Respiratory Medicine (2014) 108, 531e537
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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 Pulmonary arterial hypertension; Pulmonary hypertension; Sildenafil; Systematic review
Summary Background: To evaluate the safety and efficacy of using sildenafil for 12 weeks to treat pulmonary arterial hypertension (PAH). Methods: Randomized controlled trials (RCTs) of sildenafil therapy in patients with PAH published through May 2013 were identified by searching PubMed, the Cochrane Library, Embase, relevant websites, and reference lists of relevant studies. Two reviewers independently assessed 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 functional 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 additional 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: [email protected], [email protected] (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 pathogenesis, 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 vasoconstriction. 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 monotherapy 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 sildenafil 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 randomization. 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 metaanalyses, we systematically reviewed the literature on sildenafil safety and efficacy for treating PAH over periods of at least 12 weeks.
Materials and methods Search strategy We systematically searched for randomized controlled trials (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 hypertension” 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 diagnosed 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 characteristics, 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, hemodynamic measures such as mean pulmonary arterial pressure (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, blinding, 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 effects 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 syndrome. 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 epoprostenol 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, symptomatic 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 improvement 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.
Table 1
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 placebo. 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%
Key details of the studies in this meta-analysis.a
Study
Patients Loss of follow-up (%)
Interventions
Simonneau 2008.15
267
4.2
Galie ` 2005.16
278
4.7
Pepke-Zaba 2008.11
278
4.7
Wirostko 2012. 12
278
4.7
Sildenafil 20 mg tid (4w); 40 mg placebo tid(4w); 80 mg tid (8w) Sildenafil 20 mg tid Sildenafil 40 mg Placebo tid Sildenafil 80 mg tid Sildenafil 20 mg tid Sildenafil 40 mg Placebo tid Sildenafil 80 mg tid Sildenafil 20 mg tid Sildenafil 40 mg Placebo tid Sildenafil 80 mg tid
Experimental group
Control group
Intervention duration
Outcomesb
16w
1/2/3/5/6/8/9/10
12w
1/2/3/4/5/6/7/8/9
12w
10
12w
11
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 Table 2
R.-chun Wang et al. Patient demographics and baseline clinical characteristics.
Study
Age Female Weight IPAH/ WHO FC (years) (%) (kg) PAH (%)
CI Concomitant 6MWD mPAP PVR (dyn RAP (m) (mmHg) sec cm5) (mmHg) (L/min/m2) medicationsa
Simonneau 200813 Galie ` 200514 Pepke-Zaba 200815 Wirostko 201216
47.65 48.8 48.8 48.8
345.2 343.7 343.7 343.7
79.8 74.4 74.4 74.4
71.4 72.7 72.7 72.7
79.4 63.1 63.1 63.1
Mainly Mainly Mainly Mainly
II,III II,III II,III II,III
51.6 52.7 52.7 52.7
805.8 956.2 956.2 956.2
8.4 8.75 8.75 8.75
NR 2.35 2.35 2.35
Epoprostenol Conventional Conventional 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 difference for those receiving 40 mg sildenafil was 29% (95% CI 16% to 42%, P < 0.001); for those receiving 80 mg, it was 35% (95% CI 22%e48%, P < 0.001).
three times daily than it did in groups receiving placebo. However, the group receiving sildenafil 20 mg three times daily showed an increase in cardiac index from baseline that was similar to that observed in the placebo group.
Quality of life HRQoL score. Two trials [11,15] reported changes in HRQoL score based on the Short Form-36 questionnaire (SF-36). Subgroup analysis indicated that the sildenafil group showed greater adjusted improvement from baseline than did the placebo group in the domains of physical functioning (MD 8.76, 95% CI 4.81 to 12.80; I2 Z 0%; P Z 0.78), general health (MD 7.84, 95% CI 4.55 to 11.12; I2 Z 0%; P Z 0.93), vitality (MD 8.76, 95% CI 3.80 to 11.53; I2 Z 0%; P Z 0.42), social heath (MD 7.15, 95% CI 2.15 to 11.56; I2 Z 0%; P Z 0.83), and mental health (MD 5.38, 95% CI 2.05 to 8.72; I2 Z 0%; P Z 0.43). The sildenafil and placebo groups did not differ significantly in bodily pain (MD 3.54, 95% CI 1.13 to 8.22; I2 Z 0%; P Z 0.52).
