Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: A placebo-controlled trial

doi:10.1016/j.healun.2009.09.005

The Journal of Heart and Lung Transplantation

Volume 29, Issue 2, February 2010, Pages 137-149

Present affiliation for author J.H.: Poona Hospital, Pune, India; K.P.: Heart Care Clinic, Ahmedabad, India; S.B.: Axis Clinicals, Hyderabad, India.

https://doi.org/10.1016/j.healun.2009.09.005 Get rights and content

Background

Pulmonary arterial hypertension (PAH) remains a poorly understood and frequently lethal disease with few treatment options.

Methods

We conducted a placebo-controlled trial of intravenous treprostinil, a prostacyclin analog, in treatment-naive PAH patients. During 12 weeks of treatment with treprostinil or placebo, we quantified 6-minute walk distance (6MW), clinical symptoms and 11 cytokines/growth factors.

Results

Forty-two of 44 study patients had idiopathic/familial PAH in New York Heart Association (NYHA) Class III. Treprostinil increased 6MW by a placebo-corrected median of 83 meters (p = 0.008; mean increase 93 ± 42 meters), reduced Borg score by a median 2.0 units (p = 0.02), and improved NYHA class by a median of 1.0 (p = 0.02). There was a trend toward improved survival with treprostinil (p = 0.051). Baseline plasma angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and platelet-derived growth factor (PDGF) were elevated compared with reported normal ranges. Treatment with treprostinil was associated with decreased Ang-2 levels. Improvement in 6MW distance after treatment was associated with reductions in Ang-2 and MMP-9 levels. Most of the cytokines and growth factors studied were not abnormal with disease nor did they change with treatment.

Conclusions

We conclude that treprostinil treatment significantly improved exercise capacity, dyspnea and functional class. Several plasma proteins that might track disease were abnormal at baseline, and changes were associated with improved exercise capacity.

Section snippets

Study design and patient population

This multicenter, randomized, double-blind, placebo-controlled trial compared continuous IV treprostinil to placebo in World Health Organization (WHO) Group 1 PAH patients residing in the Indian sub-continent. We confined this study to those with idiopathic PAH (sporadic or familial) and those whose PAH was associated with human immunodeficiency virus (HIV) or collagen vascular disease. Other entry criteria included: mean pulmonary arterial (PA) pressure >35 mm Hg; pulmonary capillary wedge

Patients

Forty-five patients were randomized and 44 (30 treprostinil, 14 placebo) were treated between March and October 2005 (Figure 1). One patient randomized to placebo died during catheter placement before receiving study drug and was excluded from analyses.

Most patients (95%) had IPAH with NYHA Class III symptoms (Table 1). The mean baseline 6MW in the treprostinil and placebo groups was 259 ± 12 meters and 231 ± 20 meters, respectively (Table 2A,p = 0.17). Baseline cardiopulmonary hemodynamics

Discussion

We have reported on the first placebo-controlled trial of intravenous therapy in PAH. This is also the first study to evaluate changes in a panel of cytokines and vascular growth factors before and after protocol-driven, blinded treatment with effective therapy. Intravenous treprostinil treatment resulted in a placebo-corrected median 6MW increase of 83 meters, which compares favorably with other approved PAH therapies.4, 5, 6, 7, 8

Doses increased steadily during the study, and the parallel

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Featured articleExercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: A placebo-controlled trial

Background

Methods

Results

Conclusions

Section snippets

Study design and patient population

Patients

Discussion

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A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial

Am J Respir Crit Care Med

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N Engl J Med

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Featured article
Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: A placebo-controlled trial