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Cochrane Database of Systematic Reviews Review - Intervention

Phosphodiesterase 5 inhibitors for pulmonary hypertension

Authors' declarations of interest

Version published: 31 January 2019 Version history

https://doi.org/10.1002/14651858.CD012621.pub2
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Background

Pulmonary hypertension (PH) comprises a group of complex and heterogenous conditions, characterised by elevated pulmonary artery pressure, and which left untreated leads to right‐heart failure and death. PH includes World Health Organisation (WHO) Group 1 pulmonary arterial hypertension (PAH); Group 2 consists of PH due to left‐heart disease (PH‐LHD); Group 3 comprises PH as a result of lung diseases or hypoxia, or both; Group 4 includes PH due to chronic thromboembolic occlusion of pulmonary vasculature (CTEPH), and Group 5 consists of cases of PH due to unclear and/or multifactorial mechanisms including haematological, systemic, or metabolic disorders. Phosphodiesterase type 5 (PDE5) inhibitors increase vasodilation and inhibit proliferation.

Objectives

To determine the efficacy of PDE5 inhibitors for pulmonary hypertension in adults and children.

Search methods

We performed searches of CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to 26 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles.

Selection criteria

We included randomised controlled trials that compared any PDE5 inhibitor versus placebo, or any other PAH disease‐specific therapies, for at least 12 weeks. We include separate analyses for each PH group.

Data collection and analysis

We imported studies identified by the search into a reference manager database. We retrieved the full‐text versions of relevant studies, and two review authors independently extracted data. Primary outcomes were: change in WHO functional class, six‐minute walk distance (6MWD), and mortality. Secondary outcomes were haemodynamic parameters, quality of life/health status, dyspnoea, clinical worsening (hospitalisation/intervention), and adverse events. When appropriate, we performed meta‐analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the GRADE approach and created 'Summary of findings' tables.

Main results

We included 36 studies with 2999 participants (with pulmonary hypertension from all causes) in the final review. Trials were conducted for 14 weeks on average, with some as long as 12 months. Two trials specifically included children.

Nineteen trials included group 1 PAH participants. PAH participants treated with PDE5 inhibitors were more likely to improve their WHO functional class (odds ratio (OR) 8.59, 95% confidence interval (CI) 3.95 to 18.72; 4 trials, 282 participants), to walk 48 metres further in 6MWD (95% CI 40 to 56; 8 trials, 880 participants), and were 22% less likely to die over a mean duration of 14 weeks (95% CI 0.07 to 0.68; 8 trials, 1119 participants) compared to placebo (high‐certainty evidence). The number needed to treat to prevent one additional death was 32 participants. There was an increased risk of adverse events with PDE5 inhibitors, especially headache (OR 1.97, 95% CI 1.33 to 2.92; 5 trials, 848 participants), gastrointestinal upset (OR 1.63, 95% CI 1.07 to 2.48; 5 trials, 848 participants), flushing (OR 4.12, 95% CI 1.83 to 9.26; 3 trials, 748 participants), and muscle aches and joint pains (OR 2.52, 95% CI 1.59 to 3.99; 4 trials, 792 participants).

Data comparing PDE5 inhibitors to placebo whilst on other PAH‐specific therapy were limited by the small number of included trials. Those PAH participants on PDE5 inhibitors plus combination therapy walked 19.66 metres further in six minutes (95% CI 9 to 30; 4 trials, 509 participants) compared to placebo (moderate‐certainty evidence). There were limited trials comparing PDE5 inhibitors directly with other PAH‐specific therapy (endothelin receptor antagonists (ERAs)). Those on PDE5 inhibitors walked 49 metres further than on ERAs (95% CI 4 to 95; 2 trials, 36 participants) (low‐certainty evidence). There was no evidence of a difference in WHO functional class or mortality across both treatments.

Five trials compared PDE5 inhibitors to placebo in PH secondary to left‐heart disease (PH‐LHD). The quality of data were low due to imprecision and inconsistency across trials. In those with PH‐LHD there were reduced odds of an improvement in WHO functional class using PDE5 inhibitors compared to placebo (OR 0.53, 95% CI 0.32 to 0.87; 3 trials, 285 participants), and those using PDE5 inhibitors walked 34 metres further compared to placebo (95% CI 23 to 46; 3 trials, 284 participants). There was no evidence of a difference in mortality. Five trials compared PDE5 inhibitors to placebo in PH secondary to lung disease/hypoxia, mostly in COPD. Data were of low quality due to imprecision of effect and inconsistency across trials. There was a small improvement of 27 metres in 6MWD using PDE5 inhibitors compared to placebo in those with PH due to lung disease. There was no evidence of worsening hypoxia using PDE5 inhibitors, although data were limited. Three studies compared PDE5 inhibitors to placebo or other PAH‐specific therapy in chronic thromboembolic disease. There was no significant difference in any outcomes. Data quality was low due to imprecision of effect and heterogeneity across trials.

Authors' conclusions

PDE5 inhibitors appear to have clear beneficial effects in group 1 PAH. Sildenafil, tadalafil and vardenafil are all efficacious in this clinical setting, and clinicians should consider the side‐effect profile for each individual when choosing which PDE5 inhibitor to prescribe.

While there appears to be some benefit for the use of PDE5 inhibitors in PH‐left‐heart disease, it is not clear based on the mostly small, short‐term studies, which type of left‐heart disease stands to benefit. These data suggest possible harm in valvular heart disease. There is no clear benefit for PDE5 inhibitors in pulmonary hypertension secondary to lung disease or chronic thromboembolic disease. Further research is required into the mechanisms of pulmonary hypertension secondary to left‐heart disease, and cautious consideration of which subset of these patients may benefit from PDE5 inhibitors. Future trials in PH‐LHD should be sufficiently powered, with long‐term follow‐up, and should include invasive haemodynamic data, WHO functional class, six‐minute walk distance, and clinical worsening.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

PDE5 inhibitors for pulmonary hypertension

Review question:

We wanted to review whether a group of drugs called PDE5 inhibitors (which may work to open up the vessels in the lung) can help people with pulmonary hypertension (increased pressures in the blood vessels of the lungs). Cochrane researchers collected and analysed all relevant studies to answer this question, and found 36 studies.

Why the review is important:

Approximately three people in every 1000 have pulmonary hypertension, due to different causes. This can lead to reduced exercise capacity, reduced quality of life, increased hospitalisations, and early death. A group of drugs called PDE5 inhibitors may improve blood circulation in the right heart and lungs. We wanted to make sure that if these drugs are being used, there is evidence of benefit and little or no harm.

Main findings:

We included 36 studies with 2999 people. Trials were conducted for 14 weeks on average, with some as long as 12 months. Most trials involved adults, and two trials specifically included children.

Nineteen trials included those with group 1 pulmonary arterial hypertension (inherited, unknown, due to connective tissue diseases). People who were given PDE5 inhibitors were compared with those not given PDE5 inhibitors. This review shows that when given PDE5 inhibitors, on average people walked 48 meters further in six minutes (8 trials, 880 people). They also improved their functional class (reducing the physical limitations associated with PH), and were less likely to die (high‐certainty evidence). They were also more likely to have side effects, including headache, flushing and muscle aches.

Five trials included people with pulmonary hypertension due to left‐heart disease. This review shows that when given PDE5 inhibitors, these people were on average able to walk 34 metres further in six minutes (3 trials, 284 people; low‐certainty evidence). However, there was no difference in survival, compared to those who were not given PDE5 inhibitors. Five trials included people with pulmonary hypertension due to lung disease (mostly chronic obstructive pulmonary disease and some idiopathic pulmonary fibrosis). When given PDE5 inhibitors, they were able to walk 27 meters further in six minutes (low‐certainty evidence), but with no difference in survival, compared to those who were not given PDE5 inhibitors. Three trials included people with pulmonary hypertension due to blood clots; there was no significant difference in outcomes for those who used PDE5 inhibitors compared to those who did not.

Limitations:

There was good‐quality evidence for those with pulmonary arterial hypertension, giving us some confidence that the results are correct. The evidence for those with pulmonary hypertension due to heart disease was less certain. The quality of evidence in this group was low because there were few trials, small numbers of people taking part, and the trials were quite different from each other, making it difficult to draw firm conclusions.

Authors' conclusions

available in

Implications for practice

  • Data from this review suggest a benefit for the use of PDE5 inhibitors in group 1 PAH, for improvement in WHO functional class, reduction in clinical worsening, and improvement in haemodynamics, six‐minute walk distance, quality of life, and mortality.

  • Sildenafil, tadalafil and vardenafil are all efficacious in this clinical setting.

  • Clinicians may wish consider the side‐effect profile for each drug when choosing which to prescribe to an individual patient.

  • This review suggests that a PDE5 inhibitor may be better than an ERA for six‐minute walk distance and quality of life, but that there appears to be no difference in WHO functional class or mortality. These conclusions are limited by the small number of trials.

  • While there appears to be some benefit for the use of PDE5 inhibitors in PH‐LHD, it is not clear based on the mostly small, short‐term studies which type of left‐heart disease stands to benefit. The use of PDE5 inhibitors does not appear to be beneficial in valvular heart disease.

  • This review suggests there is no clear benefit for PDE5 inhibitors in pulmonary hypertension secondary to lung disease or CTEPH.

  • There may be evidence of harm in the use of PDE5 inhibitors for pulmonary hypertension secondary to sickle cell disease.

Implications for research

  • Further research is required into the mechanisms of pulmonary hypertension secondary to left‐heart disease.

  • Clinical trials in PH‐LHD should be sufficiently powered, with long‐term follow‐up, and should include invasive haemodynamic data, WHO functional class, six‐minute walk distance, and clinical worsening.

Summary of findings

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Summary of findings for the main comparison. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo

Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo

Patient or population: people with pulmonary arterial hypertension
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

61 per 1000

358 per 1000
(204 to 549)

OR 8.59
(3.95 to 18.72)

282
(4 RCTs)

⊕⊕⊕⊕
HIGH

‐

Six‐minute walk distance

Ranges from 170 ‐ 319 ma

MD 48 metres higher
(40 higher to 56 higher)

‐

880
(8 RCTs)

⊕⊕⊕⊝b
MODERATE

6MWD in PAH MCID is 41 metres

Mortality

41 per 1000

9 per 1000
(3 to 28)

OR 0.22
(0.07 to 0.68)

1119
(8 RCTs)

⊕⊕⊕⊕
HIGH

‐

Quality of life

SF‐36: (scores 1 to 100, higher scores indicate better QoL)

EQ‐5D questionnaire: (higher scores indicate worse QoL)

CHFQ: (lower scores indicate worse QoL)

Galiè 2005a found a statistically significant improvement in all SF‐36 domains for sildenafil‐treated participants, and when compared to placebo in physical functioning (P < 0.001), general health (P < 0.001), and vitality (P < 0.05). There was also a statistically significant improvement in placebo‐treated participants in the physical functioning domain.

Galiè 2005a found statistically significant improvements for the EQ‐5D current health status (P < 0.01) and utility index (P < 0.01).
Sastry 2004 found a statistically significant difference for the CHFQ fatigue domain (sildenafil post‐treatment score 22.33, SD 4.82 compared to placebo post‐treatment score 20.67, SD 5.19; P = 0.04), and a non‐statistically significant difference in the emotional function domain (sildenafil post‐treatment score 37.33, SD 9.3, compared to placebo post‐treatment score 34.71, SD 10.91; P = 0.06), favouring sildenafil compared with placebo.

163

(2 RCTs)

‐

Data considered too heterogeneous to meta‐analyse

PAP

‐

MD 6.43 mmHg lower (8.13 lower to 4.74 lower)

‐

453
(6 RCTs)

⊕⊕⊕⊝b
MODERATE

The higher the mean PAP, the worse the PH

RAP

‐

MD 1.35 mmHg lower (2.34 lower to 0.36 lower)

‐

341
(3 RCTs)

⊕⊕⊕⊕
HIGH

The higher the RAP, the worse the PH

Cardiac index

‐

MD 0.28L/min/m2 higher (0.16 higher to 0.4 higher)

‐

239
(4 RCTs)

⊕⊕⊕⊝b
MODERATE

The lower the cardiac index, the worse the PH

PVR

‐

MD 4.74 WU lower (6.13 lower to 3.35 lower)

‐

266
(3 RCTs))

⊕⊕⊕⊕
HIGH

The higher the PVR. the worse the PH

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; EQ‐5D: EuroQoL 5D; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RCT: randomised controlled trials; SD: standard deviation; SF‐36: Medical Outcomes Study 36‐item short form; WU: woods units; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aPost‐treatment values for participants in the placebo group were presented in two studies only; the remaining included studies presented a mean difference only.
bDowngraded due to imprecision owing to significantly high heterogeneity, although the direction of effect is consistent.

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Summary of findings 2. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy

Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy

Patient or population: people with pulmonary arterial hypertension
Setting: outpatients
Intervention: PDE5 inhibitors plus other disease‐modifying therapies
Comparison: placebo plus other disease‐modifying therapies

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo, on combination therapy

Risk with PDE5i

Improvement in WHO functional class

263 per 1000

300 per 1000
(191 to 437)

OR 1.20
(0.66 to 2.17)

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Six‐minute walk distance

Ranges from 341 ‐ 377 mb

MD 20 metres higher
(9 higher to 30 higher)

‐

509
(4 RCTs)

⊕⊕⊕⊝
MODERATEa

6MWD in PAH MCID is 41 metres

Mortality

32 per 1000

9 per 1000
(2 to 34)

OR 0.26
(0.07 to 1.06)

492
(3 RCTs)

⊕⊕⊕⊝
MODERATEc

‐

Quality of life

physical functioning on SF‐36 (higher scores indicate better quality of life)

0.3 (4.7 higher to 4.1 higher)

7.8 (3.6 higher to 12.1 higher)

‐

267

(1 RCT)

⊕⊕⊕⊝
MODERATEd

‐

PAP

‐

MD 4.58 mmHg lower
(6.14 lower to 3.01 lower)

‐

387
(2 RCTs)

⊕⊕⊕⊕
HIGH

The higher the PAP, the worse the pulmonary hypertension

Cardiac output

‐

MD 0.87 L/min higher
(0.53 higher to 1.21 higher)

‐

310
(3 RCTs)

⊕⊕⊕⊕
HIGH

The lower the cardiac output, the worse the pulmonary hypertension

PVR

‐

SMD 0.48 lower
(0.72 lower to 0.25 lower)

‐

303
(3 RCTs)

⊕⊕⊕⊕
HIGH

The higher the PVR, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PVR: pulmonary vascular resistance; RCT: randomised controlled trials; SMD: standardised mean difference; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded due to imprecision owing to small participant numbers and inconsistent direction of effect.
bRange of baseline values, as studies only presented mean difference values for analysis.
cDowngraded due to imprecision as the confidence interval crosses the line of no difference.
dDowngraded due to imprecision owing to small participant numbers in one trial.

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Summary of findings 3. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to ERA

Group 1 Pulmonary Arterial Hypertension ‐ PDE5i compared to ERA

Patient or population: people with pulmonary arterial hypertension
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: endothelin receptor antagonists(ERA)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with ERA

Risk with PDE5i

Improvement in WHO functional class

339 per 1000

325 per 1000
(220 to 450)

OR 0.94
(0.55 to 1.60)

244
(1 RCT)

⊕⊕⊕⊝
MODERATEa

‐

Six‐minute walk distance

Ranges from 290 ‐ 354 mb

MD 49 higher
(4 higher to 95 higher)

‐

36
(2 RCTs)

⊕⊕⊝⊝
LOWc

6MWD in PAH MCID is 41 metres

Mortality

14 per 1000

45 per 1000
(11 to 167)

OR 3.19
(0.74 to 13.64)

272
(2 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Quality of life

Kansas City Cardiomyopathy Quality‐of‐Life questionnaire (higher scores indicate better quality of life)

‐

MD 22 higher
(9 higher to 35 higher)

‐

25
(1 RCT)

⊕⊕⊝⊝
LOWc

‐

PAP

‐

MD 7.00 mmHg lower (4.82 lower to 18.82 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The higher the mean PAP, the worse the PH

RAP

‐

MD 2 mmHg higher (2.14 lower to 6.14 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The higher the RAP, the worse the PH

Cardiac index

‐

MD 0 L/min/m2 higher (0.49 lower to 0.49 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The lower the cardiac index, the worse the PH

PVR

‐

MD 0 WU lower (1.93 lower to 1.93 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The higher the PVR. the worse the PH

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PDE‐5i: phosphodiesterase‐5 inhibitor; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded once due to imprecision.
bRange of baseline values, as studies only presented mean difference values for analysis.
cDowngraded twice due to imprecision and small participant numbers.
dDowngraded twice due to very small participant numbers and high risk of bias.

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Summary of findings 4. Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo

Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension due to left‐heart disease
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

403 per 1000

263 per 1000
(178 to 370)

OR 0.53
(0.32 to 0.87)

285
(3 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Six‐minute walk distance

No data reported

MD 34 metres higher
(23 higher to 46 higher)

‐

284
(3 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Mortality

22 per 1000

27 per 1000 (6 to 114)

OR 1.27 (0.28 to 5.80)

286
(3 RCTs)

⊕⊕⊕⊝
MODERATEb

‐

Quality of life

19.83 points higher (8.23 higher to 31.44 higher)

12.05 points higher (1.14 higher to 22.96 higher)

‐

52

(1 RCT)

⊕⊕⊝⊝
LOWc

Kansas City Cardiomyopathy Questionnaire (higher scores reflect better health status)

Mean PAP

‐

MD 10.17 mmHg lower
(11.99 lower to 8.35 lower)

‐

130
(3 RCTs)

⊕⊕⊕⊝
MODERATEa

The higher the mean PAP, the worse the pulmonary hypertension

Cardiac index

‐

MD 0.07 L/min/m2 higher
(0.17 lower to 0.3 higher)

‐

96
(2 RCTs)

⊕⊕⊕⊝
MODERATEa

The lower the cardiac index, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded due to high heterogeneity and inconsistent direction of effect.
bDowngraded due to imprecision as the confidence interval crosses the line of no difference.
cDowngraded twice due to imprecision owing to few participant numbers in one trial.