Safety
Borg dyspnea score Two studies [15,16] reported change in Borg dyspnea score from baseline. The change was similar between the sildenafil group and the placebo group. Hemodynamic parameters Two studies reported data on mPAP and PVR [15,16]. The WMD between sildenafil patients and placebo patients was 3.84 mm Hg (95% CI 5.17 to 2.50; Fig. 4(a)) for mPAP and 190.16 dyne s cm5 (95% CI 260.08 to 120.25; Fig. 4(b)) for PVR. One study involving 278 patients reported data on cardiac index [16]. Cardiac index increased from baseline significantly more in groups receiving 40 or 80 mg sildenafil
Serious adverse events and total adverse events Two studies [15,16] reported information on serious adverse events and total adverse events. In one trial [15], 68 serious adverse events occurred among 267 patients, but among them, only 2 in the placebo group and 3 in the sildenafil group were considered to be treatment-related. A total of 138 treatment-related adverse events were reported by 61 patients (47%) in the placebo group, significantly fewer than the 290 reported by 92 patients (69%) in the sildenafil group (difference of 22%, 95% CI 11%e34%). Most adverse events were mild or moderate in nature. In another trial [16], 42 of 278 patients (15%) reported 68 serious adverse events, of which only 2 were considered to be related to sildenafil. Most adverse events in either treatment group were of mild or moderate severity. Many of the adverse events were attributed to the vasodilatory effect of sildenafil; these events included headache, flushing, body pain (back, extremity pain or myalgia) and blurred vision. Ocular safety One trial [12] specifically assessed the ocular safety of sildenafil in patients with PAH. The results suggest that 80 mg of the drug delivered three times daily for 12 weeks was safe for ocular function and well-tolerated. No significant detrimental effects were observed on best corrected visual acuity, contrast sensitivity, color vision, visual field, or intraocular pressure, as measured by slit lamp examinations 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 about each risk of bias item as percentages across all.
Previous studies showed the safety and efficacy of sildenafil 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 widespread 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 worsening is a composite endpoint widely used to assess the clinical status and disease progression in patients [11,20e24]. While our findings suggest that sildenafil therapy can delay disease progression, it is possible that other drugs, either in use or under development, may slow progression better or work more effectively against refractory forms of the disease [25]. We meta-analyzed 6MWD as a measure of exercise capacity 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 significant 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 antagonists 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 selective 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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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 Pulmonary arterial hypertension; Pulmonary hypertension; Sildenafil; Systematic review
Summary Background: To evaluate the safety and efficacy of using sildenafil for 12 weeks to treat pulmonary arterial hypertension (PAH). Methods: Randomized controlled trials (RCTs) of sildenafil therapy in patients with PAH published through May 2013 were identified by searching PubMed, the Cochrane Library, Embase, relevant websites, and reference lists of relevant studies. Two reviewers independently assessed 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 functional 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 additional 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: [email protected], [email protected] (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 pathogenesis, 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 vasoconstriction. 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 monotherapy 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 sildenafil 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 randomization. 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 metaanalyses, we systematically reviewed the literature on sildenafil safety and efficacy for treating PAH over periods of at least 12 weeks.
Materials and methods Search strategy We systematically searched for randomized controlled trials (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 hypertension” 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 diagnosed 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 characteristics, 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, hemodynamic measures such as mean pulmonary arterial pressure (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, blinding, 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 effects 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 syndrome. 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 epoprostenol 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
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Efficacy Clinical worsening Clinical worsening refers to death, hospitalization, symptomatic 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 improvement 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.
Table 1
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 placebo. 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%
Key details of the studies in this meta-analysis.a
Study
Patients Loss of follow-up (%)
Interventions
Simonneau 2008.15
267
4.2
Galie ` 2005.16
278
4.7
Pepke-Zaba 2008.11
278
4.7
Wirostko 2012. 12
278
4.7
Sildenafil 20 mg tid (4w); 40 mg placebo tid(4w); 80 mg tid (8w) Sildenafil 20 mg tid Sildenafil 40 mg Placebo tid Sildenafil 80 mg tid Sildenafil 20 mg tid Sildenafil 40 mg Placebo tid Sildenafil 80 mg tid Sildenafil 20 mg tid Sildenafil 40 mg Placebo tid Sildenafil 80 mg tid
Experimental group
Control group
Intervention duration
Outcomesb
16w
1/2/3/5/6/8/9/10
12w
1/2/3/4/5/6/7/8/9
12w
10
12w
11
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 Table 2
R.-chun Wang et al. Patient demographics and baseline clinical characteristics.
