Prostacyclin in pulmonary arterial hypertension

Review question

We wanted to review whether a group of drugs called prostacyclin analogues help people with pulmonary hypertension. Cochrane researchers collected and analysed all relevant studies to answer this question.

Why this review is important

Pulmonary hypertension can cause breathlessness, reduced exercise tolerance, reduced quality of life, hospitalisations, and early death. Prostacyclin analogues may improve blood circulation in the right heart and lungs. We wanted to make sure if these drugs are being used, there is evidence of benefit and little or no harm.

Main findings

We found and included 17 trials with 3765 people. Most of the studies were 12 weeks long. Some trials were as long as 52 weeks. Most trials involved adults. People who were given prostacyclin analogues were compared to people who were not given prostacyclin. People in four trials were given the drugs by a continuous drip (24 hours/day) into a vein (intravenous) and in one trial through continuous injection under the skin (subcutaneous). In five trials people inhaled the drugs through a nebuliser and in five trials they took tablets (oral). People in two studies took selexipag tablets. Selexipag is an agonist of the prostacyclin receptor and the trials in selexipag were analysed separately.

People who were given prostacyclins via intravenous drip showed improved survival (a lower chance of dying). They could also walk on average 92 metres further in six minutes than people not given the prostacyclin drip. They were also more likely to improve their functional class (what you can and cannot do on a daily basis). People with intravenous prostacyclins had better heart function on average than those who had no treatment.

Overall, the results were less clear for people given oral, inhaled or subcutaneous prostacyclins. It was not clear whether giving the drug in these ways led to improved survival. People who took inhaled (nebuliser) prostacyclins improved their functional class, walked on average 27 metres further in six minutes, and had better heart function. There was also some evidence that subcutaneous prostacyclins improved heart function. It was not clear if taking tablets improved functional class or heart function. People receiving this treatment only walked 15 metres further in six minutes than those not receiving prostacyclin tablets.

Whilst this review found evidence was best for prostacyclin via continuous drip, it may be inconvenient, and might increase risks such as intravenous line-related infections. Furthermore almost all people taking recommended doses in any form have important drug-related side effects (including flushing, headache, jaw pain, diarrhoea, pain in their extremities, upper respiratory tract side effects, nausea and vomiting).

People taking selexipag had less clinical worsening, and a small 13-metre difference in their six-minute walk test compared to people taking placebo. People who used selexipag were also more likely to have side effects including flushing, jaw pain, diarrhoea, nausea/vomiting, and pain in the muscles/extremities.

Limitations

There is moderate-certainty evidence that prostacyclin helps people compared to those who do not use it. The benefit is best for those who receive the drug via a continuous drip, but the risks are higher. Also, on average, the studies only lasted three months (some up to 1 year), and this may not be enough time to see benefit or risks.

This review only looked at those with a diagnosis of pulmonary arterial hypertension, not those with pulmonary hypertension associated with left heart disease, lung disease, or pulmonary hypertension due to blood clots.

This review is current to September 2018.

Authors' conclusions: 

This review demonstrates clinical and statistical benefit for intravenous prostacyclin (compared to control) with improved functional class, 6MWD, mortality, symptoms scores, and cardiopulmonary haemodynamics, but at a cost of adverse events. This may be due to a true effect, or may be overestimated due to the inclusion of small, short or open-label studies. There was a statistical and small clinical benefit in function and haemodynamics for inhaled prostacyclin, but the effect is uncertain for mortality. The effect of oral prostacyclins are less certain. Selexipag demonstrated less clinical worsening without discernable impact on survival, increased adverse events; and the effect on other outcomes is less certain. Real-world registry data may provide further information about clinical effect.

Read the full abstract...
Background: 

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular changes, leads to elevated pulmonary artery pressures, dyspnoea, a reduction in exercise tolerance, right heart failure, and ultimately death.

Prostacyclin analogue drugs mimic endogenous prostacyclin which leads to vasodilation, inhibition of platelet aggregation, and reversal of vascular remodelling. Prostacyclin's short half-life theoretically enhances selectivity for the pulmonary vascular bed by direct (via central venous catheter) administration. Initial continuous infusion prostacyclins were efficacious, but use of intravenous access increases the risk of adverse events. Newer and safer subcutaneous, oral and inhaled preparations are now available, though possibly less potent.

Selexipag is an oral selective prostacyclin receptor (IP receptor) agonist that works similarly to prostacyclin, potentially more stable, with less complex administration and titration.

Objectives: 

To determine the efficacy and safety of prostacyclin, prostacyclin analogues or prostacyclin receptor agonists for PAH in adults and children.

Search strategy: 

We performed searches on CENTRAL, MEDLINE, and Embase up to 16 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles.

Selection criteria: 

We included any randomised controlled trials (RCTs) which compared prostacyclin, prostacyclin analogues or prostacyclin receptor agonists to control (placebo, any other treatment or usual care) for at least six weeks.