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Summary of findings 5. Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo

Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension due to lung disease
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

50 per 1000

700 per 1000
(201 to 956)

OR 44.33
(4.78 to 410.94)

40
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Six‐minute walk distance

Ranges from 237 ‐ 297 metres

MD 27 metres higher
(2 higher to 51 higher)

‐

350
(5 studies)

⊕⊕⊕⊕
HIGH

‐

Mortality

‐

‐

‐

No studies

‐

‐

Quality of life

‐

MD 0.19 higher
(0.07 lower to 0.44 higher)

‐

238
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

SF‐36 overall quality of life (higher scores indicate better quality of life)

Mean PAP

‐

MD 0.14 mmHg lower
(6.65 lower to 6.37 higher)

‐

61
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The higher the mean PAP, the worse the pulmonary hypertension

Cardiac index

‐

MD 0.3 L/min/m2 higher
(0.14 lower to 0.74 higher)

‐

28
(1 RCT)

⊕⊕⊝⊝
LOWa

The lower the cardiac index, the worse the pulmonary hypertension

PVR

‐

MD 1.31 WU lower
(3.67 lower to 1.05 higher)

‐

28
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the PVR, the worse the pulmonary hypertension

RAP

‐

MD 0.36 mmHg higher
(2.76 lower to 3.48 higher)

‐

28
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the RAP, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded twice due to imprecision owing to small participant numbers.
bDowngraded once due to imprecision.

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Summary of findings 6. Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo

Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension due to CTEPH
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with comparison (placebo/sildenafil)

Risk with PDE5i

Improvement in WHO functional class

0 per 1000

444 per 1000

OR 17.18
(0.78 to 380.84)

19
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Six‐minute walk distance ‐ sildenafil compared to placebo

Baseline 331 metres

MD 18 metres higher
(24 lower to 59 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Six‐minute walk distance ‐ sildenafil compared to bosentan

Ranges from 422 ‐ 455 metres

MD 20 metres higher
(28 lower to 69 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

‐

Mortality ‐ sildenafil versus placebo

No deaths reported

not estimable

20
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Mortality ‐ sildenafil versus bosentan

40 per 1000

54 per 1000
(9 to 261)

OR 1.36 (0.22 to 8.48)

106
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Quality of life

‐

MD 0.26 lower
(1.17 lower to 0.64 higher)

‐

34
(1 RCT)

⊕⊕⊝⊝
LOWa

CamPHOR scale; higher scores indicate worse quality of life

Mean PAP ‐ sildenafil versus placebo

‐

MD 6.2 mmHg lower
(12.4 lower to 0 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the PAP, the worse the pulmonary hypertension

Mean PAP ‐ sildenafil versus bosentan

‐

MD 0.76 mmHg higher
(3.96 lower to 5.48 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The higher the PAP, the worse the pulmonary hypertension

Cardiac index ‐ sildenafil versus placebo

‐

MD 0 L/min/m2 higher
(0.4 lower to 0.4 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

The lower the cardiac index, the worse the pulmonary hypertension

Cardiac index ‐ sildenafil versus bosentan

‐

MD 0.04 L/min/m2 higher
(0.22 lower to 0.31 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The lower the cardiac index, the worse the pulmonary hypertension

PVR ‐ sildenafil versus placebo

‐

MD 0.89 WU lower
(1.85 lower to 0.06 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the PVR, the worse the pulmonary hypertension

PVR ‐ sildenafil versus bosentan

‐

MD 0.01 WU lower
(0.27 lower to 0.25 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The higher the PVR, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; CTEPH: chronic thromboembolic pulmonary hypertension; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PVR: pulmonary vascular resistance; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded twice due to imprecision owing to small participant numbers in only one trial.
bDowngraded once due to imprecision.

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Summary of findings 7. Mixed Pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo

Mixed pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension group 2 ‐ 4
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

Study population

OR 11.31
(4.90 to 26.14)

146
(2 RCTs)

⊕⊕⊕⊝
MODERATEa,b

‐

137 per 1000

642 per 1000
(438 to 806)

Six‐minute walk distance

No data provided

MD 51 metres higher
(7 higher to 95 higher)

‐

106
(1 RCT)

⊕⊕⊕⊝
MODERATEa,b

‐

Mortality

‐

‐

no studies

‐

‐

‐

Quality of life

‐

‐

no studies

‐

‐

‐

PASP

‐

MD 10 mmHg lower
(11.92 lower to 8.08 lower)

‐

146
(2 RCTs)

⊕⊕⊕⊝
MODERATEa,b

The higher the PASP, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; MD: mean difference; OR: odds ratio; PASP: pulmonary artery systolic pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded due to imprecision owing to small participant numbers.
bThe information is from studies at low or unclear risk of bias.

Background

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Description of the condition

Pulmonary hypertension (PH) (defined as a mean pulmonary artery pressure ≥ 25 mmHg at rest on right‐heart catheterisation) comprises a complex group of conditions (see Table 1), characterised by increased right ventricular afterload, which ultimately leads to right‐heart failure (McLaughlin 2009). The increased afterload may be due to passive transmission of high left‐sided pressures (post‐capillary pulmonary hypertension), obstruction of the pulmonary arterial bed (pre‐capillary pulmonary hypertension) or a combination of both. Pulmonary arterial hypertension (PAH‐WHO Group 1) is a group of diseases where pulmonary hypertension occurs in the setting of increased pulmonary vascular resistance. The more recent availability of medications and therapies targeting the pulmonary arterial bed has led to the prospect of an improvement in what had previously been a very poor prognosis. Although PAH is rare, PH secondary to left‐heart disease and lung disease is much more common. The availability of drugs with efficacy in PAH has led to great interest in the use of these drugs in other forms of pulmonary hypertension.

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Table 1. World Health Organisation/World Symposium classification of pulmonary hypertension

WHO group

Classification

Group 1

Pulmonary arterial hypertension

  • idiopathic PAH

  • PAH with vasoreactivity

  • heritable PAH

  • drugs and toxins

  • associated with:

    • connective tissue disease;

    • HIV;

    • portal hypertension;

    • congenital heart disease;

    • schistosomiasis.

Pulmonary veno‐occlusive disease/pulmonary capillary haemangiomatosis

Persistent pulmonary hypertension of the newborn

Group 2

Pumonary hypertension due to left heart disease

  • due to left heart failure with preserved ejection fraction

  • due to left heart failure with reduced ejection fraction

Valvular heart disease

Congenital post‐capillary obstructive lesions

Group 3

Pulmonary hypertension due to chronic lung disease or chronic hypoxaemia, or both

  • obstructive lung disease

  • restrictive lung disease

  • other lung diseases with a mixed obstructive/restrictive pattern

  • sleep disordered breathing

  • alveolar hypoventilation disorders

  • chronic exposures to high altitudes

  • developmental lung diseases

Group 4

Pulmonary hypertension due to pulmonary artery obstruction

  • chronic thromboembolic pulmonary hypertension

  • other pulmonary artery obstructions

Group 5

Pulmonary hypertension with unclear mechanisms

  • haematologic disorders (chronic haemolytic anaemia, myeloproliferative disorders, splenectomy)

  • systemic disorders (sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis)

  • metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders)

  • others (pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension)

PAH: pulmonary arterial hypertension

In PAH, increased pulmonary vascular resistance is caused by vascular remodelling and thickening in the small‐ and medium‐sized arterioles, fibrinoid necrosis, the formation of eccentric, concentric, or plexiform lesions, and the loss of vascular tone. This process of cellular hypertrophy and hyperplasia is mediated by intracellular calcium and protein kinase C, inflammatory cytokines, and altered energy metabolism. Remodelling and vasoconstriction lead to hypoxia, causing further vasoconstriction and further hypoxia (Guignabert 2013; Sim 2010).

Pulmonary hypertension is classified into five groups of multiple clinical conditions, grouped according to similar clinical presentations and pathophysiological and haemodynamic characteristics, with distinct treatment strategies for each group. Group 1 pulmonary arterial hypertension (PAH) includes idiopathic and heritable PAH and PAH due to pathology of the small pulmonary arterioles resulting from connective tissue disorders, drugs or toxins, portal pulmonary hypertension, and others (see Table 1). Pulmonary arterial hypertension is caused by increased pulmonary vascular resistance due to occlusive vasculopathy of the small pulmonary arteries and arterioles. Pulmonary arterial hypertension is a rare disease, with an estimated prevalence of 10 to 52 cases per million (Ling 2012; Peacock 2007). However, screening for pulmonary hypertension for all causes demonstrates a prevalence of 320 cases per 100,000 (Strange 2012).

Group 2 consists of pulmonary hypertension due to left‐heart disease, caused by increased flow through the pulmonary vasculature, or increased pulmonary pressures (e.g. mitral valve disease, left ventricular disease, and constrictive myopathies). Group 3 comprises pulmonary hypertension as a result of lung diseases or hypoxia, or both, caused by a decrease in the area of the pulmonary vascular bed (e.g. interstitial lung disease), or conditions that induce hypoxic vasoconstriction. Group 4 refers to cases of pulmonary hypertension due to chronic thromboembolic occlusion of pulmonary vasculature, and Group 5 consists of cases of pulmonary hypertension due to unclear or multifactorial mechanisms or both, including haematological, systemic, or metabolic disorders (see Table 1) (McLaughlin 2009). The extent to which WHO Groups 2 to 5 have pulmonary arterial bed changes analogous to WHO Group 1 (and thus respond similarly to the medications) remains unclear. Furthermore, potential detrimental effects of selective arterial vasodilatation (pulmonary oedema in WHO Group 2 and hypoxia in WHO group 3) will probably present a quite different risk/benefit profile to the same medications used in PAH.

People with PAH often present with symptoms of dyspnoea, fatigue, syncope, and right‐heart failure (Galiè 2016b). Right‐heart catheterisation remains the gold standard of diagnosis to confirm pulmonary hypertension and to further investigate potential causes and treatment targets. Pulmonary arterial hypertension is defined as a mean pulmonary artery pressure equal to or greater than 25 mmHg; a pulmonary artery wedge pressure, left atrial pressure, or left ventricular end‐diastolic pressure less than or equal to 15 mmHg; and a pulmonary vascular resistance greater than three Wood units (Galiè 2016b). Elevation of the pulmonary artery wedge pressure suggests pulmonary hypertension secondary to left‐heart disease. People with confirmed PAH should undergo acute vasodilator testing to assess for pulmonary vasoreactivity, as a small proportion may respond very favourably to long‐term high‐dose calcium channel blocker therapy (McLaughlin 2009).

Following history, examination, electrocardiogram, echocardiogram, and chest X‐ray, other investigations for people with pulmonary hypertension should include pulmonary function tests and high‐resolution computed tomography chest to assess for underlying lung disease, a ventilation/perfusion scan to assess for chronic thromboembolic pulmonary hypertension, thyroid function tests, autoimmune serology, HIV and hepatitis screening to assess for underlying aetiologies, and a six‐minute walk test or exercise testing, biomarkers to monitor response to treatment and for prognostication (Galiè 2016b).

The natural history and prognosis of pulmonary hypertension varies amongst the WHO Groups. However the presence of pulmonary hypertension irrespective of WHO group generally reflects the presence of a progressive and often fatal condition. Known independent predictors of poor prognosis include advanced WHO functional class, poor performance in six‐minute walk test, high right atrial pressure, significant right ventricular dysfunction, evidence of right ventricular failure, elevated pro‐B‐type natriuretic peptide (BNP), and low cardiac index (Thenappan 2007).

Description of the intervention

Recent years have seen the introduction of evolving therapies for PAH, with an improvement in the one‐year survival rate to 84% from 68% in the 1980s (Archer 2009). The goals of therapy are to achieve a state associated with good quality of life and exercise tolerance with low mortality risk and to maintain right ventricular function, using supplemental oxygen and treatment of the underlying cause. The underlying pulmonary artery endothelial dysfunction in Group 1 PAH enables the use of PAH‐specific targeted treatments promoting vasorelaxation and suppression of cellular proliferation within the pulmonary artery wall, including nitric oxide and phosphodiesterase type 5 inhibitors (PDE5i, prostanoids, endothelin receptor antagonists, and calcium channel blockers) (McLaughlin 2009).

How the intervention might work

Nitric oxide performs as a pulmonary vasodilator by activating soluble guanylate cyclase, stimulating the production of cyclic guanosine monophosphate (cGMP), which in turn activates myosin light chain phosphatase, which reduces phosphorylation of myosin to reduce pulmonary vascular tone. Increased intracellular cGMP also inhibits calcium entry, thereby reducing intracellular calcium leading to less hypertrophy and hyperplasia, as well as antiproliferative and pro‐apoptotic effects that may reverse pulmonary artery remodelling. Nitric oxide also inhibits platelet recruitment, adhesion, and aggregation (Sim 2010).

However, nitric oxide administration is not without risk. High levels of inhaled nitric oxide may lead to oxidative stress and cause tissue damage, reperfusion injury, and a pulmonary inflammatory reaction. Inhaled nitric oxide is rapidly absorbed into the blood stream, where it is converted to methaemoglobin, leading to impaired rather than improved oxygen delivery (Sim 2010).

Phosphodiesterase type 5 (PDE5) specifically reduces cGMP‐degrading enzyme activity, thereby increasing cGMP production. Phosphodiesterase type 5 inhibitors are not thought to induce the same levels of oxidation as inhaled nitric oxide (Ghofrani 2004d). Phosphodiesterase type 5 inhibitors that have been investigated for use in Group 1 PAH include sildenafil, tadalafil, and vardenafil. These agents have been shown in clinical trials to improve six‐minute walk distance and haemodynamics (Archer 2009; Galiè 2016b; McLaughlin 2009).

The data are less clear in WHO Group 2 to 5 patients, in whom this class of drug may be potentially harmful. There are different pathobiological and pathophysiological factors at play, leading to the development of pulmonary hypertension in these people. The nature of the pulmonary arteriopathy may be quite different (e.g. hypoxic vasoconstriction and pulmonary vascular bed obstruction in Group 3; thrombotic obstruction in Group 4). The consequences of 'selective' pulmonary arterial vasodilation may also be detrimental (pulmonary oedema in WHO group 2 and hypoxia in Group 3). Thus, as with other selective pulmonary vasodilators, a reduction in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) by PDE5 inhibitors may not improve the overall well‐being of patients, especially in the non‐PAH Groups (2 to 5) (Guazzi 2012).

Phosphodiesterase type 5 inhibitors may theoretically improve function in Group 2 patients with left‐heart disease. Previous studies in heart‐failure patients have demonstrated that nitric oxide is responsible for regulation of vascular tone, and infusion of NG‐monomethyl‐L‐arginine, an inhibitor of nitric oxide synthase, caused less vasoconstriction in heart‐failure patients compared to those with a normal pulmonary vascular resistance (Cooper 1996). Trials using sildenafil in Group 2 pulmonary hypertension patients have shown some evidence of improvement in exercise capacity, ventilation efficiency, and quality of life (Lewis 2007). However, other studies have demonstrated unbalanced pulmonary dilatation as a consequence of nitric oxide and analogues may lead to increased preload due to a poorly compliant left ventricle, and therefore a significant increase in pulmonary artery wedge pressure, which may even precipitate acute pulmonary oedema (Bocchi 1994).

Furthermore, trials using other PAH‐specific therapies including epoprostenol and endothelin receptor antagonists in people with Group 2 pulmonary hypertension demonstrated an increased risk of hospitalisations, disease progression, and hypoxaemia. People with left ventricular dysfunction may not be able to tolerate the increased flow across a newly‐dilated pulmonary vascular bed (Guazzi 2012).

People with Group 3 chronic lung diseases may experience worsening ventilation perfusion mismatch and increased hypoxaemia. A study in people with pulmonary hypertension associated with chronic obstructive pulmonary disease demonstrated an improvement in pulmonary artery pressures, but at the cost of worsening arterial oxygenation (Blanco 2010).

Why it is important to do this review

Given recent advances in the understanding of the pathophysiological mechanisms and treatments for pulmonary hypertension with significant contributions in the area in the last decade, we planned to summarise the current evidence relating to the use of PDE5 inhibitors in pulmonary hypertension.

This review aimed to quantify any potential benefit for PDE5 inhibitors in people with PAH in terms of haemodynamic measurements and patient‐centred outcomes, and to balance this against any potential treatment harms, in order to guide patient preference, clinician treatment choices, and guidelines for policymakers.

This review also examines the available evidence to determine whether there is any potential benefit or harm in using PDE5 inhibitors in people with Group 2 to 5 pulmonary hypertension.

This review builds on a previous review (Kanthapillai 2004), since which further concepts about pathophysiology have been developed, and a number of more recent randomised controlled trials using PDE5 inhibitors have been published.

Objectives

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To determine the efficacy of PDE5 inhibitors for pulmonary hypertension in adults and children.

Methods

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Criteria for considering studies for this review

Types of studies

We include single‐ or double‐blinded randomised controlled trials (RCTs) in which PDE5 inhibitors are compared to placebo or to any other treatment. We defined 'randomised' as studies described by the author as 'randomised' anywhere in the study report. All trials defined as such, published or unpublished, in any language, were eligible for inclusion.

Types of participants

We include any individual with a diagnosis of pulmonary hypertension from any cause who required medical treatment for their condition. We define pulmonary hypertension according to accepted criteria (Galiè 2016b; McLaughlin 2009).

  1. Comparison 1 specifically assesses the effects of PDE5 inhibitors compared to placebo on Group 1 PAH, confirmed as a mean pulmonary artery pressure ≥ 25 mmHg by right‐heart catheterisation.

  2. Comparison 2 compares PDE5 inhibitors with placebo in PAH participants on combination therapy.

  3. Comparison 3 compares PDE5 inhibitors to ERAs in PAH participants.

  4. Comparison 4 includes group 2 pulmonary hypertension participants with a diagnosis of pulmonary hypertension and left‐heart disease, as defined by the authors.

  5. Comparison 5 includes group 3 pulmonary hypertension participants with a diagnosis of pulmonary hypertension and lung disease, as defined by the authors.

  6. Comparison 6 includes group 4 pulmonary hypertension participants with a diagnosis of pulmonary hypertension and chronic thromboembolic disease (CTEPH), as defined by the authors.

  7. Comparison 7 includes mixed group 2 to 5 pulmonary hypertension participants with a diagnosis of pulmonary hypertension as defined by the authors.

We planned to specify subgroups of adults (older than 18 years) and a paediatric population younger than 18 years.

Types of interventions

We include studies comparing any type of PDE5 inhibitors by any route of administration with placebo or any other treatment used for pulmonary hypertension. We include studies with co‐interventions provided they are not part of the randomised treatment. We aimed to perform subgroup analyses depending on the co‐interventions used. Where studies were too heterogenous for meta‐analyses, we describe them in narrative form.

