Prostanoid therapies in the management of pulmonary arterial hypertension

Figures & data

Figure 1 Forest plot of randomized clinical trials utilizing prostanoid therapies: All cause mortality. Cumulative relative risk (RR) estimate of death in active treatment groups was compared with that in control groups, excluding non-event trials. No heterogeneity was found. Fixed effect model for combined effect size was adopted.

Notes: Data points to the left of the solid line favor the prostanoid treatments, while data points to the right of the solid line favor placebo. Overall relative risk of death with active therapy was 0.56 (95% confidence interval 0.35–0.88, P=0.01). Springer and European Journal of Clinical Pharmacology, 70, 2013, 13–21, Prostanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomes, Zheng Y, Yang T, Chen G, et al, Figure 2, © Springer-Verlag Berlin Heidelberg 2013, with kind permission from Springer Science and Business Media.⁸
Abbreviations: RR, relative risk; CI, confidence interval; AIR, Aerosolized Iloprost Randomized study; TRIUMPH, TReprostinil sodium Inhalation Used in the Management of Pulmonary arterial Hypertension.

Table 1 Major randomized controlled trials of prostanoid therapy in pulmonary arterial hypertension (PAH)

Study	Population	Intervention	Results	Limitations
Rubin et al^Citation32	Patients (n=23) with idiopathic PAH, on conventional therapy	Addition of continuous intravenous infusion of epoprostenol (mean dose 7.9 ng/kg/min at 8 weeks, n=11) or conventional therapy alone (n=12) for 8 weeks	Total pulmonary resistance decreased by 7.9 Wood units (P=0.022 compared with baseline) in the treatment group	Study was not blinded or placebo controlled. The majority of study outcomes were changes in hemodynamics, with most clinical impacts unstudied
Barst et al^Citation4	Patients (n=81) with idiopathic PAH, on conventional therapy	Addition of continuous intravenous infusion of epoprostenol (mean dose 9.2 ng/kg/min at 12 weeks, n=41) or conventional therapy alone (n=40) for 12 weeks	6MWD increased by 31 m in the treatment group and decreased by 29 m in the conventional therapy group (P=0.002). Functional class, hemodynamics, and dyspnea scores improved in the treatment group. Eight deaths occurred, all in the conventional therapy group (P=0.003 for mortality difference)	Study was not blinded or placebo controlled. Baseline 6MWD was slightly lower (nonsignificant) in conventional therapy group
Badesch et al^Citation33	Patients (n=111) with PAH secondary to connective tissue disease, on conventional therapy	Addition of continuous intravenous infusion of epoprostenol (mean dose 11.2 ng/kg/min at 12 weeks, n=56) or conventional therapy alone (n=55) for 12 weeks	The treatment group experienced a between- treatment group 6MWD increase of +108 m (P<0.001). Functional class, hemodynamics, and dyspnea scores improved in the treatment group	Study was not blinded or placebo controlled. Mortality difference was not seen but study was not powered for this outcome
Simonneau et al^Citation39	Patients (n=469) with PAH of idiopathic cause (58%) or related connective tissue disease or congenital heart disease	Continuous subcutaneous infusion of treprostinil (mean dose 9.3 ng/kg/min at 12 weeks, n=233) or placebo (n=236) for 12 weeks	The treatment group experienced a placebo- corrected 6MWD increase of +16 m (P=0.006). Hemodynamics and dyspnea scores improved in the treatment group	Improvement in 6MWD was relatively modest for a monotherapy trial. High rates of infusion-site pain were noted, leading to 8% drug discontinuation
Olschewski et al AIR^Citation66	Patients (n=203) with idiopathic PAH (50%), PAH related to connective tissue disease or anorexigens, or CTEPH	Inhaled iloprost 2.5 or 5.0 μg (n=101) or placebo (n=102) six or nine times daily for 12 weeks	The primary end point of improvement in functional class and 10% increase in 6MWD was met by 16.8% of the treatment group, versus 4.9% of placebo group (P=0.007). Hemodynamics, dyspnea scores, and quality of life scores improved in the treatment group	A relatively small percentage (16.8%) of treatment patients met the primary outcome. Dosing at six to nine times per day may be more difficult in the non-research setting
McLaughlin et al^Citation67	Patients (n=67) with idiopathic (55%) or associated PAH, on bosentan at baseline	Addition of inhaled iloprost 5 μg (n=34) or placebo (n=33) six to nine times daily for 12 weeks	The treatment group experienced a nonsignificant placebo-corrected 6MWD increase of +26 m (P=0.051). Functional class and hemodynamics improved in the treatment group and clinical worsening was delayed	Almost all patients were functional class III. Significance for the primary outcome was not technically met (P=0.051)
McLaughlin et al TRIUMPH I^Citation74	Patients (n=235) with PAH of familial or idiopathic cause (56%) or related to connective tissue disease, HIV, or anorexigens; on bosentan or sildenafil monotherapy at baseline	Addition of inhaled treprostinil (up to 54 μg/dose; n=115) or placebo (n=120) four times daily for 12 weeks	The treatment group experienced a placebo- corrected peak 6MWD increase of +20 m (P=0.0004). Quality of life scores and NT-pro BNP improved. No change in dyspnea scores, functional class, or time to clinical worsening	Almost all patients were functional class III. All patients were on background therapy; role of inhaled treprostinil as monotherapy was not studied
Tapson et al FREEDOM-C^Citation83	Patients (n=350) with PAH of familial or idiopathic cause (66%) or related to congenital heart disease, connective tissue disease, or HIV; on ERA and/or PDE-5I at baseline	Addition of dose-titrated oral treprostinil (mean dose 3.0 mg at week 16, n=174) or placebo (n=176) twice daily for 16 weeks	No significant increase in placebo-corrected 6MWD (+11 m in the treatment group, P=0.07). Dyspnea fatigue index score improved in treatment group. No significant change in functional class, Borg dyspnea score, or clinical worsening	Primary endpoint was not met. At study initiation a starting dose of 1 mg twice daily was used; this was later decreased due to poor tolerability and high discontinuation rates
Jing et al FREEDOM-M^Citation82	Patients (n=349) with PAH of familial or idiopathic cause (75%) or related to congenital heart disease, connective tissue disease, or HIV; not on PAH therapy at baseline	Dose-titrated oral treprostinil (mean dose 3.4 mg at week 12, n=233) or placebo (n=116) twice daily for 12 weeks	The treatment group experienced a placebo- corrected 6MWD increase of +23 m (modified intention-to-treat analysis, P=0.0125). No change in functional class, dyspnea scores, or clinical worsening	Improvement in 6MWD was relatively modest for a monotherapy trial. Most secondary end points did not meet significance. High incidence of adverse effects
Tapson et al FREEDOM-C2^Citation84	Patients (n=310) with PAH of familial or idiopathic cause (65%) or related to congenital heart disease, connective tissue disease, or HIV; on ERA and/or PDE-5I at baseline	Addition of dose-titrated oral treprostinil (mean dose 3.1 mg at week 16, n=157) or placebo (n=153) twice daily for 16 weeks	No significant increase in placebo-corrected 6MWD (+10 m in the treatment group, P=0.089). No significant change in functional class, dyspnea scores, or clinical worsening	Primary endpoint was not met. Despite use of lower starting and titration doses, adverse effects were still common, with 11% drug discontinuation

