Safety and Efficacy of IV Treprostinil for Pulmonary Arterial Hypertension: A Prospective, Multicenter, Open-Label, 12-Week Trial

doi:10.1378/chest.129.3.683

Chest

Volume 129, Issue 3, March 2006, Pages 683-688

https://doi.org/10.1378/chest.129.3.683 Get rights and content

Background:

Pulmonary arterial hypertension (PAH) is a life-threatening disease for which both continuous IV epoprostenol and continuous subcutaneous treprostinil have proven effective. With continuous IV treprostinil having potential advantages over both of the above therapies, we investigated the safety and efficacy of this regimen in patients with PAH.

Methods:

We conducted a 12-week, prospective, open-label, uncontrolled, multicenter study of continuous IV treprostinil in 16 patients with PAH that was idiopathic (n = 8), related to connective tissue disease (n = 6), or related to congenital heart disease (n = 2). The primary end point was change from baseline to week 12 in exercise capacity assessed by the 6-min walk (6MW) test.

Results:

Continuous IV treprostinil increased 6MW distance (mean ± SE) by 82 m from baseline (319 ± 22 m) to week 12 (400 ± 26 m) [n = 14; p = 0.001]. There were also significant improvements in the secondary end points of Naughton-Balke treadmill time (p = 0.007), Borg dyspnea score (p = 0.008), and hemodynamics (mean pulmonary artery pressure, p = 0.03; cardiac index, p = 0.002; pulmonary vascular resistance, p = 0.001) at week 12 compared with baseline. Side effects were mild and consistent with those reported with prostacyclin treatment. One death, unrelated to study drug, occurred during the 12-week study in a patient who received 3 days of treprostinil and died 2 weeks later.

Conclusions:

Long-term IV infusion of treprostinil is safe and appears to be effective for the treatment of patients with PAH.

Section snippets

Patient Population

Patients with PAH that was idiopathic, related to connective tissue disease,¹⁷ or related to underlying congenital heart disease who were at least 12 years of age with symptomatic PAH despite treatment with anticoagulants, cardiac glycosides, diuretics, supplemental oxygen, and calcium-channel blockers (if indicated), in whom treatment with continuous IV epoprostenol was considered, were eligible for study participation if they met the following criteria: (1) a baseline 6-min walk (6MW)

Patients and Treprostinil Dosing

Sixteen patients with PAH were enrolled between February 2003 and September 2004. Fourteen of the 16 patients completed the 12-week protocol. One patient received drug for 3 days and died 2 weeks later. A second patient completed the 6-week study but was hospitalized and could not return for the 12-week studies. Thus, 16 patients are included in the baseline characteristics, 16 in the safety table, and 14 in the 12-week data table. Baseline demographic and hemodynamic characteristics are shown

Discussion

This is the first prospective evaluation of treprostinil, a stable prostacyclin analog, administered by the continuous IV route in patients with PAH. We demonstrated that IV treprostinil improved exercise capacity (assessed by the 6MW test and by the Naughton-Balke treadmill test), Borg dyspnea score, WHO functional class, and hemodynamics at week 12 compared to baseline. The most frequent side effects were those commonly attributed to prostacyclin therapy.

Potential advantages of IV

ACKNOWLEDGMENT:

We thank Abby Krichman, RRT (Duke University Medical Center) for contributing to the study design and development of the protocol. We also thank the study coordinators from each of the centers involved: Ginger Ward, RN (Duke University Medical Center), Daniela Brady, RN (Columbia University College of Physicians & Surgeons), and Susie McDevitt, RN (University of Michigan), as well as Carl Arneson, MStat, for statistical advice.

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Cited by (278)