Types of outcome measures

Primary outcomes

  1. Change in WHO functional class

  2. Six‐minute walk distance (6MWD)

  3. Mortality

Secondary outcomes

  1. Haemodynamic parameters, including change in mean pulmonary artery pressure, change in cardiac output, cardiac index

  2. Exercise capacity other than six‐minute walk distance

  3. Quality of life/health status, by any validated scale

  4. Dyspnoea score, including visual analogue scale or Borg scale

  5. Hospitalisation/intervention

  6. Adverse events

Reporting one or more of the outcomes listed here in the study was not an inclusion criterion for the review.

Search methods for identification of studies

Electronic searches

We identified trials from searches of the following databases up to 26 September 2018:

  1. The Cochrane Airways Group Register of Trials;

  2. Cochrane Central Register of Controlled Trials (CENTRAL) through the Cochrane Register of Studies Online (crso.cochrane.org);

  3. MEDLINE (Ovid) 1950 to 26 September 2018;

  4. Embase (Ovid) 1974 to 26 September 2018;

  5. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);

  6. World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch/).

We provide the database search strategies in Appendix 1. We searched all databases from their inception to the present, with no restriction on language of publication. We searched for handsearched conference abstracts and grey literature through the CENTRAL database.

Searching other resources

We checked the reference lists of all primary studies and review articles for additional references. We handsearched reference lists of included studies, relevant chapters, and review articles. We used Google to search for grey literature and conference abstracts. We translated any relevant article into English for potential inclusion. Where data were missing, we attempted to contact the trial investigators.

Data collection and analysis

Selection of studies

Two review authors (HB and ZB) independently screened all abstracts to determine if they met the inclusion criteria for the review. We sought full‐text publications for those papers that possibly or definitely met the inclusion criteria. Two review authors independently reviewed all full‐text articles to determine eligibility, recording reasons for ineligibility of those that did not. We resolved any disagreements through discussion, or by seeking consensus from a third review author (AB). We included a PRISMA study flow diagram in the full review to document the screening process, and included a Characteristics of included studies table (Moher 2009).

Data extraction and management

Two review authors (HB and ZB) independently extracted data from included studies, and where appropriate, pooled data in the Cochrane statistical software Review Manager 5 for further analysis (RevMan 2014). We used a data collection form that we piloted on one study for inclusion in the review, containing the following data.

  1. Methods: study design, duration, study setting, date of study.

  2. Participants: number, mean age and age range, gender, inclusion and exclusion criteria.

  3. Intervention: type of PDE5 inhibitor, dose, mode of administration, control drug, co‐interventions, and exclusions.

  4. Outcomes: primary and secondary outcomes as specified, type of scale used, time points collected.

  5. Risk of bias summary.

  6. Other: funding for trial, any conflicts of interest for trial authors.

Assessment of risk of bias in included studies

Two review authors (HB and ZB) independently assessed the included studies for risks of bias using the Cochrane 'Risk of bias' assessment tool (Higgins 2011). We assessed the following domains.

  1. Random sequence generation.

  2. Allocation concealment.

  3. Blinding of participants and personnel.

  4. Blinding of outcome assessment

  5. Incomplete outcome data.

  6. Selective outcome reporting.

  7. Other potential sources of bias.

We judged each potential source of bias as low risk, unclear risk (insufficient information to form a judgement), or high risk, and provided justification with evidence from each trial in the ‘Risk of bias’ table. When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the previously published protocol, and justified any deviations from it in the Differences between protocol and review section of the review.

Measures of treatment effect

Where possible, we pooled and presented results from dichotomous data as odds ratios (ORs). Where possible, we presented results from continuous variables and calculated the mean difference (MD) or standardised mean difference (SMD) where scales are combined, with the 95% confidence interval (95% CI). Where we combined data from rating scales in a meta‐analysis, we ensured that they were entered with a consistent direction of effect (e.g. lower scores always indicate improvement). If both change from baseline and endpoint scores were available for continuous data, we used change from baseline scores. Where outcomes were reported at multiple time points, we consistently extracted and included the latest reported time point, but also considered outcomes reported at other time points. We only combined data reported at different time points if this was clinically appropriate.

We described skewed data narratively (e.g. as medians and interquartile ranges for each group).

We used intention‐to‐treat or 'full analysis set' analyses where they were reported (i.e. those where data have been imputed for participants who were randomly assigned but did not complete the study) instead of completer or per‐protocol analyses.

Unit of analysis issues

For dichotomous outcomes, we used participants rather than events as the unit of analysis (i.e. number of children admitted to hospital, rather than number of admissions per child). Where rate ratios were reported in a study, we analysed them on that basis. We planned to only meta‐analyse data from cluster‐randomised controlled trials if the available data have been adjusted (or could be adjusted) to account for the clustering, however there were no cluster‐randomised controlled trials identified for inclusion.

Dealing with missing data

We contacted investigators in order to verify key study characteristics including methods of randomisation, and obtained missing numerical outcome data where possible (e.g. when we identified a study as an abstract only). Where this was not possible, and the missing data were thought to introduce serious bias, we took this into consideration in the GRADE rating for affected outcomes. We planned to only meta‐analyse data from cluster‐RCTs if the available data had been adjusted (or could be adjusted), to account for the clustering.

Assessment of heterogeneity

For pooled analyses we quantified statistical heterogeneity using the I2 statistic, which describes the percentage of total variation across trials due to heterogeneity rather than to sampling error. We considered significant statistical heterogeneity to be present if the I2 is greater than 50%. Where we identified significant heterogeneity, we attempted to explore possible causes using prespecified subgroup analyses.

Assessment of reporting biases

Where sufficient studies were present, we planned to create and examine a funnel plot to explore small‐study and publication biases; however, there are currently insufficient studies.

Data synthesis

We used a fixed‐effects model and performed a sensitivity analysis comparing the fixed‐ and random‐effects model. Where possible we pooled dichotomous outcome variables using a Mantel‐Haenszel OR with 95% CIs. For continuous outcomes, we analysed data as MDs or standardised mean difference (SMD) where scales are combined, with the 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) from the pooled OR and assumed control risk using the formula described in Section 12.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

'Summary of findings' table

We created seven 'Summary of findings' tables that include WHO functional class status, quality of life, mortality, change in haemodynamics, and six‐minute walk distance. We used the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data for the prespecified outcomes. We used the methods and recommendations described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Schüneman 2017), employing GRADEpro software (GRADEpro GDT). We justified all decisions to downgrade the quality of studies using footnotes, and made comments to aid the reader's understanding of the review where necessary.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses:

  1. Paediatric population up to 18 years and an adult population aged 18 years or over.

  2. Dosage of PDE5 inhibitor.

  3. Mode of administration.

With the following outcomes in subgroup analyses:

  1. WHO functional class.

  2. Mortality.

  3. Six‐minute walk distance.

  4. Haemodynamic criteria.

However, there were insufficient studies per comparison to perform meta‐analyses for these subgroups, so we present narrative results (described in‐text where applicable).

Sensitivity analysis

We planned to carry out the following sensitivity analyses:

  • Exclusion of trials identified as being at high risk of selection bias (described in‐text where applicable).

  • Fixed‐effect model compared with random‐effects model (presented in table form).

Results

Description of studies

Results of the search

We identified 4840 citations in the initial search, and after screening abstracts, selected 136 studies for full‐text review. We included 36 trials with 2999 participants in the final review, plus earlier published abstracts, further post hoc analyses and analyses of secondary outcomes (see Figure 1). We also found five ongoing studies (see Characteristics of ongoing studies).

Figure 1
Study flow diagram.

Study flow diagram.

Included studies

Group 1: Pulmonary arterial hypertension

We included all but two of the 36 studies in the final meta‐analysis; Jalalian 2015 included participants with pulmonary hypertension secondary to sickle cell disease, and Machado 2009 included participants with pulmonary hypertension secondary to beta‐thalassemia, and was stopped early due to increased adverse events in the treatment arm. All studies were randomised; 30 were parallel‐controlled and six were cross‐over trials.

Nineteen trials included group 1 PAH participants (Albini 2017; Bharani 2003; Bharani 2007; Boonstra 2005; Galiè 2005a; Galiè 2009; Galiè 2015; Iversen 2009 (specifically Eisenmenger's syndrome); Jing 2011; Mazzanti 2013; Mukhopadhyay 2011; (Barst 2012; Palii 2014 ‐ specifically children with PAH); Sastry 2004; Simonneau 2008; Singh 2006; Vizza 2017a; Wilkins 2005; Zhuang 2014). Most trials recruited participants with WHO functional class II and III (see Characteristics of included studies).

Eleven trials in PAH participants compared a PDE5 inhibitor to placebo: seven trials compared sildenafil to placebo (Barst 2012; Bharani 2003; Boonstra 2005; Galiè 2005a; Palii 2014; Sastry 2004; Singh 2006), three compared tadalafil to placebo (Bharani 2007; Galiè 2009; Mukhopadhyay 2011), and one compared vardenafil to placebo (Jing 2011).

Four studies compared PDE5 inhibitors to placebo, whilst on additional combination therapy (all as add‐on therapy) (Iversen 2009; Simonneau 2008; Vizza 2017a; Zhuang 2014), and four studies (Albini 2017; Galiè 2015; Mazzanti 2013; Wilkins 2005) compared PDE5 inhibitors to endothelin receptor antagonists.

In the PAH trials, sildenafil was prescribed in eight hourly divided doses, with dosages ranging from 20 to 100 mg three times daily. Where multiple doses were compared, we used results from the highest dose where appropriate (e.g. haemodynamics), and aggregated doses where appropriate (e.g. mortality). Tadalafil was dosed 2.5 to 40 mg daily and vardenafil 5 mg twice daily. The duration of trials ranged from two weeks to 12 months, with a mean treatment duration of 14 weeks.

In PAH participants, the primary outcomes of six‐minute walk distance (6MWD) was reported in 15 trials (Albini 2017; Bharani 2003; Bharani 2007; Boonstra 2005; Galiè 2005a; Galiè 2009; Iversen 2009; Jing 2011; Mukhopadhyay 2011; Palii 2014; Sastry 2004; Simonneau 2008; Singh 2006; Vizza 2017a; Zhuang 2014), WHO functional class improvement in seven of 19 trials (Bharani 2007; Galiè 2005a; Galiè 2015; Jing 2011; Mukhopadhyay 2011; Vizza 2017a; Zhuang 2014), and mortality in 13 of 19 trials (Barst 2012; Bharani 2003; Bharani 2007; Galiè 2005a; Galiè 2009; Galiè 2015; Jing 2011; Palii 2014; Sastry 2004; Simonneau 2008; Wilkins 2005; Vizza 2017a; Zhuang 2014). Haemodynamic data were reported in 12 of 19 trials (Albini 2017; Barst 2012; Bharani 2003; Bharani 2007; Galiè 2005a; Iversen 2009; Jing 2011; Mukhopadhyay 2011; Sastry 2004; Simonneau 2008; Singh 2006; Zhuang 2014), For quality of life, two trials used the SF‐36 form (scores 1 to 100, higher scores indicate better quality of life) (Galiè 2005a; Simonneau 2008); minimum clinical improvement difference (MCID) for physical functioning domain for PAH = 13, vitality = 15 (Gilbert 2009). One used a heart failure questionnaire (Sastry 2004), where the higher the score the better the quality of life, and one (Wilkins 2005) used the Kansas City Cardiomyopathy Questionnaire, where higher scores indicated better quality of life. Six trials measured dyspnoea using the Borg dyspnoea scale (MCID for PAH = 1 (Khair 2016)) (Bharani 2003; Bharani 2007; Galiè 2005a; Jing 2011; Sastry 2004; Vizza 2017a). Eleven studies reported adverse events (Albini 2017; Galiè 2005a; Galiè 2009; Galiè 2015; Iversen 2009; Jing 2011; Mukhopadhyay 2011; Sastry 2004; Simonneau 2008; Vizza 2017a; Zhuang 2014).

Group 2: Pulmonary hypertension due to left‐heart disease

Five trials included PH secondary to left‐heart disease (Bermejo 2017 (valvular heart disease); Guazzi 2011a (HFpEF); Hoendermis 2015 (HFpEF); Lewis 2007 (systolic heart failure); Ovchinnov 2015 (diastolic heart failure)). Heart failure was reported as optimally treated according to accepted guidelines at the time of enrolment. All five trials used sildenafil 25 to 75 mg three times daily compared to placebo. Three trials had a 12‐week duration, one trial was for six months (Bermejo 2017), and one trial (Guazzi 2011a) had a 12‐month duration. In terms of primary outcomes, three of the five reported improvement in WHO functional class (Bermejo 2017; Hoendermis 2015; Lewis 2007), three of the five reported 6MWD (Bermejo 2017; Lewis 2007; Ovchinnov 2015), and three of the five reported mortality (Bermejo 2017; Hoendermis 2015; Lewis 2007). Haemodynamic data were assessed using right‐heart catheterisation in three of the five trials (Guazzi 2011a; Hoendermis 2015; Lewis 2007), and pulmonary artery systolic pressure (PASP) using transthoracic ultrasound in one trial (Bermejo 2017). Quality of life was reported in one trial (Hoendermis 2015) using the Kansas City Cardiomyopathy Questionnaire (23 items, a higher score indicating better quality of life), and one trial (Guazzi 2011a) reported dyspnoea. Two trials reported adverse events, including exacerbation of heart failure (Bermejo 2017; Guazzi 2011a).

Group 3: Pulmonary hypertension due to lung disease

Five trials included PH secondary to lung disease, predominantly that of COPD (Blanco 2013; Goudie 2014; Rao 2011; Vitulo 2016), and one with IPF (Han 2013). The duration was 12 to 16 weeks (median 12 weeks). Four compared sildenafil to placebo (Blanco 2013; Han 2013; Rao 2011; Vitulo 2016) and one (Goudie 2014) compared tadalafil to placebo. The primary outcomes of improvement in WHO functional class were reported in only one trial (Rao 2011); 6MWD in all five trials, and no trials reported mortality. Only two trials (Rao 2011; Vitulo 2016) reported haemodynamic data. Blanco 2013 reported quality of life using SFGRQ (although this was reported using median and IQR) and SF‐36. Goudie 2014 reported SF‐36 and Minnesota Questionnaire. Vitulo 2016 reported SF‐36 and BODE index. No trials reported dyspnoea. Three trials reported adverse events, although insufficient data were provided to produce a meta‐analysis.

Group 4: Chronic thromboembolic pulmonary hypertension

Three trials included CTEPH participants (Galiè 2016a; Palazzini 2010; Suntharalingham 2008). All trials used sildenafil, with two (Palazzini 2010; Suntharalingham 2008) comparing to placebo, and Galiè 2016a comparing to bosentan. Trial duration was a mean of 3.5 months. Improvement in functional class was reported in one study, 6MWD in all three studies, mortality in all three studies, and haemodynamic data in all three studies. One study (Suntharalingham 2008) measured quality of life using the CAMPHOR scale (higher scores indicate worse quality of life), and also reported dyspnoea using the Borg scale. Only one study reported adverse events.

Mixed group 2 to 4 pulmonary hypertension

Two trials enrolled participants with PH across WHO Groups 2 and 3 (Dwivedi 2015; Salem 2013), including participants with secondary pulmonary hypertension due to COPD, heart failure, valvular heart disease, and cardiomyopathy. Sildenafil 20 to 50 mg three times daily was compared to placebo. Only improvement in functional class, 6MWD, and PASP were reported.

Group 5: Haematological disorders

Two trials included participants with PH secondary to haematological disorders (Machado 2009 (sickle cell disease); Jalalian 2015 (beta‐thalassemia)). We analysed these trials descriptively and separately.

Excluded studies

We excluded 65 studies for the following reasons: ineligible participant population (6); ineligible intervention (13); ineligible study design (22); extension of a previous study (9); post‐hoc analysis (15) (see Characteristics of excluded studies).

Risk of bias in included studies

We assessed the risks of bias in the included studies using the Cochrane 'Risk of bias' assessment tool (Higgins 2017), and included the domains of allocation, blinding, incomplete outcome data, selective reporting, and other potential sources of bias. Please see Figure 2 for a summary of the 'Risk of bias' findings.

Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We assessed random sequence generation as low risk for 23 studies. Albini 2017; Bharani 2003; Bharani 2007; Boonstra 2005; Galiè 2016a; Jalalian 2015; Machado 2009; Mazzanti 2013; Mukhopadhyay 2011; Ovchinnov 2015; Palii 2014; Suntharalingham 2008; Zhuang 2014 were at unclear risk, as they did not report methods of random sequence generation.

We assessed allocation concealment as low risk for 26 studies and unclear risk for Albini 2017; Barst 2012; Bharani 2003; Bharani 2007; Boonstra 2005; Dwivedi 2015; Galiè 2016a; Palazzini 2010, as allocation concealment was not reported. We assessed Mazzanti 2013 and Ovchinnov 2015 as high risk, as each study was reported as an open‐label study.

Blinding

We assessed Bharani 2003; Bharani 2007; Blanco 2013; Boonstra 2005; Galiè 2016a; Palazzini 2010; Palii 2014; Rao 2011; Salem 2013; Suntharalingham 2008; Vitulo 2016 as being at unclear risk, as blinding of participants and personnel was not clearly reported. Ovchinnov 2015 and Mazzanti 2013 were assessed as being at high risk as the trials were reported as open‐label studies, so it was likely that participants knew which intervention they were receiving.

We assessed Albini 2017; Bharani 2003; Bharani 2007; Blanco 2013; Boonstra 2005; Dwivedi 2015; Galiè 2016a; Jalalian 2015; Mukhopadhyay 2011; Ovchinnov 2015; Palazzini 2010; Palii 2014; Rao 2011; Salem 2013; Suntharalingham 2008; Vitulo 2016; Zhuang 2014 as being at unclear risk of detection bias, as methods for blinding of outcomes were not clearly reported. We assessed Mazzanti 2013 as being at high risk, as this trial was reported as open‐label and there were no specified methods to keep outcomes blinded from assessors.

Incomplete outcome data

We assessed attrition bias as unclear risk in 15 studies: Albini 2017; Bharani 2007; Galiè 2005a; Galiè 2009; Galiè 2016a; Goudie 2014; Han 2013; Lewis 2007; Mukhopadhyay 2011; Palii 2014; Salem 2013; Sastry 2004; Simonneau 2008; Singh 2006; Suntharalingham 2008, given that only a proportion of participants who were enrolled completed the study, for reasons which were not given; however, this included both intervention and comparator arms in approximately equal proportions.

