Key messages
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Combination therapies for people with group 1 pulmonary arterial hypertension are more effective at preventing clinical worsening (becoming more ill) and likely reduce hospitalisation rates compared to treatment with an endothelin receptor antagonist alone. It is uncertain whether they offer greater benefit in preventing clinical worsening or hospitalisations compared to a phosphodiesterase type 5 inhibitor alone.
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There is also no strong evidence that combination therapy improves people's ability to perform physical tasks or deaths compared to either medication alone.
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People taking combination therapy and those taking just one medicine had similar serious unwanted effects and were about as likely to stop treatment. Slightly fewer people stopped treatment when using combination therapy compared to phosphodiesterase type 5 inhibitor.
What is group 1 pulmonary arterial hypertension?
Pulmonary hypertension is high blood pressure in the arteries of the lungs (pulmonary arteries). It is split into five categories (groups 1 to 5), with each requiring a different treatment approach. Group 1 pulmonary arterial hypertension is rare and involves high pressure specifically in the pulmonary arteries, without problems in other parts of the lungs. It can be caused by factors such as genetics, some medications, or other medical conditions. Ignoring or not treating group 1 pulmonary arterial hypertension properly can reduce quality of life, increase the risk of hospitalisation, and increase deaths.
What is the treatment for group 1 pulmonary arterial hypertension?
Medicines for treating group 1 pulmonary arterial hypertension help widen the blood vessels in the lungs, which in turn lowers the pressure in the pulmonary arteries. Medications called endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin analogues can be used alone or in combinations. According to guidelines, a common combination is endothelin receptor antagonist with phosphodiesterase type 5 inhibitor.
What did we want to find out?
We wanted to see how well endothelin receptor antagonists and phosphodiesterase type 5 inhibitors work alone or together to treat group 1 pulmonary arterial hypertension. We wanted to know how many people became more ill (called disease worsening), needed hospitalisation, and died. We also wanted to see if there were any serious unwanted effects from treatment.
What did we do?
We looked for studies that compared endothelin receptor antagonist alone, phosphodiesterase type 5 inhibitor alone, or endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor (combination therapy) in people with group 1 pulmonary arterial hypertension. We checked each study to ensure it was fair and reliable, considering factors like study methods and size.
What did we find?
We found nine studies with 1807 people who were monitored for around 16 weeks.
Combination treatment reduces disease worsening compared to endothelin receptor antagonist alone and likely reduces the risk of hospitalisation. It is unclear whether combination therapies are more effective than a phosphodiesterase type 5 inhibitor alone in preventing disease worsening or hospitalisations. There was no strong evidence that combination treatment improves people's ability to perform physical tasks or deaths compared to endothelin receptor antagonist or phosphodiesterase type 5 inhibitor alone. Serious unwanted effects were similar for people using combination or single therapies. Slightly fewer people stopped treatment with combination therapy compared to phosphodiesterase type 5 inhibitor.
What are the limitations of the evidence?
Not all studies reported deaths, which makes it harder for us to be sure about our conclusions for this. Many people dropped out of some studies when comparing combination therapy to single therapies, which could have influenced the results. More research might be needed to understand these aspects better.
How up to date is the evidence?
This evidence is up to date to 13 March 2024.
Pročitajte cijeli sažetak
Ciljevi
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.
Metode pretraživanja
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.
Zaključak autora
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.