Study
Age Female Weight IPAH/ WHO FC (years) (%) (kg) PAH (%)
CI Concomitant 6MWD mPAP PVR (dyn RAP (m) (mmHg) sec cm5) (mmHg) (L/min/m2) medicationsa
Simonneau 200813 Galie ` 200514 Pepke-Zaba 200815 Wirostko 201216
47.65 48.8 48.8 48.8
345.2 343.7 343.7 343.7
79.8 74.4 74.4 74.4
71.4 72.7 72.7 72.7
79.4 63.1 63.1 63.1
Mainly Mainly Mainly Mainly
II,III II,III II,III II,III
51.6 52.7 52.7 52.7
805.8 956.2 956.2 956.2
8.4 8.75 8.75 8.75
NR 2.35 2.35 2.35
Epoprostenol Conventional Conventional 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 difference for those receiving 40 mg sildenafil was 29% (95% CI 16% to 42%, P < 0.001); for those receiving 80 mg, it was 35% (95% CI 22%e48%, P < 0.001).
three times daily than it did in groups receiving placebo. However, the group receiving sildenafil 20 mg three times daily showed an increase in cardiac index from baseline that was similar to that observed in the placebo group.
Quality of life HRQoL score. Two trials [11,15] reported changes in HRQoL score based on the Short Form-36 questionnaire (SF-36). Subgroup analysis indicated that the sildenafil group showed greater adjusted improvement from baseline than did the placebo group in the domains of physical functioning (MD 8.76, 95% CI 4.81 to 12.80; I2 Z 0%; P Z 0.78), general health (MD 7.84, 95% CI 4.55 to 11.12; I2 Z 0%; P Z 0.93), vitality (MD 8.76, 95% CI 3.80 to 11.53; I2 Z 0%; P Z 0.42), social heath (MD 7.15, 95% CI 2.15 to 11.56; I2 Z 0%; P Z 0.83), and mental health (MD 5.38, 95% CI 2.05 to 8.72; I2 Z 0%; P Z 0.43). The sildenafil and placebo groups did not differ significantly in bodily pain (MD 3.54, 95% CI 1.13 to 8.22; I2 Z 0%; P Z 0.52).
Safety
Borg dyspnea score Two studies [15,16] reported change in Borg dyspnea score from baseline. The change was similar between the sildenafil group and the placebo group. Hemodynamic parameters Two studies reported data on mPAP and PVR [15,16]. The WMD between sildenafil patients and placebo patients was 3.84 mm Hg (95% CI 5.17 to 2.50; Fig. 4(a)) for mPAP and 190.16 dyne s cm5 (95% CI 260.08 to 120.25; Fig. 4(b)) for PVR. One study involving 278 patients reported data on cardiac index [16]. Cardiac index increased from baseline significantly more in groups receiving 40 or 80 mg sildenafil
Serious adverse events and total adverse events Two studies [15,16] reported information on serious adverse events and total adverse events. In one trial [15], 68 serious adverse events occurred among 267 patients, but among them, only 2 in the placebo group and 3 in the sildenafil group were considered to be treatment-related. A total of 138 treatment-related adverse events were reported by 61 patients (47%) in the placebo group, significantly fewer than the 290 reported by 92 patients (69%) in the sildenafil group (difference of 22%, 95% CI 11%e34%). Most adverse events were mild or moderate in nature. In another trial [16], 42 of 278 patients (15%) reported 68 serious adverse events, of which only 2 were considered to be related to sildenafil. Most adverse events in either treatment group were of mild or moderate severity. Many of the adverse events were attributed to the vasodilatory effect of sildenafil; these events included headache, flushing, body pain (back, extremity pain or myalgia) and blurred vision. Ocular safety One trial [12] specifically assessed the ocular safety of sildenafil in patients with PAH. The results suggest that 80 mg of the drug delivered three times daily for 12 weeks was safe for ocular function and well-tolerated. No significant detrimental effects were observed on best corrected visual acuity, contrast sensitivity, color vision, visual field, or intraocular pressure, as measured by slit lamp examinations 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 about each risk of bias item as percentages across all.
Previous studies showed the safety and efficacy of sildenafil 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 widespread 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 worsening is a composite endpoint widely used to assess the clinical status and disease progression in patients [11,20e24]. While our findings suggest that sildenafil therapy can delay disease progression, it is possible that other drugs, either in use or under development, may slow progression better or work more effectively against refractory forms of the disease [25]. We meta-analyzed 6MWD as a measure of exercise capacity 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 significant 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 antagonists 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 selective 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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