For Boonstra 2005 and Dwivedi 2015, about one‐third of enrolled participants did not complete the study, for unknown reasons, so we assigned this a high risk of bias. For Ovchinnov 2015, the number of enrolled participants and the number of completers were not reported, so we rated this at high risk.

Selective reporting

We found reporting bias to be high risk in Boonstra 2005, as only one outcome was reported. Han 2013 was a substudy of the STEP‐IPF trial, and it is not clear if this analysis was planned a priori so we assessed it as high risk. Ovchinnov 2015 only reported quantitative data from the intervention group and not from the comparator group, and no between‐group effect sizes were reported, so we rated it at high risk. Simonneau 2008 reported that they only assessed secondary outcomes if the primary outcomes were significant, although it is unclear if this affected the overall reporting of the trial outcomes, as a number of secondary outcomes were reported; we assessed this as high risk of bias.

Other potential sources of bias

We assessed Albini 2017; Boonstra 2005; Galiè 2016a; Ovchinnov 2015; Palazzini 2010; and Palii 2014 as unclear risk of other bias, as these were abstracts from conference proceedings, and were not recorded in any clinical trials registry, with limited information about methods used and limited data presented to determine if other significant risk was present.

Effects of interventions

See: Summary of findings for the main comparison Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo; Summary of findings 2 Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy; Summary of findings 3 Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to ERA; Summary of findings 4 Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo; Summary of findings 5 Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo; Summary of findings 6 Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo; Summary of findings 7 Mixed Pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo

Group 1: Pulmonary arterial hypertension

PDE5 inhibitors compared to placebo
Change in WHO functional class

Four studies assessed change in WHO functional class (Comparison 1). There was a significant improvement in WHO functional class favouring PDE5 inhibitors when compared to placebo, (odds ratio (OR) 8.59, 95% CI 3.95 to 18.72; P < 0.001; 4 trials, 282 participants; I2 = 0%; Analysis 1.1; see Figure 3).

Figure 3
Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.1 Improvement in WHO functional class.

Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.1 Improvement in WHO functional class.

Six‐minute walk distance

Eight studies assessed 6MWD. There was a significant improvement in 6MWD using PDE5 inhibitors compared to placebo (mean difference between PDE5i and placebo (MD) 48 metres, 95% CI 40 to 56; P <0.001; 8 trials, 880 participants; Analysis 1.2). The effect was clinically significant, with a mean difference of 48 metres (MCID in PAH is 41 metres (Gilbert 2009)). The effect on 6MWD was comparable between drugs (sildenafil MD 57 metres, 95% CI 44 to 69; P < 0.001; 4 trials, 339 participants; tadalafil MD 38 metres, 95% CI 28 to 49; P < 0.001; 3 trials, 477 participants; vardenafil MD 69 metres, 95% CI 41 to 97; P < 0.001; 1 trial, 64 participants). There was significant heterogeneity between trials (I2 = 71; P = 0.03), which is not fully explained by the different drugs used in each trial (subgroup difference I2 = 51%; P = 0.03).

Mortality

There was a significant effect on mortality using PDE5 inhibitors compared to placebo (OR 0.22, 95% CI 0.07 to 0.68, P = 0.009; 8 trials, 1119 participants; Analysis 1.3; see Figure 4). In the placebo group four people out of 100 died, compared to one (95% CI 0 to 3) out of 100 for the PDE5 inhibitor group; see Figure 5. The number needed to treat to prevent one additional death was 32 (95% CI 27 to 78).

Figure 4
Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.3 Mortality.

Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.3 Mortality.

Figure 5
Cates Plot for mortality with PDE5 inhibitor treatment in Group 1 PAH

Cates Plot for mortality with PDE5 inhibitor treatment in Group 1 PAH

Haemodynamics

There was a significant reduction in the mean PAP (MD −6.43 mmHg, 95% CI −8.13 to −4.74; P < 0.001; 6 trials, 453 participants; Analysis 1.4), in the right arterial pressure (RAP) (MD −1.35 mmHg, 95% CI −2.34 to −0.36; P = 0.008; 3 trials, 341 participants; Analysis 1.5), in cardiac index (MD 0.28 L/min/m2, 95% CI 0.16 to 0.40; P < 0.001; 4 trials, 239 participants; Analysis 1.6), in PVR (MD −4.74 WU, 95% CI −6.13 to −3.35; P < 0.0001; 3 trials, 266 participants; Analysis 1.7), and in PASP (MD −11.62 mmHg, 95% CI −25.18 to 1.94; P = 0.09; 2 trials, 48 participants; Analysis 1.8). There was significant heterogeneity between trials for mean PAP (I2 = 76%; P = 0.01). However, the test for subgroup difference was not significant (P = 0.23; I2 = 31%), suggesting that factors other than different drugs across trials may account for this heterogeneity. There was also significant heterogeneity for cardiac index (I2 = 77%; P = 0.005). The test for subgroup difference (P = 0.03; I2 = 82%) indicated that the difference between different drugs used may account for this heterogeneity.

Exercise capacity other than six‐minute walk distance

Two studies assessed exercise capacity. Sastry 2004 examined time on treadmill (using the Naughton protocol) and found a statistically significant difference favouring sildenafil with post‐treatment sildenafil 686.82 metres (SD 224.02) compared to placebo 475.05 metres (SD 168.02; P < 0.001). Singh 2006 assessed Mets achieved using a modified Bruce exercise protocol. There was a statistically significant difference favouring sildenafil post‐treatment 687 seconds (SD 243.9 sec) compared to placebo 452.1 seconds (SD 165.6 sec) (P < 0.001).

Quality of life

Only two studies assessed quality of life, and data were considered too heterogenous to combine in a meta‐analysis. Galiè 2005a assessed quality of life using two measures: the Medical Outcomes Study 36‐item short form (SF‐36), divided into physical functioning, general health, and vitality domains (scores 1 to 100, higher scores indicate better quality of life), and found a statistically significant improvement in all SF‐36 domains for sildenafil‐treated participants, and when compared to placebo in physical functioning (P < 0.001), general health (P < 0.001), and vitality (P < 0.05). There was also a statistically significant improvement in placebo‐treated participants in the physical functioning domain. They also used the EuroQol 5D (EQ‐5D) questionnaires at baseline and after 12 and 24 weeks of treatment (comprise five dimensions: mobility, self‐care, usual activities, pain/discomfort and anxiety/depression; higher scores indicate worse quality of life). Statistically significant improvements were also observed for the EQ‐5D current health status (P < 0.01) and utility index (P < 0.01).

Sastry 2004 assessed quality of life using a chronic heart failure questionnaire, includes the following domains: dyspnoea, fatigue, and emotional function of daily living; lower scores indicate worse quality of life. There was a statistically significant difference in the fatigue domain (sildenafil post‐treatment score 22.33, SD 4.82 compared to placebo post‐treatment score 20.67, SD 5.19; P = 0.04), and a statistically non‐significant difference in the emotional function domain (sildenafil post‐treatment score 37.33, SD 9.3, compared to placebo post‐treatment score 34.71, SD 10.91; P = 0.06), favouring sildenafil compared with placebo.

Dyspnoea

Five trials assessed dyspnoea: four (Bharani 2003; Bharani 2007; Galiè 2005a; Jing 2011) used the Borg scale and one (Sastry 2004) used a chronic heart failure questionnaire. When we combined the studies using Borg scale, there was a statistically significant improvement in dyspnoea (MD −0.72, 95% CI −0.99 to −0.44; P < 0.001; 4 studies, 239 participants; Analysis 1.9), but the effect size did not meet the minimum clinical improvement difference (MCID = 1, Khair 2016). There was significant heterogeneity across trials (I2 = 64%; P = 0.04), but the test for subgroup differences (I2 = 37%; P = 0.20) suggests that factors other than different drugs may account for differences across the trials.

Hospitalisation/intervention

Three trials (746 participants) reported clinical worsening requiring intervention, including hospitalisation and initiation or addition of new therapy. There was no statistically significant difference, although the effect estimate favoured PDE5 inhibitors compared to placebo (OR 0.58, 95% CI 0.27 to 1.23; P = 0.16; Analysis 1.10).

Adverse events

There were more adverse events in the PDE5 inhibitor participants compared to placebo (Analysis 1.11).

There was a statistically significant increase in headache (OR 1.97, 95% CI 1.33 to 2.92; P < 0.001; 5 studies, 848 participants), in gastrointestinal (GI) upset (OR 1.63, 95% CI 1.07 to 2.48; P = 0.02; 5 studies, 848 participants), in flushing (OR 4.12, 95% CI 1.83 to 9.26; P < 0.001; 3 studies, 748 participants), and in muscle aches and joint pains (OR 2.52, 95% CI 1.59 to 3.99; P < 0.001; 4 studies, 792 participants).

There was no statistically significant difference in epistaxis (OR 2.37, 95% CI 0.83 to 6.77; P = 0.11; 2 studies, 682 participants), in respiratory symptoms (OR 1.74, 95% CI 0.89 to 3.40; P = 0.10; 3 studies, 748 participants), or in visual disturbance (OR 2.04, 95% CI 0.58 to 7.14; P = 0.27; 3 studies, 748 participants).

Although different formulation of drugs were not compared head‐to‐head, when comparing the odds of developing an adverse event, tadalafil appeared to cause greater frequency of headaches (OR 2.86, 95% CI 1.51 to 5.42; P = 0.001) compared to sildenafil (OR 1.43, 95% CI 0.83 to 2.44; P = 0.20), greater GI upset (OR 1.93, 95% CI 1.07 to 3.50; P = 0.03) compared to sildenafil (OR 1.50, 95% CI 0.81 to 2.78; P = 0.19), and greater frequency of muscle and joint pains (OR 4.02, 95% CI 2.05 to 7.89; P < 0.001) compared to sildenafil (OR 1.48, 95% CI 0.93 to 2.99; P = 0.27).

Subgroup analyses

There were no individual patient data to compare outcomes for a paediatric population versus an adult population. Palii 2014 recruited only children with PAH due to congenital cardiac shunts and found benefit in improvement in functional class, mortality (5 of 39 died at 6 to 12 months in the placebo group compared to none of 38 in the sildenafil group), improved exercise tolerance, and improved haemodynamics. Barst 2012 recruited only children with pulmonary arterial hypertension, and found no significant difference in terms of exercise duration or cardiopulmonary haemodynamics.

Almost all trials included participants with WHO functional class II/III. Boonstra 2005 compared participants with WHO FC I/II and III/IV and found that the six‐minute walk distance improved in both groups (49 metres improvement in WHO FC I/II (n = 27) and 54 metres improvement in WHO FC III/IV (n = 42)).

PDE5 inhibitors compared to placebo on additional therapy

Four trials compared PDE5 inhibitors to placebo, whilst on other therapy for pulmonary hypertension (Comparison 2). Iversen 2009 and Vizza 2017a compared sildenafil to placebo as add‐on therapy to bosentan. Simonneau 2008 compared sildenafil to placebo as add‐on therapy to intravenous epoprostenol. Zhuang 2014 compared tadalafil to placebo as add‐on therapy to ambrisentan.

Change in WHO functional class

There was no significant difference in WHO functional class (OR 1.20, 95% CI 0.66 to 2.17; P = 0.55; 2 trials, 227 participants; Analysis 2.1).

Six‐minute walk distance

There was a statistically significant difference in 6MWD using PDE5 inhibitors compared to placebo as add‐on therapy (MD 20, 95% CI 9 to 30; P < 0.001; 4 trials, 509 participants; Analysis 2.2), but this did not meet the MCID threshold (41 metres; Gilbert 2009).

Mortality

There was no statistically significant difference in mortality using PDE5 inhibitors compared to placebo as add‐on therapy (OR 0.26, 95% CI 0.07 to 1.06; P = 0.06; 3 trials, 492 participants; Analysis 2.3).

Haemodynamics

There was a statistically significant reduction in mean PAP (MD −4.58 mmHg, 95% CI −6.14 to −3.01; P < 0.001; 2 trials, 387 participants; Analysis 2.4), and in PVR (SMD −0.48, 95% CI −0.72 to −0.25; P > 0.001; 3 trials, 303 participants; Analysis 2.6) and a statistically significant increase in cardiac output (MD 0.87 L/min, 95% CI 0.53 to 1.21; P < 0.001; 3 trials, 310 participants; Analysis 2.5) using sildenafil compared to placebo as add‐on therapy.

Exercise capacity other than six‐minute walk distance

No studies reported additional exercise testing.

Quality of life

One trial (Simonneau 2008) assessed quality of life using SF‐36. There was a significant improvement in the sildenafil group in terms of physical functioning (MD 0.3, 95% CI 4.7 to 4.1 for placebo versus MD 7.8, 95% CI 3.6 to 12.1 for sildenafil; P = 0.003), general health (MD 1.4, 95% CI 4.8 to 2.1 versus MD 6.6, 95% CI 3.3 to 9.9; P = 0.001), vitality (MD 0.8, 95% CI 3.3 to 4.9 versus MD 10.2, 95% CI 6.2 to 14.2; P = 0.001), social functioning (MD 2.5, 95% CI 7.8 to 2.9 versus MD 4.0, 95% CI 1.1 to 9.2; P = 0.05), and mental health (MD 3.7, 95% CI 7.0 to 0.5 versus MD 3.0, 95% CI 0.1 to 6.2; P = 0.001), but not in physical role (MD 3.6, 95% CI 5.4 to 12.7 versus MD 10.7, 95% CI 2.0 to 19.4; P = 0.20), bodily pain (MD 0.6, 95% CI 4.3 to 5.5 versus MD 5.8, 95% CI 1.0 to 10.6; P = 0.09), or emotional role (MD 4.6, 95% CI 4.2 to 13.5 versus MD 1.8, 95% CI 6.8 to 10.3; P = 0.60).

Dyspnoea

No studies assessed the effect on dyspnoea.

Hospitalisation/intervention

Four studies assessed clinical worsening requiring hospitalisation or additional therapy. There was a statistically significant difference favouring PDE5 inhibitors compared to placebo as add‐on therapy (OR 0.38, 95% CI 0.21 to 0.68; P = 0.001; 4 trials, 717 participants; Analysis 2.7).

Adverse events

There was a statistically significant increased risk of headache (OR 2.49, 95% CI 1.74 to 3.56; P < 0.001; 5 studies, 768 participants), GI upset (OR 1.95, 95% CI 1.30 to 2.93; P = 0.001; 4 studies, 726 participants), muscle and joint pain (OR 2.17, 95% CI 1.28 to 3.67; P = 0.004; 3 studies, 494 participants), and visual disturbance (OR 3.95, 95% CI 0.97 to 16.08; P = 0.06; 2 studies, 368 participants). There was no statistically significant difference in flushing (OR 1.11, 95% CI 0.63 to 1.96; P = 0.71; 2 studies, 368 participants) or epistaxis (OR 1.32, 95% CI 0.34 to 5.12; P = 0.69; 2 studies, 358 participants) Analysis 2.8.

PDE5 inhibitors compared to endothelin receptor antagonists (ERA)

Three trials compared PDE5 inhibitors head‐to‐head with an endothelin receptor antagonist (Comparison 3): Albini 2017 compared monotherapy (ambrisentan or tadalafil) with combination therapy; for the purpose of this meta‐analysis ambrisentan was compared to tadalafil. Galiè 2015 compared ambrisentan monotherapy with tadalafil monotherapy with combination therapy; for this meta‐analysis, ambrisentan 10 mg daily monotherapy was compared to tadalafil 40 mg daily monotherapy. Wilkins 2005 compared sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) with bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily).

Change in WHO functional class

There was no significant difference in WHO functional class (OR 0.94, 95% CI 0.55 to 1.60; P = 0.82; 1 trial, 244 participants; Analysis 3.1).

Six‐minute walk distance

There was a statistically and clinically significant difference in 6MWD favouring sildenafil compared to bosentan (MD 49 metres, 95% CI 4 to 95; P = 0.03; 2 trials, 36 participants; Analysis 3.2). As Galiè 2015 reported 6MWD as median and IQR, it was not possible to include it in the meta‐analysis (Higgins 2011). The median change from baseline distance in the tadalafil group was 23 metres (IQR −8 to 66) compared to the ambrisentan group 27 metres (IQR −14 to 63).

Mortality

There was no significant difference in mortality comparing PDE5 inhibitors to ERA (OR 3.19, 95% CI 0.74 to 13.64; P = 0.12; 2 trials, 272 participants; Analysis 3.3).

Haemodynamics

There was no significant difference in haemodynamics in one small study (32 participants), including mean PAP (MD 7.00, 95% CI −4.82 to 18.82; P = 0.25), RAP (MD 2.00, 95% CI −2.14 to 6.14; P = 0.34), cardiac index (MD 0.00, 95% CI −0.49 to 0.49; P = 1.00), and PVR (MD 0.00, 95% CI −1.93 to 1.93; P = 1.00). Wilkins 2005 assessed participants using cardiac magnetic resonance imaging (MRI) and found no significant difference in cardiac index (MD 0 L/min/m2, 95% CI −0.2 to 0.2).

Exercise capacity other than six‐minute walk distance

No studies reported additional exercise testing.

Quality of life

One study (Wilkins 2005) found a significant difference in quality of life favouring sildenafil compared to bosentan using the Kansas City Cardiomyopathy Quality‐of‐Life questionnaire (higher scores indicate better quality of life) (MD 22.00, 95% CI 9.00 to 35.00; P = 0.009).

Dyspnoea

No studies assessed dyspnoea.

Hospitalisation/intervention

There was a statistically significant incidence of clinical worsening in the ERA group compared to the PDE5 inhibitor group (OR 0.52, 95% CI 0.30 to 0.89; P = 0.02; 2 trials, 275 participants; Analysis 3.9).

Adverse events

Only one trial assessed adverse events (Analysis 3.10). There was no significant difference in headache (OR 1.10, 95% CI 0.65 to 1.87; P = 0.72), GI upset (OR 0.79, 95% CI 0.42 to 1.45; P = 0.44), flushing (OR 0.60, 95% CI 0.27 to 1.33; P = 0.21), muscle or joint pain (OR 1.34, 95% CI 0.60 to 3.00; P = 0.47), or respiratory symptoms (OR 0.80, 95% CI 0.47 to 1.35; P = 0.40).

Group 2: Pulmonary hypertension due to left‐heart disease

Five trials assessed participants with pulmonary hypertension secondary to left‐heart disease (Comparison 4). All trials compared sildenafil with placebo.

