Prostacyclin for pulmonary arterial hypertension

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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 methods 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). 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.

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Barnes, H., Yeoh, H. L., Fothergill, T., Burns, A., Humbert, M., & Williams, T. (2019, May 1). Prostacyclin for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd. https://doi.org/10.1002/14651858.cd012785.pub2

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