Data collection and analysis: 

We used standard methods specified by Cochrane. Primary outcomes included change in World Health Organization (WHO) functional class, six-minute walk distance (6MWD), and mortality.

Main results: 

Seventeen trials with 3765 mostly adult participants were included; median trial duration was 12 weeks. Fifteen trials used prostacyclin analogues: intravenous (N = 4); subcutaneous (N = 1); oral (N = 5); inhaled (N = 5); two used oral prostacyclin receptor agonists. Three intravenous and two inhaled trials were open-label.

Participants using prostacyclin had 2.39 times greater odds of improving by at least one WHO functional class (95% confidence interval (CI) 1.72 to 3.32; 24 per 100 (95% CI 18.5 to 30.4) with prostacyclin compared to 12 per 100 with control; 8 trials, 1066 participants; moderate-certainty evidence). Improvement occurred with intravenous (odds ratio (OR) 14.96, 95% CI 4.76 to 47.04), and inhaled (OR 2.94, 95% CI 1.53 to 5.66), but not with oral preparations. Participants using prostacyclin increased their 6MWD by 19.50 metres (95% CI 14.82 to 24.19; 13 trials, 2283 participants; low-certainty evidence), which was clinically significant with intravenous (mean difference (MD) 91.76 metres; 95% CI 58.97 to 124.55), but not with non-intravenous preparations (subcutaneous: MD 16.00 metres, 95% CI 7.38 to 24.62; oral: MD 14.76 metres, 95% CI 7.81 to 21.70; inhaled: MD 26.97 metres, 95% CI 17.21 to 36.73). Mortality was reduced in the intravenous (OR 0.29, 95% CI 0.12 to 0.69; risk of death 6 per 100 (95% CI 2.38 to 12.31) with prostacyclin compared to 17 per 100 with control; 4 trials, 255 participants), but not in the non-intravenous studies (OR 0.82, 95% CI 0.48 to 1.40; risk of death 21 per 1000 (95% CI 12.00 to 34.20) with prostacyclin compared to 25 per 1000 with control; moderate-certainty evidence; 12 trials, 2299 participants). We reduced the certainty of evidence due to few studies per subgroup and use of open-label trials.

Prostacyclins improved cardiopulmonary haemodynamics (reduction in mean pulmonary artery pressure by 3.60 mmHg (95% CI -4.73 to -2.48); pulmonary vascular resistance by 2.81 WU (95% CI -3.80 to -1.82); right atrial pressure by 1.90 mmHg (95% CI -2.58 to -1.22), and increase in cardiac index by 0.31 L/min/m2 (95% CI 0.23 to 0.38); low-certainty evidence), improved dyspnoea (low-certainty evidence, and improved quality of life (moderate-certainty evidence), when compared to control. When only subcutaneous/inhaled trials were included the effect was still significant, but the magnitude was smaller. There was no difference across oral trials.

Adverse events were increased in all prostacyclin preparations, including vasodilation (OR 5.03, 95% CI 3.84 to 6.58), headache (OR 3.16, 95% CI 2.62 to 3.80), jaw pain (OR 5.25, 95% CI 3.96 to 6.98), diarrhoea (OR 2.81, 95% CI 2.29 to 3.46), nausea/vomiting (OR 2.39, 95% CI 1.98 to 2.88), myalgias (OR 2.75, 95% CI 1.65 to 4.58), upper respiratory tract events (OR 1.61, 95% CI 1.22 to 2.13), extremity pain (OR 3.36, 95% CI 2.32 to 4.85), and infusion site reactions (OR 14.41, 95% CI 9.16 to 22.66). In the intravenous trials, there was a 12%-25% risk of serious non-fatal events including sepsis, haemorrhage, pneumothorax and pulmonary embolism.

Two trials (1199 participants) compared oral selexipag to placebo; no trials compared selexipag with prostacyclin. There was a small 12.62 metre improvement in 6MWD (95% CI 1.90 to 23.34; high-certainty evidence), and weak evidence for haemodynamics. The effect was uncertain for WHO functional class. The risk of death with selexipag was five per 100 compared to three per 100 with placebo, though the CI crossed zero so the true effect is uncertain (risk difference (RD) 0.02 (95% CI -0.00 to 0.04). There was less clinical worsening with selexipag (OR 0.47, 95% CI 0.37 to 0.60), though more side effects, including vasodilation (OR 2.67, 95% CI 1.72 to 4.17), headache (OR 3.91, 95% CI 3.07 to 4.98), jaw pain (OR 5.33, 95% CI 3.64 to 7.81), diarrhoea (OR 3.11, 95% CI 2.39 to 4.05), nausea/vomiting (OR 2.92, 95% CI 2.29 to 3.73), pain in the extremities (OR 2.44, 95% CI 1.69 to 3.52), and myalgias (OR 3.05, 95% CI 2.02 to 4.58).

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