Change in WHO functional class

Significantly fewer people receiving sildenafil improved in WHO functional class compared to placebo (OR 0.53, 95% CI 0.32 to 0.87; P = 0.01; 3 trials, 285 participants; Analysis 4.1), although there was considerable heterogeneity between trials (I2 = 67%, P = 0.05).

Six‐minute walk distance

Three studies assessed the 6MWD. There was a significant difference favouring sildenafil (MD 34 metres, 95% CI 23 to 46; P < 0.001; 3 studies, 284 participants; Analysis 4.2; see Figure 6).

Figure 6
Forest plot of comparison: 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), outcome: 4.2 Six‐minute walk distance.

Forest plot of comparison: 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), outcome: 4.2 Six‐minute walk distance.

Mortality

Three studies assessed mortality. There was no significant difference between sildenafil and placebo (OR 1.27, 95% CI 0.28 to 5.80; P = 0.76; 3 trials, 286 participants; Analysis 4.3).

Haemodynamics

There was a significant reduction in mean PAP (MD −10.17 mmHg, 95% CI −11.99 to −8.35; P < 0.001, although with significant heterogeneity (I2 = 98%, P < 0.001); 3 trials, 130 participants; Analysis 4.4), transpulmonary pressure gradient (TPG) (MD −14.60 mmHg, 95% CI −15.63 to −13.57; P < 0.001; 1 trial, 44 participants; Analysis 4.6), and PASP (MD −27.60 mmHg, 95% CI −30.37 to −24.83; P < 0.001; 1 trial, 44 participants; Analysis 4.8) using sildenafil compared to placebo. There was no significant difference in cardiac index (MD 0.07 L/min/m2, 95% CI −0.17 to 0.30; P = 0.59; 2 trials, 96 participants; Analysis 4.5) or RAP (MD −1.00 mmHg, 95% CI −3.77 to 1.77; P = 0.48; 1 trial, 34 participants; Analysis 4.7). Bermejo 2017 reported results in median and IQR so we could not combine the data in the meta‐analysis, but there was no significant difference in haemodynamic parameters measured by Doppler echocardiography or magnetic resonance.

Exercise capacity other than six‐minute walk distance

Two studies reported exercise capacity testing. Hoendermis 2015 reported no significant difference in VO2 peak (treatment effect sildenafil MD 0.2 mL/kg/min‐1 (95% CI ‐0.9 to 1.4) compared to placebo MD 0.70 mL/kg/min‐1 (95% CI −0.3 to 1.6); P = 0.51). Lewis 2007 reported a statistically significant difference in VO2 peak favouring sildenafil (post‐treatment sildenafil MD 1.8 ± 0.7 mL/kg/min‐1 compared to placebo MD 0.27 mL/kg/min‐1; P = 0.02).

Quality of life

One study (Hoendermis 2015) assessed quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ: higher scores reflect better health status). The mean change in the KCCQ clinical summary score from baseline to 12 weeks was 12.05 points higher (95% CI 1.14 to 22.96) in the sildenafil group and 19.83 points higher (95% CI 8.23 to 31.44) in the placebo group, although the difference was not significant (P = 0.32).

Dyspnoea

One study (Guazzi 2011a) assessed dyspnoea using the 16‐item Chronic Heart Failure Questionnaire (CHQ) (Guyatt 1989). There was a significant improvement in dyspnoea using sildenafil compared to placebo (MD 1.15, 95% CI 0.51 to 1.79; P < 0.001; 1 trial, 44 participants; Analysis 4.9).

Hospitalisation/intervention

There were mixed results in terms of clinical worsening requiring intervention including hospitalisation. Lewis 2007 (PH with systolic dysfunction) reported no significant difference in clinical worsening (OR 0.32, 95% CI 0.05 to 1.95; P = 0.22; 34 participants; Analysis 4.10), but Bermejo 2017 (valvular heart disease) reported an increased risk of hospitalisations, particularly relating to heart failure in those treated with sildenafil compared to placebo (OR 1.43; 95% CI 0.76 to 2.70; P = 0.05; 200 participants).

Adverse events

Three studies reported adverse events. In Lewis 2007 the incidence of headache occurred more commonly in those treated with sildenafil compared to placebo (1 trial; P < 0.05) but there was no significant difference in terms of arrhythmias, hypotension, diarrhoea, flushing, or myalgia, and no incidence of visual disturbance. Hoendermis 2015 reported that adverse events occurred in 22 participants (85%) who received sildenafil and 21 participants (81%) who received placebo (P = 1.00). Prevalence of known adverse effects of sildenafil, such as headache, dyspepsia, (orthostatic) hypotension, increased erection and respiratory tract infection, were reported to be higher in the sildenafil group, but event data were not supplied. Bermejo 2017 reported an increased risk of gastrointestinal events (OR 2.82, 95% CI 0.91 to 10.41; P = 0.06), and infections (OR 0.22, 95% 0.02 to 1.13; P = 0.05).

Group 3: Pulmonary hypertension due to lung disease

Five trials included participants with pulmonary hypertension secondary to lung disease or hypoxaemia; in four trials this was secondary to COPD, and in one trial secondary to IPF (Comparison 5) (Han 2013) . Four trials compared sildenafil to placebo, and one trial (Goudie 2014) compared tadalafil to placebo.

Change in WHO functional class

One trial assessed improvement in WHO functional class, and found a statically significant improvement using sildenafil compared with placebo (OR 44.33, 95% CI 4.78 to 410.93; P < 0.001; 40 participants; Analysis 5.1).

Six‐minute walk distance

There was a significant improvement in the 6MWD with the use of sildenafil compared to placebo (MD 27 metres, 95% CI 2 to 51; P < 0.001; 5 trials, 350 participants; Analysis 5.2; see Figure 7).

Figure 7
Forest plot of comparison: 5 Group 3 Pulmonary Hypertension due to lung disease, outcome: 5.2 Six‐minute walk distance.

Forest plot of comparison: 5 Group 3 Pulmonary Hypertension due to lung disease, outcome: 5.2 Six‐minute walk distance.

Mortality

No studies assessed mortality.

Haemodynamics

There was no significant difference in terms of mean PAP (MD −0.14 mmHg, 95% CI −6.65 to 6.37; P = 0.97; 2 trials, 61 participants; Analysis 5.4), cardiac index (MD 0.30 L/min/m2, 95% CI −0.14 to 0.74; P = 0.18; 1 trial, 28 participants; Analysis 5.5), RAP (MD 0.36 mmHg, 95% CI −2.76 to 3.48; P = 0.82; 1 trial, 28 participants; Analysis 5.7) and PVR (MD −1.31 mmHg, 95% CI −3.67 to 1.05; P = 0.28; 1 trial, 28 participants; Analysis 5.6).

Exercise capacity other than six‐minute walk distance

Blanco 2013 reported exercise capacity after three months pulmonary rehabilitation and treatment with sildenafil or placebo. There was no difference in the placebo‐corrected difference in the cycle endurance time: −7 seconds, 90% CI −540 to 244; P = 0.77, or maximal exercise tolerance 1 watt, 90% CI −2 to 5; P = 0.60.

Quality of life

Three studies assessed quality of life. Goudie 2014 used SF‐36 (lower scores indicate worse quality of life), and Vitulo 2016 assessed the BODE index and the Minnesota Questionnaire. Han 2013 used the St George's Respiratory Questionnaire (SGRQ), the EuroQOL, and the SF‐36. We pooled data for the SF‐36 physical function, and demonstrated no significant difference in overall quality of life (MD 0.19, 95% CI −0.07 to 0.44; P = 0.15; 2 trials, 238 participants; Analysis 5.3). Blanco 2013 reported outcomes using mean and IQR, so results could not be pooled in the meta‐analysis. There was no significant difference in SGRQ score (placebo‐corrected difference median 1.3, IQR −3.5 to 6.9, P = 0.53), or SF‐36 physical score (median −1.7, IQR −7.2 to 2.3, P = 0.38), or SF‐36 mental score (median 1.6, IQR −3.7 to 8.5 P = 0.64).

Dyspnoea

No studies assessed dyspnoea.

Hospitalisation/intervention

No studies assessed clinical worsening.

Adverse events

Three trials reported adverse events, but none reported event data that could be pooled in a meta‐analysis. Blanco 2013 reported that adverse events were similar across groups. Rao 2011 reported that headache was the most common side effect with sildenafil. Other adverse effects noted were epigastric pain or discomfort, headache, paraesthesias, and numbness. Vitulo 2016 reported that adverse events were observed in five participants in the sildenafil arm. The events were mild to moderate and included headache, diarrhoea, flushing, limb pain, dyspnoea, myalgia, and peripheral oedema. None interrupted the study treatment because of adverse events. No significant adverse effects were reported in the placebo arm. Two studies reported oxygenation parameters. Vitulo 2016 reported no difference in SpO2 or PaO2 in the sildenafil group from the start to the end of the study. Blanco 2013 reported no significant differences in arterial oxygen tension or saturation between the sildenafil and placebo groups.

Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)

Three trials included CTEPH participants (Galiè 2016a; Palazzini 2010; Suntharalingham 2008; Comparison 6). All trials used sildenafil, two (Palazzini 2010; Suntharalingham 2008) compared to placebo, and Galiè 2016a compared to bosentan.

Change in WHO functional class

Only one trial examined improvement in WHO functional class in CTEPH participants, and found no significant difference in the use of PDE5 inhibitors compared to placebo (OR 17.18, 95% CI 0.78 to 380.84; P = 0.07; 1 trial, 19 participants; Analysis 6.1).

Six‐minute walk distance

There was no significant difference in 6MWD using PDE5 inhibitors when compared to placebo (MD 18 metres, 95% CI −24 to 59; P = 0.41; 1 trial, 19 participants; Analysis 6.2; see Figure 8) or when compared to bosentan (MD 20 metres, 95% CI −28 to 69; P = 0.41; 2 trials, 227 participants).

Figure 8
Forest plot of comparison: 6 Group 4 Pulmonary Hypertension due to CTEPH, outcome: 6.2 Six‐minute walk distance.

Forest plot of comparison: 6 Group 4 Pulmonary Hypertension due to CTEPH, outcome: 6.2 Six‐minute walk distance.

Mortality

There were no deaths in either arm in one trial comparing sildenafil with placebo (20 participants). There was no significant difference in mortality in one trial comparing PDE5 inhibitors to bosentan (OR 1.36, 95% CI 0.22 to 8.48; P = 0.74; 106 participants; Analysis 6.3).

Haemodynamics

There was no difference in haemodynamic parameters. There was no difference in mean PAP using PDE5 inhibitors when compared to placebo (MD −6.20 mmHg, 95% CI −12.40 to −0.00; P = 0.05; 1 trial, 19 participants; Analysis 6.4) or when compared to bosentan (MD 0.76 mmHg, 95% CI −3.96 to 5.48; P = 0.75; 2 trials, 227 participants). There was no difference in cardiac index using PDE5 inhibitors when compared to placebo (MD 0.00 L/min/m2, 95% CI −0.40 to 0.40; P = 1.0; 1 trial, 19 participants; Analysis 6.5) or when compared to bosentan (MD 0.04 L/min/m2, 95% CI −0.22 to 0.31; P = 0.76; 2 trials, 227 participants). There was no difference in PVR using PDE5 inhibitors when compared to placebo (MD −0.89, 95% CI −1.85 to 0.06; P = 0.07; 1 trial, 19 participants; Analysis 6.6) or when compared to bosentan (MD −0.01, 95% CI −0.27 to 0.25; P = 0.96; 2 trials, 227 participants). There was no difference in RAP using PDE5 inhibitors when compared to placebo (MD −0.90 mmHg, 95% CI −6.10 to 4.30; P = 0.73; 1 trial, 19 participants; Analysis 6.7) or when compared to bosentan (MD −1.00 mmHg, 95% CI −3.77 to 1.77; P = 0.48; 1 trial, 121 participants).

Exercise capacity other than six‐minute walk distance

No studies reported exercise capacity testing.

Quality of life

Only one trial examined quality of life, using the CamHOR scale (higher scores indicate worse quality of life). There was no significant difference (MD −0.26, 95% CI −1.17 to 0.64; P = 0.57; 34 participants; Analysis 6.8).

Dyspnoea

No trials assessed dyspnoea.

Hospitaisation/intervention

No trials examined clinical worsening.

Adverse events

There were no significant differences in terms of headache (OR 2.57, 95% CI 0.19 to 34.47; P = 0.48; 19 participants; Analysis 6.9) or GI upset (OR 4.50, 95% CI 0.37 to 54.16; P = 0.24; 19 participants) between PDE5‐inhibitors and placebo in one trial.

Mixed group 2 to 4 pulmonary hypertension

We combined two studies in this meta‐analysis: Salem 2013, which included participants with secondary pulmonary hypertension due to valvular heart disease, chronic thromboembolic disease, COPD, IPF, and idiopathic dilated cardiomyopathy, and Dwivedi 2015, which included participants with symptomatic secondary PAH including idiopathic dilated cardiomyopathy, heart failure with preserved ejection fraction, COPD, and other lung parenchymal disease, and valvular heart disease (Comparison 7).

Change in WHO functional class

There was a significant improvement in WHO functional class favouring PDE5 inhibitors (OR 11.31, 95% CI 4.90 to 26.14; P < 0.001; 2 trials, 146 participants; Analysis 7.1).

Six‐minute walk distance

There was a significant difference in 6MWD in one trial favouring PDE5 inhibitors (MD 51 metres, 95% CI 7 to 95; P=0.02; 106 participants; Analysis 7.2).

Mortality

No trials assessed mortality.

Haemodynamics

There was a significant improvement in PASP (MD −10.00 mmHg, 95% CI −11.92 to −8.08; P < 0.001; 2 trials, 146 participants; Analysis 7.3). No other haemodynamic parameters were measured.

Exercise capacity other than six‐minute walk distance

No studies reported exercise capacity testing.

Quality of life

No trials assessed quality of life.

Dyspnoea

No trials assessed dyspnoea.

Hospitalisation/intervention

No trials assessed clinical worsening.

Adverse events

No trials reported adverse events.

Sensitivity analyses

We planned to use the fixed‐effect model a priori to assess effect sizes. We present a comparison of fixed‐ versus random‐effects in Table 2. Where effect sizes differed, this was explained by high heterogeneity between trials.

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Table 2. Sensitivity analysis: fixed‐effect versus random‐effects

Meta‐analysis

Number of studies

Effect measure

Fixed‐effect size and CI

Random‐effect size and CI

Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo

Improvement in WHO functional class

4

OR

8.59 (3.95 to 18.72)

8.53 (3.90 to 18.67)

Six‐minute walk distance

8

MD

48.17 (40.30 to 56.04)

52.98 (40.74 to 65.23)1

Mortality

7

OR

0.22 (0.07 to 0.68)

0.28 (0.08 to 0.95)

PAP

5

MD

−6.33 (−8.12 to −4.53)

−8.94 (−13.73 to −4.15)

RAP

2

MD

−1.52 (−2.79 to −0.24)

−1.52 (−2.79 to −0.24)

Cardiac index

4

MD

0.28 (0.16 to 0.40)

0.35 (0.08 to 0.61)a

PVR

3

MD

−4.74 (−6.13 to −3.35)

−5.02 (−7.02 to −3.02)

PASP

2

MD

−11.62 (−25.18 to 1.94)

−11.62 (−25.18 to 1.94)

Dypnoea

4

MD

−0.72 (−0.99 to −0.44)

−0.61 (−1.19 to −0.02)

Clinical worsening requiring intervention

3

OR

0.58 (0.27 to 1.23)

0.55 (0.25 to 1.23)

Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo to on combination therapy

Improvement in WHO functional Class

2

OR

1.20 (0.66 to 2.17)

1.09 (0.41 to 2.92)

Six‐minute walk distance

4

MD

19.66 (9.22 to 30.10)

18.94 (0.23 to 37.65)

Mortality

3

OR

0.26 (0.07 to 1.06)

0.38 (0.04 to 3.81)

PAP

2

MD

−4.58 (−6.14 to −3.01)

−5.12 (−8.21 to −2.03)

Cardiac output

2

MD

0.87 (0.53 to 1.21)

0.87 (0.53 to 1.21)

PVR

3

SMD

−0.48 (−0.72 to −0.25)

−0.36 (−0.84 to 0.12)a

Clinical worsening

3

OR

0.34 (0.18 to 0.63)

0.34 (0.18 to 0.63)

Group 1 Pulmonary arterial hypertension ‐ PDE5i versus ERA

Improvement in WHO functional Class

1

OR

0.94 (0.55 to 1.60)

0.94 (0.55 to 1.60)

Six‐minute walk distance

2

MD

49.38 (3.65 to 95.11)

49.38 (3.65 to 95.11)

Mortality

2

OR

3.19 (0.74 to 13.64)

3.19 (0.74 to 13.64)

Quality of life

1

MD

22.00 (9.00 to 35.00)

22.00 (9.00 to 35.00)

PAP

1

MD

7.00 (−4.82 to 18.82)

7.00 (−4.82 to 18.82)

RAP

1

MD

2.00 (−2.14 to 6.14)

2.00 (−2.14 to 6.14)

Cardiac index

1

MD

0.00 (−0.49 to 0.49)

0.00 (−0.49 to 0.49)

PVR

1

MD

0.00 (−1.93 to 1.93)

0.00 (−1.93 to 1.93)

Clinical worsening

2

OR

0.52 (0.30 to 0.89)

0.52 (0.30 to 0.89)

Group 2 Pulmonary hypertension due to left‐heart disease

Improvement in WHO functional Class

3

OR

0.53 (0.32 to 0.87)

0.70 (0.20 to 2.37)

Six‐minute walk distance

3

MD

34.31 (22.75 to 45.87)

28.44 (‐1.82 to 58.69)a

Mortality

3

OR

0.01 (−0.03 to 0.04)

0.01 (−0.03 to 0.04)

Mean PAP

3

MD

−10.17 (−11.99 to −8.35)

−6.58 (−22.28 to 9.12)a

Cardiac index

2

MD

0.07 (−0.17 to 0.30)

0.06 (−0.22 to 0.34)

TPG

1

MD

−14.60 (−15.63 to −13.57)

−14.60 (−15.63 to −13.57)

RAP

1

MD

−1.00 (−3.77 to 1.77)

−1.00 (−3.77 to 1.77)

PASP

1

MD

−27.60 (−30.37 to −24.83)

−27.60 (−30.37 to −24.83)

Dypnoea

1

MD

1.15 (0.51 to 1.79)

1.15 (0.51 to 1.79)