Abbreviations: 6MWD, 6-minute walk distance; AIR, Aerosolized Iloprost Randomized study; NT-proBNP, N-terminal pro-B-type natriuretic peptide; CTEPH, chronic thromboembolic pulmonary hypertension; ERA, endothelin-receptor antagonist; m, meters; PDE-5I, phosphodiesterase-5 inhibitor; TRIUMPH, TReprostinil sodium Inhalation Used in the Management of Pulmonary arterial Hypertension.

ZhengYYangTChenGHuEGuQXiongCProstanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomesEur J Clin Pharmacol2014701132124026627

 PubMed Web of Science ®Google Scholar

RubinLJMendozaJHoodMTreatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trialAnn Intern Med199011274854912107780

 PubMed Web of Science ®Google Scholar

BarstRJRubinLJLongWAA comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertensionN Engl J Med199633452963018532025

 PubMed Web of Science ®Google Scholar

BadeschDBTapsonVFMcGoonMDContinuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trialAnn Intern Med2000132642543410733441

 PubMed Web of Science ®Google Scholar

SimonneauGBarstRJGalièNContinuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trialAm J Respir Crit Care Med2002165680080411897647

 PubMed Web of Science ®Google Scholar

OlschewskiHSimonneauGGalièNAerosolized Iloprost Randomized Study GroupInhaled iloprost for severe pulmonary hypertensionN Engl J Med2002347532232912151469

 PubMed Web of Science ®Google Scholar

McLaughlinVVOudizRJFrostARandomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertensionAm J Respir Crit Care Med2006174111257126316946127

 PubMed Web of Science ®Google Scholar

McLaughlinVVBenzaRLRubinLJAddition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trialJ Am Coll Cardiol201055181915192220430262

 PubMed Web of Science ®Google Scholar

TapsonVFTorresFKermeenFOral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trialChest201214261383139022628490

 PubMed Web of Science ®Google Scholar

JingZCParikhKPulidoTEfficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trialCirculation2013127562463323307827

 PubMed Web of Science ®Google Scholar

TapsonVFJingZCXuKFFREEDOM-C2 Study TeamOral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trialChest2013144395295823669822

 PubMed Web of Science ®Google Scholar