considerable heterogeneity between trials (I2 = 89%, Fig. 5). We conducted sensitivity analysis by excluding one study [36] which involved surgery with low-quality. Results showed that sildenafil reduced mean PAP (MD=-2.70 mmHg, 95% CI -5.26 to -0.14). When compared to symptomatic treatment, sildenafil could reduce the mean PAP with no statistically significant difference found (MD=-4.90 mmHg, 95% CI -10.36 to 0.55, Fig. 6).
Systemic arterial oxygen saturation
Two NRSIs [22, 33] evaluated the systemic arterial oxygen saturation. When compared with symptomatic treatment, patients received sildenafil had higher level of systemic arterial oxygen saturation (MD = 2.48 %, 95% CI 1.26 to 3.71). There was no heterogeneity between trials (I2 = 0%, Fig. 7).
Haemodynamic parameters other than mean PAP
Two studies [22, 31] (one RCT and one NRSI) evaluated PVR. When compared to placebo, sildenafil was associated with a greater reduction in PVR (MD=-171.00 dyn·sec·cm-5, 95% CI -311.49 to -30.51). When compared to symptomatic treatment, sildenafil could decrease PVR with no statistically significant difference (MD=-1.02 Wood Units, 95% CI -3.73 to 1.69).
Four studies [22,31,33−34] (one RCT and three NRSIs) evaluated RAP. When compared to symptomatic treatment, the results showed that sildenafil therapy decreased RAP (MD=-1.17 mm Hg, 95% CI -2.14 to -0.20). When compared to placebo, reduction in RAP was also observed with no statistically significant difference found (MD=-1.10 mm Hg, 95% CI -2.73 to 0.53).
Three studies [22, 31, 34] (one RCT and two NRSIs) evaluated CI. When compared to symptomatic treatment, the use of sildenafil improved the level of CI (MD = 0.35 L/(min·m2), 95% CI 0.07 to 0.63). While no statistically significant difference was observed in the level of CI (MD = 0.23 L/(min·m2), 95% CI -0.18 to 0.64) between sildenafil and placebo.
Adverse events
Five studies [22, 31, 33–34, 36] (two RCTs and three NRSIs) evaluated adverse events. One study that reported adverse events with no data available was excluded from the pooled analysis [36]. When compared to symptomatic treatment or placebo, there was no statistically significant difference in the risk of headache, flushing, dyspepsia, diarrhea, limb pain, skin rash (Fig. 8).
No statistically significant difference was also observed in blood pressure (systolic and diastolic) and ocular safety (including change in intraocular pressure and risk of deterioration in visual acuity). In general, sildenafil was mild and well tolerated in most patients.
Long-term prognosis
Four studies reported outcomes related to long-term prognosis. Three studies [22, 31, 33] (one RCT and two NRSIs) evaluated mortality (OR 1.01, 95% CI 0.06 to 16.55) and incidence of clinical worsening (OR 3.36, 95% CI 0.19 to 60.54), when compared sildenafil to symptomatic treatment and placebo, no statistically significant difference was found.
Galiè 2005 [31] evaluated quality of life. There was a statistically significant improvement in SF-36 domains of physical functioning, general health and vitality for sildenafil treated participants when compared to placebo. Statistically significant improvements were also observed in terms for current health status and utility index in the EQ-5D questionnaires. Results from Webb 2015 [37] showed that sildenafil treatment improved kidney function when compared to placebo, but the difference was not statistically significant.
In addition, there was no significant difference in hospitalization, heart rate, pulmonary capillary wedge pressure and systemic vascular resistance index when compared to placebo or symptomatic treatment.
Publication bias
Due to insufficient studies for each outcome, we were unable to evaluate publication bias.