Clinical worsening requiring intervention

2

OR

1.19 (0.66 to 2.14)

0.87 (0.22 to 3.46)

Group 3 Pulmonary hypertension due to lung disease

Improvement in WHO functional Class

1

OR

44.33 (4.78 to 410.93)

44.33 (4.78 to 410.93)

Six‐minute walk distance

5

MD

14.04 (7.05 to 21.02)

26.70 (2.00 to 51.39)1

Mean PAP

2

MD

−0.14 (−6.65 to 6.37)

−0.14 (−6.65 to 6.37)

Cardiac index

1

MD

0.30 (−0.14 to 0.74)

0.30 (−0.14 to 0.74)

PVR

1

MD

−1.31 (−3.67 to 1.05)

−1.31 (−3.67 to 1.05)

RAP

1

MD

0.36 (−2.76 to 3.48)

0.36 (−2.76 to 3.48)

Quality of life

3

MD

0.19 (−0.07 to 0.44)

0.19 (−0.07 to 0.44)

Group 4 Pulmonary hypertension due to CTEPH

Improvement in WHO functional Class

1

OR

17.18 (0.78 to 380.85)

17.18 (0.78 to 380.85)

Six‐minute walk distance

3

MD

18.73 (−12.72 to 50.19)

18.73 (−12.72 to 50.19)

Mortality

2

OR

0.01 (−0.06 to 0.08)

0.01 (−0.06 to 0.08)

Mean PAP

2

MD

−1.79 (−5.55 to 1.96)

−1.67 (−6.48 to 3.15)

Cardiac index

3

MD

0.03 (−0.19 to 0.25)

0.03 (−0.19 to 0.25)

PVR

3

MD

−0.07 (−0.32 to 0.18)

−0.12 (−0.50 to 0.25)

RAP

2

MD

−0.98 (−3.42 to 1.47)

−0.98 (−3.42 to 1.47)

Quality of life

1

MD

−0.26 (−1.17 to 0.64)

−0.26 (−1.17 to 0.64)

Mixed pulmonary hypertension group 2 to 4

Improvement in WHO functional Class

2

OR

11.33 (4.91 to 26.15)

11.33 (4.91 to 26.15)

Six‐minute walk distance

1

MD

50.97 (44.88 to 57.06)

50.97 (44.88 to 57.06)

PASP

2

MD

−10.00 (−11.92 to −8.08)

−10.00 (−11.92 to −8.08)

astatistically high heterogeneity

CI ‐ confidence interval; CTEPH ‐ chronic thromboembolic pulmonary hypertension; OR ‐ odds ratio; MD ‐ mean difference; PAP ‐ pulmonary artery pressure; PASP ‐ pulmonary artery systemic pressure; PDE5i ‐ phosphodiesterase‐5 inhibitor; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure; SMD ‐ standardised mean difference; TPG ‐ transpulmonary gradient; WHO ‐ World Health Organization

Group 5: Haematological disorders

Jalalian 2015 included 44 participants with beta‐thalassaemia intermedia and pulmonary hypertension on transthoracic echocardiogram, and were treated for six weeks with tadalafil (40 mg daily) or placebo. The authors reported a significant improvement in the PASP (post‐treatment tadalafil MD 34.26 mmHg; SE 1.15, compared to post‐treatment placebo MD 44.57 mmHg; SE 0.56; P < 0.001). In the tadalafil group two participants dropped out due to severe headache and one due to severe oedema. Three other participants experienced a mild headache with initiation of tadalafil, which resolved after one week. No deaths occurred after six weeks of this trial.

Machado 2009 included those with pulmonary hypertension secondary to sickle cell disease and tested sildenafil versus placebo. The study was prematurely stopped due to a statistically significant increase in serious adverse events requiring hospitalisation in the sildenafil arm.

Discussion

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Summary of main results

This review demonstrates clear statistical and clinical benefit for the use of PDE5 inhibitors in group 1 PAH compared to placebo, in terms of mortality, improvement in WHO functional class, time to clinical worsening, haemodynamics, six‐minute walk distance (6MWD), and quality of life including dyspnoea. Clinicians and patients should be aware of side effects, especially headache, flushing, GI upset, and muscle and joint pain.

Three formulations of PDE5 inhibitors were used: sildenafil, tadalafil and vardenafil. Although none of these were compared head‐to‐head, a beneficial direction of effect appeared across all three drugs. Although the magnitude of effect appeared greater in sildenafil compared with tadalafil or vardenafil, this could be due to more studies and participant numbers in the sildenafil arm. In terms of adverse events, there appeared to be a higher chance of headache, GI upset and muscle aches and pains in the tadalafil arm compared to the sildenafil arm.

We demonstrate mixed evidence for the use of PDE5 inhibitors for left‐heart disease. The trials included were heterogenous in left‐heart disease secondary to different mechanisms. Overall, there was a statistically and clinically significant improvement across all trials in terms of WHO functional class and 6MWD, and an improvement in haemodynamics, quality of life, and dyspnoea, but this did not confer a clear benefit for mortality. It is unclear if this is due to underpowered studies. In addition, there was some evidence of heart failure exacerbations in one study which included participants with valvular heart disease, but despite this being a known potential side effect of these drugs, few studies reported any adverse events.

There is no clear benefit from the use of PDE5 inhibitors in pulmonary hypertension secondary to lung disease, according to this meta‐analysis. There was a statistically but not clinically significant difference in 6MWD, but no benefit for mortality, haemodynamics, quality of life, and clinical worsening. Most studies included COPD patients with pulmonary hypertension; only one included IPF patients. There are no data on PDE5 inhibitors in other lung disease patients.

There was no significant benefit for the use of PDE5 inhibitors in CTEPH, when compared to placebo or bosentan, for mortality, clinical worsening, 6MWD, and haemodynamics, but the numbers of participants were small.

There may be an improvement in cardiopulmonary haemodynamics with the use of PDE5 inhibitors in pulmonary hypertension due to beta‐thalassaemia intermedia. There may be evidence of harm from the use of PDE5 inhibitors in people with pulmonary hypertension secondary to sickle cell disease.

Overall completeness and applicability of evidence

There are sufficient trials of high quality in the use of PDE5 inhibitors compared to placebo for group 1 PAH. Most trials had a low risk of bias, and the direction of effect was consistent across studies. PDE5 inhibitors are one of five classes of drugs now available for group 1 PAH. Current European Society of Cardiology (ESC) guidelines stratify patients according to levels of risk, which correlate with expected survival (Boucly 2017; Hoeper 2017; Kylhammar 2018). The guidelines suggest the use of monotherapy with either a PDE5 inhibitor or an endothelin receptor antagonist (ERA) for people at low risk, and the use of combination therapy or intravenous prostacyclin for those at high risk. Two studies compared the use of PDE5 inhibitors with ERAs, and found a possible benefit for ERA in terms of 6MWD and quality of life, and a non‐statistically significant benefit for improvement in WHO functional class, and clinical worsening, favouring ERAs.

The use of step‐up or upfront combination therapy in people at intermediate risk has been suggested by several recent studies, including SERAPHIN 2013 (where macitentan was added to a PDE5 inhibitor or non‐parenteral prostacyclin, and demonstrated delay in clinical worsening), COMPASS‐2 2014 (where bosentan was added to sildenafil, and demonstrated a small but statistically significant improvement in 6MWD (22 m), but no change in morbidity or mortality), PACES (Simonneau 2008) (where sildenafil was added to epoprostenol and demonstrated a delay in clinical worsening), and GRIPHON 2015 (where the addition of selexipag to monotherapy demonstrated a delay in clinical worsening). The AMBITION 2015 study (included in this review) examined upfront combination therapy and demonstrated a reduction in clinical failure, and an improvement in 6MWD.

Pulmonary hypertension secondary to left‐heart disease (PH‐LHD) is by far the most common cause of pulmonary hypertension, and the presence of PH‐LHD leads to worse survival (Strange 2012). Studies including participants with PH‐LHD were mixed; when we pooled the studies there was a benefit for exercise parameters and quality of life, but an increased risk of heart failure exacerbations. Previous studies (Jiang 2014; Lindman 2012) have demonstrated acute haemodynamic benefit in these participants, but the long‐term effect remains controversial. Bermejo 2017 suggested an initial benefit in 6MWD at three months (although not statistically significant), but this effect disappeared at six months, with no difference in effect between the two arms. In contrast, the other long‐term study (Guazzi 2011a (12 months)) demonstrated a continued, persistent benefit in haemodynamics over time. This suggests that the controversy may lie in the heterogeneity of the cause of left‐heart disease leading to pulmonary hypertension.

The evidence for pulmonary hypertension secondary to lung disease was limited to people with COPD. Although there was one small study (an a priori planned substudy of a larger trial) in people with IPF, it is difficult to extrapolate the evidence presented in this meta‐analysis beyond the COPD population. Theoretically, worsening ventilation‐perfusion mismatch induced by pulmonary vasodilators may lead to more pronounced dyspnoea and clinical worsening (Smith 2013), but included studies did not assess dyspnoea, and limited data were provided on clinical worsening. Further trials should include these outcomes.

Appropriate and accurate outcome assessment did not occur in all studies. In trials with PH‐LHD, although most participants were initially diagnosed using right‐heart catheterisation, outcome assessment was performed with noninvasive measures such as PASP on transthoracic echocardiogram (TTE). Previous studies (Farber 2011) have demonstrated that these noninvasive techniques do not always correlate with invasive haemodynamics, especially in those with left‐heart disease. In addition, the presence of pulmonary hypertension in left‐heart disease has been shown to reduce exercise tolerance and increase hospitalisations for heart failure (Vachiéry 2013). However, despite this, only three of five studies reported exercise tolerance, and only two of five reported heart failure exacerbations. Any further studies in PH‐LHD should include 6MWD, invasive haemodynamic data, clinical worsening including heart failure exacerbations, and be adequately powered to detect a difference in these outcomes.

Quality of the evidence

For trials including group 1 PAH participants comparing PDE5 inhibitors to placebo, the quality of evidence was high across all outcomes except for six‐minute walk distance, and cardiac index, which were downgraded to moderate due to high heterogeneity, although the effect was consistent across trials. For PAH trials comparing PDE5 inhibitors to placebo whilst on additional therapy and trials comparing PDE5 inhibitors to ERAs, the quality of the evidence was reduced due to smaller participant numbers. Follow‐up was as long as 12 months, but the average follow‐up was only 14 weeks. Open‐label extension or real world registry data may be useful for longer‐term effects.

Although there were five studies examining PH‐LHD, the numbers in each study were small, and studies were significantly heterogeneous. Ovchinnov 2015 was a poor‐quality study, where randomisation and allocation concealment were not reported, dropouts and cross‐overs were not reported, and only quantitative data from the intervention arm was reported.

Potential biases in the review process

We conducted this review in accordance with established Cochrane standards. Two review authors independently screened search results and resolved discrepancies by discussion and consensus. We did not restrict the literature search by language. Publication bias is possible, whereby failure to identify unpublished negative trials could have led to an overestimation of effect.

Agreements and disagreements with other studies or reviews

Our findings are consistent with the current ESC/ERS guidelines (Galiè 2016b), which recommend the use of PDE5 inhibitors for monotherapy as level IA/B evidence for WHO functional class I ‐ III patients, and as level IIb evidence for WHO functional class IV patients (as there is stronger evidence of effect for combination therapy and intravenous prostacyclins). Similarly, the current ESC/ERS guidelines do not recommend the use of PDE5 inhibitors for left‐heart disease‐ or lung disease‐related pulmonary hypertension. Where PDE5 inhibitors are used as part of combination therapy, caution should be used in adding these to riociguat, due to potentially unfavourable side effects and lack of additional clinical benefit (Galiè 2015b).

No trials have compared individual PDE5 inhibitors head‐to‐head, and given the overall class benefit it is unlikely that these studies will be conducted. Our data suggest that there may be a better treatment effect with sildenafil compared to tadalafil, but this may be influenced by the greater number of studies conducted using sildenafil compared to tadalafil. The choice of agent is likely to be nuanced and influenced by the individual patient profile with respect to side effects. The SITAR study (Frantz 2014) rotated participants from sildenafil to tadalafil, and found an initial increase in side effects including headache and gastrointestinal upset, but this improved over time.

Our data demonstrating no clear benefit for the use of PDE5 inhibitors in those with lung disease‐associated pulmonary hypertension is consistent with the ESC guidelines (Galiè 2016b) and with other published data using PH‐specific therapy in people with interstitial lung disease (ILD). Han 2013 (pulmonary hypertension associated with lung disease) was a prespecified substudy of the STEP‐IPF trial (Zisman 2010), which included people with idiopathic pulmonary fibrosis (IPF), and found no benefit in terms of 6MWD, exacerbations or mortality.

Interestingly, there appeared to be no significant benefit for the use of PDE5 inhibitors in people with CTEPH. Current ESC/ERS guidelines (Galiè 2016b) recommend surgical pulmonary endarterectomy as first line treatment based on long term international registry data which demonstrates a mortality benefit (Delcroix 2016), and the use of riociguat medical therapy in those who are non‐operable candidates (Ghofrani 2013). Therefore, these treatments could be considered in preference to PDE5 inhibitors.

Study flow diagram.
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Figure 1

Study flow diagram.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.1 Improvement in WHO functional class.
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Figure 3

Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.1 Improvement in WHO functional class.

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Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.3 Mortality.
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Figure 4

Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.3 Mortality.

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Cates Plot for mortality with PDE5 inhibitor treatment in Group 1 PAH
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Figure 5

Cates Plot for mortality with PDE5 inhibitor treatment in Group 1 PAH

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Forest plot of comparison: 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), outcome: 4.2 Six‐minute walk distance.
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Figure 6

Forest plot of comparison: 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), outcome: 4.2 Six‐minute walk distance.

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Forest plot of comparison: 5 Group 3 Pulmonary Hypertension due to lung disease, outcome: 5.2 Six‐minute walk distance.
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Figure 7

Forest plot of comparison: 5 Group 3 Pulmonary Hypertension due to lung disease, outcome: 5.2 Six‐minute walk distance.

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Forest plot of comparison: 6 Group 4 Pulmonary Hypertension due to CTEPH, outcome: 6.2 Six‐minute walk distance.
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Figure 8

Forest plot of comparison: 6 Group 4 Pulmonary Hypertension due to CTEPH, outcome: 6.2 Six‐minute walk distance.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 1 Improvement in WHO functional class.
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Analysis 1.1

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 1 Improvement in WHO functional class.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 2 Six‐minute walk distance.
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Analysis 1.2

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 2 Six‐minute walk distance.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 3 Mortality.
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Analysis 1.3

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 3 Mortality.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 4 PAP.
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Analysis 1.4

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 4 PAP.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 5 RAP.
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Analysis 1.5

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 5 RAP.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 6 CI.
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Analysis 1.6

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 6 CI.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 7 PVR.
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Analysis 1.7

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 7 PVR.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 8 PASP.
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Analysis 1.8

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 8 PASP.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 9 Dyspnoea.
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Analysis 1.9

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 9 Dyspnoea.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 10 Clinical worsening requiring intervention.
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Analysis 1.10

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 10 Clinical worsening requiring intervention.

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Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 11 Adverse events.
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Analysis 1.11

Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 11 Adverse events.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 1 Improvement in WHO functional Class.
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Analysis 2.1

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 1 Improvement in WHO functional Class.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 2 Six‐minute walk distance.
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Analysis 2.2

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 2 Six‐minute walk distance.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 3 Mortality.
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Analysis 2.3

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 3 Mortality.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 4 PAP.
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Analysis 2.4

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 4 PAP.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 5 Cardiac Output.
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Analysis 2.5

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 5 Cardiac Output.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 6 PVR.
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Analysis 2.6

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 6 PVR.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 7 Clinical worsening.
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Analysis 2.7

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 7 Clinical worsening.

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Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 8 Adverse events.
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Analysis 2.8

Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 8 Adverse events.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 1 Improvement in WHO functional class.
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Analysis 3.1

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 1 Improvement in WHO functional class.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 2 Six‐minute walk distance.
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Analysis 3.2

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 2 Six‐minute walk distance.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 3 Mortality.
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Analysis 3.3

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 3 Mortality.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 4 PAP.
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Analysis 3.4

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 4 PAP.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 5 RAP.
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Analysis 3.5

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 5 RAP.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 6 CI.
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Analysis 3.6

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 6 CI.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 7 PVR.
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Analysis 3.7

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 7 PVR.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 8 Quality of life.
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Analysis 3.8

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 8 Quality of life.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 9 Clinical worsening requiring hospitalisation.
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Analysis 3.9

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 9 Clinical worsening requiring hospitalisation.

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Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 10 Adverse events.
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Analysis 3.10

Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 10 Adverse events.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 1 Improvement in WHO functional class.
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Analysis 4.1

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 1 Improvement in WHO functional class.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 2 Six‐minute walk distance.
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Analysis 4.2

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 2 Six‐minute walk distance.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 3 Mortality.
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Analysis 4.3

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 3 Mortality.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 4 mean PAP.
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Analysis 4.4

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 4 mean PAP.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 5 Cardiac Index.
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Analysis 4.5

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 5 Cardiac Index.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 6 TPG.
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Analysis 4.6

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 6 TPG.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 7 RAP.
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Analysis 4.7

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 7 RAP.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 8 PASP.
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Analysis 4.8

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 8 PASP.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 9 Dyspnoea.
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Analysis 4.9

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 9 Dyspnoea.

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Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 10 Clinical worsening.
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Analysis 4.10

Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 10 Clinical worsening.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 1 Improvement in WHO functional class.
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Analysis 5.1

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 1 Improvement in WHO functional class.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 2 Six‐minute walk distance.
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Analysis 5.2

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 2 Six‐minute walk distance.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 3 QOL.
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Analysis 5.3

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 3 QOL.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 4 mean PAP.
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Analysis 5.4

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 4 mean PAP.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 5 Cardiac Index.
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Analysis 5.5

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 5 Cardiac Index.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 6 PVR.
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Analysis 5.6

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 6 PVR.

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Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 7 RAP.
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Analysis 5.7

Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 7 RAP.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 1 Improvement in WHO functional class.
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Analysis 6.1

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 1 Improvement in WHO functional class.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 2 Six‐minute walk distance.
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Analysis 6.2

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 2 Six‐minute walk distance.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 3 Mortality.
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Analysis 6.3

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 3 Mortality.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 4 mean PAP.
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Analysis 6.4

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 4 mean PAP.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 5 Cardiac Index.
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Analysis 6.5

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 5 Cardiac Index.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 6 PVR.
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Analysis 6.6

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 6 PVR.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 7 RAP.
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Analysis 6.7

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 7 RAP.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 8 QOL.
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Analysis 6.8

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 8 QOL.

