Prostacyclin for Pulmonary Hypertension

Summary

A Cochrane review [Abstract] 1 included 9 RCTs of mixed duration (3 days-52 weeks) with a total of 1175 participants (NYHA functional classes II-IV).

• Intravenous prostacyclin versus usual care (4 studies): There were significant improvements in exercise capacity of around 90 metres (SMD 0.69, 95% CI 0.40 to 0.97; 3 trials), cardiopulmonary haemodynamics and NYHA functional class over 3 days-12 weeks. Effects were consistent in primary and secondary pulmonary hypertension.
• Oral prostacyclin versus placebo (2 studies): Short-term data (3-6 months) indicated that there was a significant improvement in exercise capacity, but data from one study of 52 weeks reported no significant difference at 12 months. No significant differences were observed for any other outcome.
• Subcutaneoustreprostinil versus placebo (2 studies, 8-12 weeks): One large study reported a significant median improvement in exercise capacity of around 16 metres. Cardiopulmonary haemodynamics and symptom scores favoured treprostinil. Infusion site pain and withdrawals due to adverse events were more frequent with treprostinil.
• Inhaled prostacyclin versus placebo (1 study, 12 weeks): There was a significant increase in exercise capacity of approximately 36 metres. Treatment led to better symptom scores and functional class status than with placebo.

Subgroup analyses reported by individual studies showed a better exercise capacity in participants with PPH, than those participants with PH secondary to other diseases. Side effects and adverse events were common in the studies.

Another Cochrane review [Abstract] 2 included 17 studies (median study duration 12 weeks) with a total of 3 765 mostly adult subjects pulmonary arterial hypertension (PAH). Fifteen studies compared a prostacyclin analogue (4 intravenous, 1 subcutaneous, 5 oral, and 5 inhaled) with placebo/conventional treatment, and 2 studies compared selexipag (an oral selective IP prostacyclin receptor agonist) to placebo.

Prostacyclin improved WHO functional class compared to control (table T1). Improvement occurred with intravenous (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. There was a small, statistically significant improvement in six-minute walk distance, 6MWD (MD 19.50 metres, 95% CI 14.82 to 24.19; 13 studies, n=2 283), though it did not meet the minimum clinically important threshold of 41 metres. Clinically significant increase was obseved with intravenous (MD 91.76 metres, 95% CI 58.97 to 124.55), but not with non-intravenous preparations (subcutaneous 16.00 metres, oral 14.76 metres, inhaled 26.97 metres). Mortality was reduced in the intravenous (OR 0.29, 95% CI 0.12 to 0.69; 4 studies, n=255), but not in the non-intravenous studies (OR 0.82, 95% CI 0.48 to 1.40; 12 studies, n=2 299). Prostacyclins improved cardiopulmonary haemodynamics, dyspnoea, and quality of life compared to control. When only subcutaneous/inhaled studies were included the effect was still significant, but the magnitude was smaller, and there was no difference in oral studies.Adverse events (vasodilation, headache T1, jaw pain, diarrhoea, nausea/vomiting, myalgias, upper respiratory tract events, extremity pain, and infusion site reactions) increased in all prostacyclin preparations . There was a 12%-25% risk of serious non-fatal events (sepsis, haemorrhage, pneumothorax and pulmonary embolism) in the intravenous studies.

Two studies (n=1 199) compared oral selexipag to placebo. There was a small improvement in 6MWD (12.62 metres, 95% CI 1.90 to 23.34), and no statistically significant effect for WHO functional class (OR 1.61, 95% CI 0.17 to 15.63). The effect of selexipag on the risk of death was uncertain (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), but more side effects (vasodilation, headache, jaw pain, diarrhoea, nausea/vomiting, pain in the extremities, and myalgias).