The Cochrane database of systematic reviews··
Combining two treatments versus using each alone for a specific type of high blood pressure in the lungs
Updated
Abstract
Combination therapy for pulmonary arterial hypertension (PAH) is associated with a 53% reduction in clinical worsening compared to endothelin receptor antagonist (ERA) alone.
- Combination therapy may likely reduce hospitalisation rates compared to ERA alone, with 70 fewer hospitalisations per 1000 participants.
- There is little to no difference in mortality associated with combination therapy compared to ERA, based on low-certainty evidence.
- Combination therapy results in a clinically negligible improvement in six-minute walk distance (6MWD) of 19.4 meters compared to ERA.
- Withdrawal from the trial is reduced with combination therapy compared to phosphodiesterase type 5 inhibitors (PDE5i), with 64 fewer withdrawals per 1000 participants.
- The evidence regarding the effects of combination therapy on functional outcomes and serious adverse events remains uncertain.
Simplified
RATIONALE: Pulmonary arterial hypertension (PAH), a rare disorder, causes elevated pressure in the pulmonary arteries, leading to heart failure. Untreated PAH has a poor prognosis, emphasising the need for effective intervention. Pharmacological treatment includes pulmonary vasodilators such as endothelin receptor antagonists (ERA), prostacyclin analogues, phosphodiesterase type 5 inhibitors (PDE5i), and soluble guanylate cyclase stimulators, often used together to improve symptoms and quality of life while reducing mortality and risk of hospitalisation.
OBJECTIVES: To assess the benefits and harms of combination therapy involving a phosphodiesterase type 5 inhibitor (PDE5i) and an endothelin receptor antagonist (ERA) in adults and adolescents with group 1 pulmonary arterial hypertension (PAH) compared to either agent alone.
SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform for randomised controlled trials (RCTs). The most recent searches were conducted on 13 March 2024.
ELIGIBILITY CRITERIA: We included published and unpublished RCTs comparing combinations of ERAs and PDE5is versus either agent alone lasting at least 12 weeks. Participants were aged 12 years or older with WHO group 1 PAH meeting specific haemodynamic criteria. We excluded cluster-, cross-over, and quasi-RCTs, and other PAH-specific medications.
OUTCOMES: Critical outcomes were clinical worsening, mortality, and hospitalisation. Important outcomes were changes in six-minute walk distance (6MWD), WHO functional class, Borg Dyspnea Scale, serious adverse events, and withdrawal from the trial.
RISK OF BIAS: Two review authors independently assessed risk of bias using the Cochrane RoB 2 tool. We resolved disagreements through discussion or consultation. This informed GRADE ratings and summary of findings tables.
SYNTHESIS METHODS: We used a random-effects model to address study differences, switching to a fixed-effect model if there was variation primarily due to random error. We conducted meta-analyses if deemed meaningful, with data pooled if treatments, participants, and clinical questions were sufficiently similar.
INCLUDED STUDIES: We included nine studies with 1807 participants. The median duration of the studies was 16 weeks, ranging from 12 to 129 weeks. Treatment regimens included combinations of medications such as ambrisentan, bosentan, macitentan, tadalafil, and sildenafil.
SYNTHESIS OF RESULTS: Combination therapy versus endothelin receptor antagonist Combination therapy reduces clinical worsening compared to ERA alone (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.41 to 0.68; 113 fewer per 1000 participants, 95% CI 141 fewer to 77 fewer; number needed to treat for an additional beneficial effect (NNTB) 9, 95% CI 7 to 13; 5 trials, 1139 participants; high-certainty evidence). Hospitalisation is likely reduced (RR 0.32, 95% CI 0.19 to 0.55; 70 fewer per 1000 participants, 95% CI 83 fewer to 46 fewer; NNTB 14, 95% CI 12 to 22; moderate-certainty evidence). Combination therapy may result in little to no difference in mortality (low-certainty evidence), and a clinically negligible improvement in 6MWD (mean difference (MD) 19.4 m, 95% CI 10.5 to 28.3; moderate-certainty evidence). There was little to no change in Borg Dyspnea Scale (low-certainty evidence). The evidence for WHO functional class was very uncertain. There may be little to no difference in serious adverse events and trial withdrawals between the groups (low-certainty evidence). Combination therapy versus phosphodiesterase type 5 inhibitor The evidence is very uncertain about the effect of combination treatment on clinical worsening compared to PDE5i alone (RR 0.68, 95% CI 0.33 to 1.39; 142 fewer per 1000 participants, 95% CI 298 fewer to 173 more; 4 trials, 1372 participants; very low-certainty evidence), although exclusion of high-bias studies suggested a potential benefit (RR 0.57, 95% CI 0.44 to 0.73). The evidence on hospitalisations was very uncertainty, while there was little to no difference in mortality (low-certainty evidence). There was a clinically negligible improvement in 6MWD (MD 20.4 m, 95% CI 10.7 to 30.2; moderate-certainty evidence) and little to no change in Borg Dyspnea Scale (low-certainty evidence). The evidence for WHO functional class was very uncertain. Serious adverse events may be comparable (low-certainty evidence). Combination therapy reduces withdrawal from the trial compared to PDE5i alone (RR 0.84, 95% CI 0.71 to 0.99; 64 fewer per 1000 participants, 95% CI 117 fewer to 4 fewer; NNTB 16, 95% CI 9 to 250; low-certainty evidence). Phosphodiesterase type 5 inhibitor versus endothelin receptor antagonist PDE5i likely results in little to no difference in clinical worsening compared to ERA (RR 0.92, 95% CI 0.71 to 1.20; 3 trials, 644 participants; moderate-certainty evidence). The evidence is very uncertain for mortality and hospitalisation. PDE5i results in little to no difference in 6MWD compared to ERA (MD 18.4 m, 95% CI -50.2 to 86.9; low-certainty evidence). The impact on WHO functional class worsening, serious adverse events, and trial withdrawal was also uncertain, with all outcomes supported by very low- or low-certainty evidence. Overall, current data do not provide reliable conclusions on the relative efficacy or safety of PDE5i versus ERA.
AUTHORS' CONCLUSIONS: Combination therapy for PAH offers benefits over monotherapies, reducing clinical worsening compared to ERA alone (high certainty). Their benefits over PDE5i are less certain, although potentially favourable when studies at high risk of bias are excluded. Hospitalisation rates are likely reduced with combination therapy compared to ERA, but the effect is very uncertain when combination therapy is compared to PDE5i. Uncertainty also persists regarding its impact on mortality and functional outcomes, such as 6MWD and WHO functional class. Serious adverse events and withdrawal rates are similar between combination therapy and monotherapies, with varying levels of certainty, although withdrawals may favour combination therapy over PDE5i. Comparative analyses of PDE5i and ERA provided mixed results with varying levels of certainty. These findings could inform whether initial combination therapy should become the standard of care in people with group 1 PAH with WHO functional class levels of II or III. However, the review's limited representation of Black people raises concerns about generalisability, given the observed differences in response to ERAs between Black and White people with PAH in the literature.
FUNDING: This review had no dedicated funding.
REGISTRATION: Protocol available via DOI10.1002/14651858.CD015824.
Funding
Competing interests
YO: is a Cochrane editor but did not participate in the editorial process. TM: none. EF: none. YG: none.
PubMed
Related papers
Nov '22
Folic acid supplements and malaria risk and severity in people using antifolate malaria drugs in affected areas
cited by 30 papers
systematic review
Oct '25
Molnupiravir for treating COVID-19
cited by 2 papers
systematic review
Oct '25
Liraglutide treatment for adults with obesity
cited by 2 papers
systematic review