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Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 9 Adverse events.
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Analysis 6.9

Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 9 Adverse events.

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Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 1 Improvement in WHO functional class.
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Analysis 7.1

Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 1 Improvement in WHO functional class.

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Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 2 6MWD.
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Analysis 7.2

Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 2 6MWD.

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Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 3 PASP.
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Analysis 7.3

Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 3 PASP.

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Summary of findings for the main comparison. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo

Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo

Patient or population: people with pulmonary arterial hypertension
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

61 per 1000

358 per 1000
(204 to 549)

OR 8.59
(3.95 to 18.72)

282
(4 RCTs)

⊕⊕⊕⊕
HIGH

‐

Six‐minute walk distance

Ranges from 170 ‐ 319 ma

MD 48 metres higher
(40 higher to 56 higher)

‐

880
(8 RCTs)

⊕⊕⊕⊝b
MODERATE

6MWD in PAH MCID is 41 metres

Mortality

41 per 1000

9 per 1000
(3 to 28)

OR 0.22
(0.07 to 0.68)

1119
(8 RCTs)

⊕⊕⊕⊕
HIGH

‐

Quality of life

SF‐36: (scores 1 to 100, higher scores indicate better QoL)

EQ‐5D questionnaire: (higher scores indicate worse QoL)

CHFQ: (lower scores indicate worse QoL)

Galiè 2005a found a statistically significant improvement in all SF‐36 domains for sildenafil‐treated participants, and when compared to placebo in physical functioning (P < 0.001), general health (P < 0.001), and vitality (P < 0.05). There was also a statistically significant improvement in placebo‐treated participants in the physical functioning domain.

Galiè 2005a found statistically significant improvements for the EQ‐5D current health status (P < 0.01) and utility index (P < 0.01).
Sastry 2004 found a statistically significant difference for the CHFQ fatigue domain (sildenafil post‐treatment score 22.33, SD 4.82 compared to placebo post‐treatment score 20.67, SD 5.19; P = 0.04), and a non‐statistically significant difference in the emotional function domain (sildenafil post‐treatment score 37.33, SD 9.3, compared to placebo post‐treatment score 34.71, SD 10.91; P = 0.06), favouring sildenafil compared with placebo.

163

(2 RCTs)

‐

Data considered too heterogeneous to meta‐analyse

PAP

‐

MD 6.43 mmHg lower (8.13 lower to 4.74 lower)

‐

453
(6 RCTs)

⊕⊕⊕⊝b
MODERATE

The higher the mean PAP, the worse the PH

RAP

‐

MD 1.35 mmHg lower (2.34 lower to 0.36 lower)

‐

341
(3 RCTs)

⊕⊕⊕⊕
HIGH

The higher the RAP, the worse the PH

Cardiac index

‐

MD 0.28L/min/m2 higher (0.16 higher to 0.4 higher)

‐

239
(4 RCTs)

⊕⊕⊕⊝b
MODERATE

The lower the cardiac index, the worse the PH

PVR

‐

MD 4.74 WU lower (6.13 lower to 3.35 lower)

‐

266
(3 RCTs))

⊕⊕⊕⊕
HIGH

The higher the PVR. the worse the PH

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; EQ‐5D: EuroQoL 5D; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RCT: randomised controlled trials; SD: standard deviation; SF‐36: Medical Outcomes Study 36‐item short form; WU: woods units; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aPost‐treatment values for participants in the placebo group were presented in two studies only; the remaining included studies presented a mean difference only.
bDowngraded due to imprecision owing to significantly high heterogeneity, although the direction of effect is consistent.

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Summary of findings for the main comparison. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo
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Summary of findings 2. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy

Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy

Patient or population: people with pulmonary arterial hypertension
Setting: outpatients
Intervention: PDE5 inhibitors plus other disease‐modifying therapies
Comparison: placebo plus other disease‐modifying therapies

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo, on combination therapy

Risk with PDE5i

Improvement in WHO functional class

263 per 1000

300 per 1000
(191 to 437)

OR 1.20
(0.66 to 2.17)

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Six‐minute walk distance

Ranges from 341 ‐ 377 mb

MD 20 metres higher
(9 higher to 30 higher)

‐

509
(4 RCTs)

⊕⊕⊕⊝
MODERATEa

6MWD in PAH MCID is 41 metres

Mortality

32 per 1000

9 per 1000
(2 to 34)

OR 0.26
(0.07 to 1.06)

492
(3 RCTs)

⊕⊕⊕⊝
MODERATEc

‐

Quality of life

physical functioning on SF‐36 (higher scores indicate better quality of life)

0.3 (4.7 higher to 4.1 higher)

7.8 (3.6 higher to 12.1 higher)

‐

267

(1 RCT)

⊕⊕⊕⊝
MODERATEd

‐

PAP

‐

MD 4.58 mmHg lower
(6.14 lower to 3.01 lower)

‐

387
(2 RCTs)

⊕⊕⊕⊕
HIGH

The higher the PAP, the worse the pulmonary hypertension

Cardiac output

‐

MD 0.87 L/min higher
(0.53 higher to 1.21 higher)

‐

310
(3 RCTs)

⊕⊕⊕⊕
HIGH

The lower the cardiac output, the worse the pulmonary hypertension

PVR

‐

SMD 0.48 lower
(0.72 lower to 0.25 lower)

‐

303
(3 RCTs)

⊕⊕⊕⊕
HIGH

The higher the PVR, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PVR: pulmonary vascular resistance; RCT: randomised controlled trials; SMD: standardised mean difference; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded due to imprecision owing to small participant numbers and inconsistent direction of effect.
bRange of baseline values, as studies only presented mean difference values for analysis.
cDowngraded due to imprecision as the confidence interval crosses the line of no difference.
dDowngraded due to imprecision owing to small participant numbers in one trial.

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Summary of findings 2. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy
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Summary of findings 3. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to ERA

Group 1 Pulmonary Arterial Hypertension ‐ PDE5i compared to ERA

Patient or population: people with pulmonary arterial hypertension
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: endothelin receptor antagonists(ERA)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with ERA

Risk with PDE5i

Improvement in WHO functional class

339 per 1000

325 per 1000
(220 to 450)

OR 0.94
(0.55 to 1.60)

244
(1 RCT)

⊕⊕⊕⊝
MODERATEa

‐

Six‐minute walk distance

Ranges from 290 ‐ 354 mb

MD 49 higher
(4 higher to 95 higher)

‐

36
(2 RCTs)

⊕⊕⊝⊝
LOWc

6MWD in PAH MCID is 41 metres

Mortality

14 per 1000

45 per 1000
(11 to 167)

OR 3.19
(0.74 to 13.64)

272
(2 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Quality of life

Kansas City Cardiomyopathy Quality‐of‐Life questionnaire (higher scores indicate better quality of life)

‐

MD 22 higher
(9 higher to 35 higher)

‐

25
(1 RCT)

⊕⊕⊝⊝
LOWc

‐

PAP

‐

MD 7.00 mmHg lower (4.82 lower to 18.82 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The higher the mean PAP, the worse the PH

RAP

‐

MD 2 mmHg higher (2.14 lower to 6.14 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The higher the RAP, the worse the PH

Cardiac index

‐

MD 0 L/min/m2 higher (0.49 lower to 0.49 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The lower the cardiac index, the worse the PH

PVR

‐

MD 0 WU lower (1.93 lower to 1.93 higher)

‐

11

(1 RCT)

⊕⊕⊝⊝
LOWd

The higher the PVR. the worse the PH

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PDE‐5i: phosphodiesterase‐5 inhibitor; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded once due to imprecision.
bRange of baseline values, as studies only presented mean difference values for analysis.
cDowngraded twice due to imprecision and small participant numbers.
dDowngraded twice due to very small participant numbers and high risk of bias.

Figures and Tables -
Summary of findings 3. Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to ERA
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Summary of findings 4. Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo

Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension due to left‐heart disease
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

403 per 1000

263 per 1000
(178 to 370)

OR 0.53
(0.32 to 0.87)

285
(3 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Six‐minute walk distance

No data reported

MD 34 metres higher
(23 higher to 46 higher)

‐

284
(3 RCTs)

⊕⊕⊕⊝
MODERATEa

‐

Mortality

22 per 1000

27 per 1000 (6 to 114)

OR 1.27 (0.28 to 5.80)

286
(3 RCTs)

⊕⊕⊕⊝
MODERATEb

‐

Quality of life

19.83 points higher (8.23 higher to 31.44 higher)

12.05 points higher (1.14 higher to 22.96 higher)

‐

52

(1 RCT)

⊕⊕⊝⊝
LOWc

Kansas City Cardiomyopathy Questionnaire (higher scores reflect better health status)

Mean PAP

‐

MD 10.17 mmHg lower
(11.99 lower to 8.35 lower)

‐

130
(3 RCTs)

⊕⊕⊕⊝
MODERATEa

The higher the mean PAP, the worse the pulmonary hypertension

Cardiac index

‐

MD 0.07 L/min/m2 higher
(0.17 lower to 0.3 higher)

‐

96
(2 RCTs)

⊕⊕⊕⊝
MODERATEa

The lower the cardiac index, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

6MWD: six‐minute walk distance; CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded due to high heterogeneity and inconsistent direction of effect.
bDowngraded due to imprecision as the confidence interval crosses the line of no difference.
cDowngraded twice due to imprecision owing to few participant numbers in one trial.

Figures and Tables -
Summary of findings 4. Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo
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Summary of findings 5. Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo

Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension due to lung disease
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

50 per 1000

700 per 1000
(201 to 956)

OR 44.33
(4.78 to 410.94)

40
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Six‐minute walk distance

Ranges from 237 ‐ 297 metres

MD 27 metres higher
(2 higher to 51 higher)

‐

350
(5 studies)

⊕⊕⊕⊕
HIGH

‐

Mortality

‐

‐

‐

No studies

‐

‐

Quality of life

‐

MD 0.19 higher
(0.07 lower to 0.44 higher)

‐

238
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

SF‐36 overall quality of life (higher scores indicate better quality of life)

Mean PAP

‐

MD 0.14 mmHg lower
(6.65 lower to 6.37 higher)

‐

61
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The higher the mean PAP, the worse the pulmonary hypertension

Cardiac index

‐

MD 0.3 L/min/m2 higher
(0.14 lower to 0.74 higher)

‐

28
(1 RCT)

⊕⊕⊝⊝
LOWa

The lower the cardiac index, the worse the pulmonary hypertension

PVR

‐

MD 1.31 WU lower
(3.67 lower to 1.05 higher)

‐

28
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the PVR, the worse the pulmonary hypertension

RAP

‐

MD 0.36 mmHg higher
(2.76 lower to 3.48 higher)

‐

28
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the RAP, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; MCID: minimal clinically important difference; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded twice due to imprecision owing to small participant numbers.
bDowngraded once due to imprecision.

Figures and Tables -
Summary of findings 5. Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo
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Summary of findings 6. Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo

Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension due to CTEPH
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with comparison (placebo/sildenafil)

Risk with PDE5i

Improvement in WHO functional class

0 per 1000

444 per 1000

OR 17.18
(0.78 to 380.84)

19
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Six‐minute walk distance ‐ sildenafil compared to placebo

Baseline 331 metres

MD 18 metres higher
(24 lower to 59 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Six‐minute walk distance ‐ sildenafil compared to bosentan

Ranges from 422 ‐ 455 metres

MD 20 metres higher
(28 lower to 69 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

‐

Mortality ‐ sildenafil versus placebo

No deaths reported

not estimable

20
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Mortality ‐ sildenafil versus bosentan

40 per 1000

54 per 1000
(9 to 261)

OR 1.36 (0.22 to 8.48)

106
(1 RCT)

⊕⊕⊝⊝
LOWa

‐

Quality of life

‐

MD 0.26 lower
(1.17 lower to 0.64 higher)

‐

34
(1 RCT)

⊕⊕⊝⊝
LOWa

CamPHOR scale; higher scores indicate worse quality of life

Mean PAP ‐ sildenafil versus placebo

‐

MD 6.2 mmHg lower
(12.4 lower to 0 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the PAP, the worse the pulmonary hypertension

Mean PAP ‐ sildenafil versus bosentan

‐

MD 0.76 mmHg higher
(3.96 lower to 5.48 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The higher the PAP, the worse the pulmonary hypertension

Cardiac index ‐ sildenafil versus placebo

‐

MD 0 L/min/m2 higher
(0.4 lower to 0.4 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

The lower the cardiac index, the worse the pulmonary hypertension

Cardiac index ‐ sildenafil versus bosentan

‐

MD 0.04 L/min/m2 higher
(0.22 lower to 0.31 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The lower the cardiac index, the worse the pulmonary hypertension

PVR ‐ sildenafil versus placebo

‐

MD 0.89 WU lower
(1.85 lower to 0.06 higher)

‐

19
(1 RCT)

⊕⊕⊝⊝
LOWa

The higher the PVR, the worse the pulmonary hypertension

PVR ‐ sildenafil versus bosentan

‐

MD 0.01 WU lower
(0.27 lower to 0.25 higher)

‐

227
(2 RCTs)

⊕⊕⊕⊝
MODERATEb

The higher the PVR, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; CTEPH: chronic thromboembolic pulmonary hypertension; MD: mean difference; OR: odds ratio; PAP: pulmonary arterial pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; PVR: pulmonary vascular resistance; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded twice due to imprecision owing to small participant numbers in only one trial.
bDowngraded once due to imprecision.

Figures and Tables -
Summary of findings 6. Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo
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Summary of findings 7. Mixed Pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo

Mixed pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo

Patient or population: people with pulmonary hypertension group 2 ‐ 4
Setting: outpatients
Intervention: PDE5 inhibitors
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with PDE5i

Improvement in WHO functional class

Study population

OR 11.31
(4.90 to 26.14)

146
(2 RCTs)

⊕⊕⊕⊝
MODERATEa,b

‐

137 per 1000

642 per 1000
(438 to 806)

Six‐minute walk distance

No data provided

MD 51 metres higher
(7 higher to 95 higher)

‐

106
(1 RCT)

⊕⊕⊕⊝
MODERATEa,b

‐

Mortality

‐

‐

no studies

‐

‐

‐

Quality of life

‐

‐

no studies

‐

‐

‐

PASP

‐

MD 10 mmHg lower
(11.92 lower to 8.08 lower)

‐

146
(2 RCTs)

⊕⊕⊕⊝
MODERATEa,b

The higher the PASP, the worse the pulmonary hypertension

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; MD: mean difference; OR: odds ratio; PASP: pulmonary artery systolic pressure; PDE‐5i: phosphodiesterase‐5 inhibitor; RCT: randomised controlled trials; WHO: World Health Organization

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

aDowngraded due to imprecision owing to small participant numbers.
bThe information is from studies at low or unclear risk of bias.

Figures and Tables -
Summary of findings 7. Mixed Pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo
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Table 1. World Health Organisation/World Symposium classification of pulmonary hypertension

WHO group

Classification

Group 1

Pulmonary arterial hypertension

  • idiopathic PAH

  • PAH with vasoreactivity

  • heritable PAH

  • drugs and toxins

  • associated with:

    • connective tissue disease;

    • HIV;

    • portal hypertension;

    • congenital heart disease;

    • schistosomiasis.

Pulmonary veno‐occlusive disease/pulmonary capillary haemangiomatosis

Persistent pulmonary hypertension of the newborn

Group 2

Pumonary hypertension due to left heart disease

  • due to left heart failure with preserved ejection fraction

  • due to left heart failure with reduced ejection fraction

Valvular heart disease

Congenital post‐capillary obstructive lesions

Group 3

Pulmonary hypertension due to chronic lung disease or chronic hypoxaemia, or both

  • obstructive lung disease

  • restrictive lung disease

  • other lung diseases with a mixed obstructive/restrictive pattern

  • sleep disordered breathing

  • alveolar hypoventilation disorders

  • chronic exposures to high altitudes

  • developmental lung diseases

Group 4

Pulmonary hypertension due to pulmonary artery obstruction

  • chronic thromboembolic pulmonary hypertension

  • other pulmonary artery obstructions

Group 5

Pulmonary hypertension with unclear mechanisms

  • haematologic disorders (chronic haemolytic anaemia, myeloproliferative disorders, splenectomy)

  • systemic disorders (sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis)

  • metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders)

  • others (pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension)

PAH: pulmonary arterial hypertension
Figures and Tables -
Table 1. World Health Organisation/World Symposium classification of pulmonary hypertension
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Table 2. Sensitivity analysis: fixed‐effect versus random‐effects

Meta‐analysis

Number of studies

Effect measure

Fixed‐effect size and CI

Random‐effect size and CI

Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo

Improvement in WHO functional class

4

OR

8.59 (3.95 to 18.72)

8.53 (3.90 to 18.67)

Six‐minute walk distance

8

MD

48.17 (40.30 to 56.04)

52.98 (40.74 to 65.23)1

Mortality

7

OR

0.22 (0.07 to 0.68)

0.28 (0.08 to 0.95)

PAP

5

MD

−6.33 (−8.12 to −4.53)

−8.94 (−13.73 to −4.15)

RAP

2

MD

−1.52 (−2.79 to −0.24)

−1.52 (−2.79 to −0.24)

Cardiac index

4

MD

0.28 (0.16 to 0.40)

0.35 (0.08 to 0.61)a

PVR

3

MD

−4.74 (−6.13 to −3.35)

−5.02 (−7.02 to −3.02)

PASP

2

MD

−11.62 (−25.18 to 1.94)

−11.62 (−25.18 to 1.94)

Dypnoea

4

MD

−0.72 (−0.99 to −0.44)

−0.61 (−1.19 to −0.02)

Clinical worsening requiring intervention

3

OR

0.58 (0.27 to 1.23)

0.55 (0.25 to 1.23)

Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo to on combination therapy

Improvement in WHO functional Class

2

OR

1.20 (0.66 to 2.17)

1.09 (0.41 to 2.92)

Six‐minute walk distance

4

MD

19.66 (9.22 to 30.10)

18.94 (0.23 to 37.65)

Mortality

3

OR

0.26 (0.07 to 1.06)

0.38 (0.04 to 3.81)

PAP

2

MD

−4.58 (−6.14 to −3.01)

−5.12 (−8.21 to −2.03)

Cardiac output

2

MD

0.87 (0.53 to 1.21)

0.87 (0.53 to 1.21)