Transition from Intravenous Epoprostenol to Treprostinil Due to Intolerable Side Effects in Patients With Pulmonary Arterial Hypertension
2023, American Journal of Cardiology
Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, it has side effects. Reviewing the side effects associated with epoprostenol and treprostinil is essential for improving the long-term treatment strategies for PAH. This retrospective review included patients with PAH who transitioned from intravenous epoprostenol to intravenous treprostinil owing to intolerable side effects, including high cardiac output symptoms, ascites, and thrombocytopenia. Of the 85 patients who received epoprostenol at our hospital between 2013 and 2021, 16 (11 women), with a median age of 33 (range 26 to 40) years (including 12 with idiopathic PAH, 3 with hereditary PAH, and 1 with connective tissue disease pulmonary hypertension), had to switch from intravenous epoprostenol to treprostinil owing to the side effects. After transitioning, epoprostenol-associated intolerable side effects, such as high cardiac output symptoms, ascites, and thrombocytopenia, were ameliorated. In conclusion, for patients with PAH who have intolerable side effects from epoprostenol and have difficulty in continuing treatment, switching from epoprostenol to treprostinil may be an option. Switching treatment leads to better adherence and improved long-term prostacyclin therapy.
Treprostinil in Neonates with Congenital Diaphragmatic Hernia-Related Pulmonary Hypertension
2023, Journal of Pediatrics
To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH).
A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores.
Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded.
In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.
Pulmonary hypertension
2022, Medicine (Spain)
La hipertensión pulmonar (HTP) es una enfermedad vascular arterial que deriva en un deterioro cardíaco y pulmonar grave. Es una patología compleja que requiere seguimiento y tratamiento en unidades multidisciplinares. Se divide en 5 grupos, englobando patologías con etiologías distintas, pero fisiopatología similar. Los pacientes clasificados como HTP grupo 1 se caracterizan por una afectación de la capacidad vasodilatadora y el remodelado de los vasos sanguíneos; los del grupo 2 por la afectación del corazón izquierdo; los del grupo 3 por la afectación secundaria a una patología pulmonar o hipoxia; los del grupo 4 por la obstrucción arterial y los del grupo 5 responden causas no conocidas o multifactoriales. Las manifestaciones clínicas se pueden solapar con otras patologías cardiopulmonares, por lo que es importante definir criterios de sospecha en pacientes con riesgo, seguir el algoritmo de diagnóstico e iniciar el tratamiento de forma precoz. El tratamiento es distinto en los tres grupos, pero su finalidad es principalmente disminuir la presión en la arteria pulmonar o tratar las causas que lo provocan.
Pulmonary hypertension (PHT) is a arterial vascular disease that leads to severe cardiac and pulmonary deterioration. It is a complex disease the requires monitoring and treatment in multidisciplinary units. It is classified into five groups, encompassing pathologies with different etiologies, but a similar pathophysiology. Patients classified as PHT group 1 are characterized by the involvement of vasodilatory capacity and remodeling of blood vessels, those in group 2 by left heart involvement, those in group 3 by involvement secondary to a pulmonary disease or hypoxia, those in group 4 by arterial obstruction, and those in group 5 by unknown or multifactorial causes. The clinical manifestations can overlap with other cardiopulmonary diseases. Therefore, it is important to define the criteria of suspicion in at-risk patients, follow the diagnostic algorithm, and start treatment early. The treatment is different in the three groups, but its purpose is mainly to decrease pulmonary artery pressure or treat the causes that trigger it.
Comprehensive review on novel targets and emerging therapeutic modalities for pulmonary arterial Hypertension
2022, International Journal of Pharmaceutics
Citation Excerpt :
However, newer stable epoprostenol formulation doesn’t require cold pouch or ice packs when diluted and administered at room temperature immediately for up to 24 h (Sitbon and Vonk Noordegraaf, 2017). Clinically, IV epoprostenol treatment in PAH patients improves hemodynamic parameters like PVR, mPAP, cardiac index, stroke volume, dyspnoea, fatigue, and 6MWD (Tapson et al., 2006). Treprostinil, another stable prostacyclin analogue, possess a similar activity as of epoprostenol and offers the advantage of IV administration at room temperature owing to its higher stability (4 hrs).
Pulmonary Arterial Hypertension (PAH) is the progressive increase in mean pulmonary arterial pressure (mPAP) (≥20 mmHg at rest). Current treatment strategies include the drugs targeting at nitric oxide pathway, endothelin receptors, prostaglandin receptors, thromboxane receptors and phosphodiesterase inhibitors, which provides the symptomatic relief. Despite of these treatments, the mortality amongst the PAH patients remains high due to non-reversal of the condition. This review primarily covers the introduction of PAH and the current treatments of the disease. This is followed by the newer disease targets expressed in the pathobiology of the disease like Rho Kinase Pathway, Vasoactive Intestinal Peptide Pathway, Receptor Tyrosine Kinases, Serotonin signalling pathway, Voltage-gated potassium (Kv) channel pathway. Newer formulation strategies for targeting at these specific receptors were covered and includes nano formulations like liposomes, Micelles, Polymeric Nanoparticles, Solid Lipid Nanoparticles (SLN), Bioresorbable stents, NONOates, Cell-Based Therapies, miRNA therapy for PAH. Novel targets were identified for their role in the pathogenesis of the PAH and needs to be targeted with new molecules or existing molecules effectively. Nanosystems have shown their potential as alternative carriers on the virtue of their better performance than traditional drug delivery systems.
Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension – A review of the past, present and future
2021, Respiratory Medicine
Therapy with intravenous prostacyclin analogues in patients with pulmonary arterial hypertension (PAH) has been established for decades and is an integral component of the current guidelines for the treatment of pulmonary hypertension.
Initially, these drugs were infused by external pump systems via tunnelled right atrial catheters with the need for cooling and frequent exchange of drug reservoirs. Associated complications included, among others, catheter-related infections.
More recently, fully implantable pump systems have been developed with drug reservoirs that are filled transcutaneously, allowing intervals between refills of several weeks. This technique results in a low rate of infections.
Epoprostenol, iloprost and treprostinil have all been used intravenously in PAH, but titration, dosing and dose escalation in long-term therapy are not standardized.
Intravenous prostacyclin analogues are still under-used, despite available data suggesting that early and broad application of these therapies as part of risk-oriented, guideline-directed combination therapy for patients with PAH may lead to a survival benefit.
This review provides a detailed overview of the drugs, infusion systems and dosing strategies used for intravenous therapy in patients with PAH.
Pulmonary Arterial Hypertension: A Palliative Medicine Review of the Disease, Its Therapies, and Drug Interactions
2020, Journal of Pain and Symptom Management
Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.

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This investigator-initiated study was supported by United Therapeutics Corporation, Research Triangle Park, NC.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Original Research: PULMONARY HYPERTENSIONSafety and Efficacy of IV Treprostinil for Pulmonary Arterial Hypertension: A Prospective, Multicenter, Open-Label, 12-Week Trial

Background:

Methods:

Results:

Conclusions:

Section snippets

Patient Population

Patients and Treprostinil Dosing

Discussion

ACKNOWLEDGMENT:

J Am Coll Cardiol

Prostaglandins Leukot Essent Fatty Acids

Prostaglandins Leukot Essent Fatty Acids

Chest

Primary pulmonary hypertension: a national prospective study

Ann Intern Med

Primary pulmonary hypertension

N Engl J Med

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

N Engl J Med

Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension

N Engl J Med

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial

Ann Intern Med

Original Research: PULMONARY HYPERTENSION
Safety and Efficacy of IV Treprostinil for Pulmonary Arterial Hypertension: A Prospective, Multicenter, Open-Label, 12-Week Trial