PVR

3

SMD

−0.48 (−0.72 to −0.25)

−0.36 (−0.84 to 0.12)a

Clinical worsening

3

OR

0.34 (0.18 to 0.63)

0.34 (0.18 to 0.63)

Group 1 Pulmonary arterial hypertension ‐ PDE5i versus ERA

Improvement in WHO functional Class

1

OR

0.94 (0.55 to 1.60)

0.94 (0.55 to 1.60)

Six‐minute walk distance

2

MD

49.38 (3.65 to 95.11)

49.38 (3.65 to 95.11)

Mortality

2

OR

3.19 (0.74 to 13.64)

3.19 (0.74 to 13.64)

Quality of life

1

MD

22.00 (9.00 to 35.00)

22.00 (9.00 to 35.00)

PAP

1

MD

7.00 (−4.82 to 18.82)

7.00 (−4.82 to 18.82)

RAP

1

MD

2.00 (−2.14 to 6.14)

2.00 (−2.14 to 6.14)

Cardiac index

1

MD

0.00 (−0.49 to 0.49)

0.00 (−0.49 to 0.49)

PVR

1

MD

0.00 (−1.93 to 1.93)

0.00 (−1.93 to 1.93)

Clinical worsening

2

OR

0.52 (0.30 to 0.89)

0.52 (0.30 to 0.89)

Group 2 Pulmonary hypertension due to left‐heart disease

Improvement in WHO functional Class

3

OR

0.53 (0.32 to 0.87)

0.70 (0.20 to 2.37)

Six‐minute walk distance

3

MD

34.31 (22.75 to 45.87)

28.44 (‐1.82 to 58.69)a

Mortality

3

OR

0.01 (−0.03 to 0.04)

0.01 (−0.03 to 0.04)

Mean PAP

3

MD

−10.17 (−11.99 to −8.35)

−6.58 (−22.28 to 9.12)a

Cardiac index

2

MD

0.07 (−0.17 to 0.30)

0.06 (−0.22 to 0.34)

TPG

1

MD

−14.60 (−15.63 to −13.57)

−14.60 (−15.63 to −13.57)

RAP

1

MD

−1.00 (−3.77 to 1.77)

−1.00 (−3.77 to 1.77)

PASP

1

MD

−27.60 (−30.37 to −24.83)

−27.60 (−30.37 to −24.83)

Dypnoea

1

MD

1.15 (0.51 to 1.79)

1.15 (0.51 to 1.79)

Clinical worsening requiring intervention

2

OR

1.19 (0.66 to 2.14)

0.87 (0.22 to 3.46)

Group 3 Pulmonary hypertension due to lung disease

Improvement in WHO functional Class

1

OR

44.33 (4.78 to 410.93)

44.33 (4.78 to 410.93)

Six‐minute walk distance

5

MD

14.04 (7.05 to 21.02)

26.70 (2.00 to 51.39)1

Mean PAP

2

MD

−0.14 (−6.65 to 6.37)

−0.14 (−6.65 to 6.37)

Cardiac index

1

MD

0.30 (−0.14 to 0.74)

0.30 (−0.14 to 0.74)

PVR

1

MD

−1.31 (−3.67 to 1.05)

−1.31 (−3.67 to 1.05)

RAP

1

MD

0.36 (−2.76 to 3.48)

0.36 (−2.76 to 3.48)

Quality of life

3

MD

0.19 (−0.07 to 0.44)

0.19 (−0.07 to 0.44)

Group 4 Pulmonary hypertension due to CTEPH

Improvement in WHO functional Class

1

OR

17.18 (0.78 to 380.85)

17.18 (0.78 to 380.85)

Six‐minute walk distance

3

MD

18.73 (−12.72 to 50.19)

18.73 (−12.72 to 50.19)

Mortality

2

OR

0.01 (−0.06 to 0.08)

0.01 (−0.06 to 0.08)

Mean PAP

2

MD

−1.79 (−5.55 to 1.96)

−1.67 (−6.48 to 3.15)

Cardiac index

3

MD

0.03 (−0.19 to 0.25)

0.03 (−0.19 to 0.25)

PVR

3

MD

−0.07 (−0.32 to 0.18)

−0.12 (−0.50 to 0.25)

RAP

2

MD

−0.98 (−3.42 to 1.47)

−0.98 (−3.42 to 1.47)

Quality of life

1

MD

−0.26 (−1.17 to 0.64)

−0.26 (−1.17 to 0.64)

Mixed pulmonary hypertension group 2 to 4

Improvement in WHO functional Class

2

OR

11.33 (4.91 to 26.15)

11.33 (4.91 to 26.15)

Six‐minute walk distance

1

MD

50.97 (44.88 to 57.06)

50.97 (44.88 to 57.06)

PASP

2

MD

−10.00 (−11.92 to −8.08)

−10.00 (−11.92 to −8.08)

astatistically high heterogeneity

CI ‐ confidence interval; CTEPH ‐ chronic thromboembolic pulmonary hypertension; OR ‐ odds ratio; MD ‐ mean difference; PAP ‐ pulmonary artery pressure; PASP ‐ pulmonary artery systemic pressure; PDE5i ‐ phosphodiesterase‐5 inhibitor; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure; SMD ‐ standardised mean difference; TPG ‐ transpulmonary gradient; WHO ‐ World Health Organization

Figures and Tables -
Table 2. Sensitivity analysis: fixed‐effect versus random‐effects
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Comparison 1. Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional class Show forest plot

4

282

Odds Ratio (M‐H, Fixed, 95% CI)

8.59 [3.95, 18.72]

1.1 Sildenafil

1

146

Odds Ratio (M‐H, Fixed, 95% CI)

10.24 [3.69, 28.47]

1.2 Tadalafil

2

72

Odds Ratio (M‐H, Fixed, 95% CI)

7.71 [1.88, 31.72]

1.3 Vardenafil

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

5.59 [0.66, 47.07]

2 Six‐minute walk distance Show forest plot

8

880

Mean Difference (Fixed, 95% CI)

48.17 [40.30, 56.04]

2.1 Sildenafil

4

339

Mean Difference (Fixed, 95% CI)

56.91 [44.40, 69.41]

2.2 Tadalafil

3

477

Mean Difference (Fixed, 95% CI)

38.46 [27.60, 49.31]

2.3 Vardenafil

1

64

Mean Difference (Fixed, 95% CI)

69.0 [41.00, 97.00]

3 Mortality Show forest plot

8

1119

Odds Ratio (M‐H, Fixed, 95% CI)

0.22 [0.07, 0.68]

3.1 Sildenafil

5

634

Odds Ratio (M‐H, Fixed, 95% CI)

0.23 [0.05, 0.98]

3.2 Tadalafil

2

421

Odds Ratio (M‐H, Fixed, 95% CI)

0.50 [0.05, 5.63]

3.3 Vardenafil

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.08 [0.00, 1.82]

4 PAP Show forest plot

6

453

Mean Difference (Fixed, 95% CI)

‐6.43 [‐8.13, ‐4.74]

4.1 Sildenafil

4

333

Mean Difference (Fixed, 95% CI)

‐7.34 [‐9.35, ‐5.33]

4.2 Tadalafil

1

56

Mean Difference (Fixed, 95% CI)

‐3.67 [‐7.55, 0.21]

4.3 Vardenafil

1

64

Mean Difference (Fixed, 95% CI)

‐5.3 [‐10.60, ‐0.00]

5 RAP Show forest plot

3

341

Mean Difference (Fixed, 95% CI)

‐1.35 [‐2.34, ‐0.36]

5.1 Sildenafil

2

277

Mean Difference (Fixed, 95% CI)

‐1.20 [‐2.30, ‐0.11]

5.2 Vardenafil

1

64

Mean Difference (Fixed, 95% CI)

‐2.0 [‐4.30, 0.30]

6 CI Show forest plot

4

239

Mean Difference (Fixed, 95% CI)

0.28 [0.16, 0.40]

6.1 Sildenafil

2

152

Mean Difference (Fixed, 95% CI)

0.47 [0.28, 0.66]

6.2 Tadalafil

1

28

Mean Difference (Fixed, 95% CI)

0.02 [‐0.18, 0.22]

6.3 Vardenafil

1

59

Mean Difference (Fixed, 95% CI)

0.4 [0.10, 0.70]

7 PVR Show forest plot

3

266

Mean Difference (Fixed, 95% CI)

‐4.74 [‐6.13, ‐3.35]

7.1 Sildenafil

1

146

Mean Difference (Fixed, 95% CI)

‐3.87 [‐5.67, ‐2.08]

7.2 Tadalafil

1

56

Mean Difference (Fixed, 95% CI)

‐7.32 [‐10.42, ‐4.22]

7.3 Vardenafil

1

64

Mean Difference (Fixed, 95% CI)

‐4.7 [‐7.80, ‐1.60]

8 PASP Show forest plot

2

48

Mean Difference (Fixed, 95% CI)

‐11.62 [‐25.18, 1.94]

8.1 Sildenafil

1

24

Mean Difference (Fixed, 95% CI)

‐7.0 [‐23.64, 9.64]

8.2 Tadalafil

1

24

Mean Difference (Fixed, 95% CI)

‐20.75 [‐44.14, 2.64]

9 Dyspnoea Show forest plot

4

239

Mean Difference (Fixed, 95% CI)

‐0.72 [‐0.99, ‐0.44]

9.1 Sildenafil

2

155

Mean Difference (Fixed, 95% CI)

‐0.57 [‐0.90, ‐0.24]

9.2 Tadalafil

1

20

Mean Difference (Fixed, 95% CI)

‐0.64 [‐1.65, 0.37]

9.3 Vardenafil

1

64

Mean Difference (Fixed, 95% CI)

‐1.15 [‐1.70, ‐0.60]

10 Clinical worsening requiring intervention Show forest plot

3

746

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.27, 1.23]

10.1 Sildenafil

1

277

Odds Ratio (M‐H, Fixed, 95% CI)

0.46 [0.17, 1.25]

10.2 Tadalafil

1

405

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.27, 5.95]

10.3 Vardenafil

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.02, 2.46]

11 Adverse events Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

11.1 Headache

5

848

Odds Ratio (M‐H, Fixed, 95% CI)

1.97 [1.33, 2.92]

11.2 GI upset

5

848

Odds Ratio (M‐H, Fixed, 95% CI)

1.63 [1.07, 2.48]

11.3 Flushing

3

748

Odds Ratio (M‐H, Fixed, 95% CI)

4.12 [1.83, 9.26]

11.4 Muscle and joint pain

4

792

Odds Ratio (M‐H, Fixed, 95% CI)

2.52 [1.59, 3.99]

11.5 Epistaxis

2

682

Odds Ratio (M‐H, Fixed, 95% CI)

2.37 [0.83, 6.77]

11.6 Respiratory symptoms

3

748

Odds Ratio (M‐H, Fixed, 95% CI)

1.74 [0.89, 3.40]

11.7 Visual disturbance

3

748

Odds Ratio (M‐H, Fixed, 95% CI)

2.04 [0.58, 7.14]
Figures and Tables -
Comparison 1. Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo
Navigate to table in Review
Comparison 2. Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional Class Show forest plot

2

227

Odds Ratio (M‐H, Fixed, 95% CI)

1.20 [0.66, 2.17]

2 Six‐minute walk distance Show forest plot

4

509

Mean Difference (Fixed, 95% CI)

19.66 [9.22, 30.10]

3 Mortality Show forest plot

3

492

Odds Ratio (M‐H, Fixed, 95% CI)

0.26 [0.07, 1.06]

4 PAP Show forest plot

2

387

Mean Difference (Fixed, 95% CI)

‐4.58 [‐6.14, ‐3.01]

5 Cardiac Output Show forest plot

3

310

Mean Difference (Fixed, 95% CI)

0.87 [0.53, 1.21]

6 PVR Show forest plot

3

303

Std. Mean Difference (Fixed, 95% CI)

‐0.48 [‐0.72, ‐0.25]

7 Clinical worsening Show forest plot

4

717

Odds Ratio (M‐H, Fixed, 95% CI)

0.38 [0.21, 0.68]

8 Adverse events Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 Headache

5

768

Odds Ratio (M‐H, Fixed, 95% CI)

2.49 [1.74, 3.56]

8.2 GI upset

4

726

Odds Ratio (M‐H, Fixed, 95% CI)

1.95 [1.30, 2.93]

8.3 Flushing

2

368

Odds Ratio (M‐H, Fixed, 95% CI)

1.11 [0.63, 1.96]

8.4 Muscle and joint pain

3

494

Odds Ratio (M‐H, Fixed, 95% CI)

2.17 [1.28, 3.67]

8.5 Epistaxis

2

358

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.34, 5.12]

8.6 Visual disturbance

2

368

Odds Ratio (M‐H, Fixed, 95% CI)

3.95 [0.97, 16.08]
Figures and Tables -
Comparison 2. Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy
Navigate to table in Review
Comparison 3. Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional class Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2 Six‐minute walk distance Show forest plot

2

36

Mean Difference (Fixed, 95% CI)

49.38 [3.65, 95.11]

3 Mortality Show forest plot

2

272

Odds Ratio (M‐H, Fixed, 95% CI)

3.19 [0.74, 13.64]

4 PAP Show forest plot

1

Mean Difference (Fixed, 95% CI)

7.00 [‐4.82, 18.82]

5 RAP Show forest plot

1

Mean Difference (Fixed, 95% CI)

2.0 [‐2.14, 6.14]

6 CI Show forest plot

1

Mean Difference (Fixed, 95% CI)

0.0 [‐0.49, 0.49]

7 PVR Show forest plot

1

Mean Difference (Fixed, 95% CI)

0.0 [‐1.93, 1.93]

8 Quality of life Show forest plot

1

Mean Difference (Fixed, 95% CI)

Subtotals only

9 Clinical worsening requiring hospitalisation Show forest plot

2

275

Odds Ratio (M‐H, Fixed, 95% CI)

0.52 [0.30, 0.89]

10 Adverse events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.1 Headache

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.2 GI upset

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.3 Flushing

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.4 Muscle or joint pain

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10.5 Respiratory symptoms

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 3. Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA
Navigate to table in Review
Comparison 4. Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional class Show forest plot

3

285

Odds Ratio (M‐H, Fixed, 95% CI)

0.53 [0.32, 0.87]

2 Six‐minute walk distance Show forest plot

3

284

Mean Difference (Fixed, 95% CI)

34.31 [22.75, 45.87]

3 Mortality Show forest plot

3

286

Odds Ratio (M‐H, Fixed, 95% CI)

1.27 [0.28, 5.80]

4 mean PAP Show forest plot

3

130

Mean Difference (Fixed, 95% CI)

‐10.17 [‐11.99, ‐8.35]

5 Cardiac Index Show forest plot

2

96

Mean Difference (Fixed, 95% CI)

0.07 [‐0.17, 0.30]

6 TPG Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

7 RAP Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

8 PASP Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

9 Dyspnoea Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

10 Clinical worsening Show forest plot

2

234

Odds Ratio (M‐H, Random, 95% CI)

0.87 [0.22, 3.46]
Figures and Tables -
Comparison 4. Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo)
Navigate to table in Review
Comparison 5. Group 3 Pulmonary Hypertension due to lung disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional class Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Six‐minute walk distance Show forest plot

5

350

Mean Difference (Random, 95% CI)

26.70 [2.00, 51.39]

3 QOL Show forest plot

2

238

Mean Difference (Random, 95% CI)

0.19 [‐0.07, 0.44]

4 mean PAP Show forest plot

2

61

Mean Difference (Fixed, 95% CI)

‐0.14 [‐6.65, 6.37]

5 Cardiac Index Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

6 PVR Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

7 RAP Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected
Figures and Tables -
Comparison 5. Group 3 Pulmonary Hypertension due to lung disease
Navigate to table in Review
Comparison 6. Group 4 Pulmonary Hypertension due to CTEPH

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional class Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Six‐minute walk distance Show forest plot

3

Mean Difference (Fixed, 95% CI)

Subtotals only

2.1 Sildenafil versus placebo

1

19

Mean Difference (Fixed, 95% CI)

17.5 [‐23.90, 58.90]

2.2 Sildenafil versus bosentan

2

227

Mean Difference (Fixed, 95% CI)

20.42 [‐27.95, 68.79]

3 Mortality Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Sildenafil versus placebo

1

20

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Sildenafil versus bosentan

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [0.22, 8.48]

4 mean PAP Show forest plot

3

Mean Difference (Fixed, 95% CI)

Subtotals only

4.1 Sildenafil versus placebo

1

19

Mean Difference (Fixed, 95% CI)

‐6.2 [‐12.40, ‐0.00]

4.2 Sildenafil versus bosentan

2

227

Mean Difference (Fixed, 95% CI)

0.76 [‐3.96, 5.48]

5 Cardiac Index Show forest plot

3

Mean Difference (Fixed, 95% CI)

Subtotals only

5.1 Sildenafil versus placebo

1

19

Mean Difference (Fixed, 95% CI)

0.0 [‐0.40, 0.40]

5.2 Sildenafil versus bosentan

2

227

Mean Difference (Fixed, 95% CI)

0.04 [‐0.22, 0.31]

6 PVR Show forest plot

3

Mean Difference (Fixed, 95% CI)

Subtotals only

6.1 Sildenafil versus placebo

1

19

Mean Difference (Fixed, 95% CI)

‐0.89 [‐1.85, 0.06]

6.2 Sildenafil versus bosentan

2

227

Mean Difference (Fixed, 95% CI)

‐0.01 [‐0.27, 0.25]

7 RAP Show forest plot

2

Mean Difference (Fixed, 95% CI)

Subtotals only

7.1 Sildenafil versus placebo

1

19

Mean Difference (Fixed, 95% CI)

‐0.9 [‐6.10, 4.30]

7.2 Sildenafil versus bosentan

1

121

Mean Difference (Fixed, 95% CI)

‐1.0 [‐3.77, 1.77]

8 QOL Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

9 Adverse events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.1 Headache

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 GI upset

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 6. Group 4 Pulmonary Hypertension due to CTEPH
Navigate to table in Review
Comparison 7. Mixed Pulmonary Hypertension group 2‐4

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Improvement in WHO functional class Show forest plot

2

146

Odds Ratio (M‐H, Fixed, 95% CI)

11.31 [4.90, 26.14]

2 6MWD Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

3 PASP Show forest plot

2

146

Mean Difference (Fixed, 95% CI)

‐10.0 [‐11.92, ‐8.08]
Figures and Tables -
Comparison 7. Mixed Pulmonary Hypertension group 2‐4
Navigate to table in Review