Pulmonary Hypertension, March 2006
Pulmonary Hypertension, March 2006
The Pulmonary Hypertension Journal Scan is the clinician's guide to the latest clinical research findings from JAMA, The New England Journal of Medicine, CHEST, and other journals of interest. Short summaries of feature articles include links to the article abstracts when available. (Access to full-text articles usually requires registration at the specific journal's Web site.)
Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al.
Chest. 2006:129;683-688
This paper reports the results of a prospective, open-label, multicenter study of intravenous treprostinil (TRE) as therapy for pulmonary arterial hypertension (PAH). TRE, which is a prostacyclin analogue, was originally approved as a continuous subcutaneous infusion for PAH. Although an effective form of therapy, the subcutaneous route is frequently hampered by severe infusion-related site pain. TRE has since received approval for administration as a continuous intravenous infusion. TRE has the advantage over epoprostenol, the only other form of IV therapy for PAH, in that it has a longer half-life, is stable at room temperature, and can be prepared every 48 hours rather than every 24 hours. Therefore, it is easier logistically for patient administration and adds a measure of safety through its longer half-life in the event of an unanticipated interruption.
This 12-week study, which was relatively small, included 16 patients with World Health Organization (WHO) functional class I PAH in whom IV prostanoid therapy was believed to be indicated. Of these 16 patients, 8 had idiopathic PAH, 6 had connective tissue disease, and 2 had congenital heart disease. Only 1 of the patients was on a specific PAH medication in the form of bosentan at baseline. Fourteen of the patients were WHO functional class III, and the remaining 2 were class IV. The mean pulmonary artery pressure of the group at baseline was 58 ± 15 mm Hg, right atrial pressure 12 ± 5 mm Hg, and the cardiac index was 1.7 ±0.4 L/min/m. In other words, this was a pretty sick group of patients. The 6-minute walk test (6MW) distance was the primary outcome measure. Patients were hospitalized for initiation of therapy, and the mean dose of IV TRE at discharge was 5 ng/kg/min. There were no specific guidelines for the uptitration of the drug, but at the end of the 12-week period, the mean dose was 41 ± 14 ng/kg/min in the 14 patients who completed the study. The 6MW distance increased by 82 meters, from 319 at baseline to 400 meters at 12 weeks. This was associated with a decrease in the Borg dyspnea score (4.3 to 2.5). Six of the 14 patients improved by at least 1 WHO functional class, and none of the remaining 8 had a deterioration in their WHO functional class.
Hemodynamic measures were also obtained, and these showed a 9% improvement in the mean pulmonary artery pressures, a 29% increase in the cardiac index, and a 33% reduction in pulmonary vascular resistance. One patient died from a subdural hematoma during the course of the study. A second patient was not included in the final analysis because he was hospitalized for urosepsis at an outside hospital and was therefore unable to complete the 12-week evaluation. Adverse events included the typical prostanoid side effects such as extremity pain, jaw pain, and gastrointestinal upset. There were no serious adverse events attributed to TRE. The mean systemic blood pressure decreased by 16.2 mm Hg, but only 1 patient reported any dizziness.
Although this was an open-label study involving a small number of patients, the results are most gratifying in that there was clear demonstration of the efficacy of IV TRE. The increase in the 6MW distance is especially remarkable and helps lay to rest any controversy arising from the pivotal study of subcutaneous TRE, in which an increase of only 16 meters was demonstrated. In that study, the mean dose at the end of the 12-week study period was only 9 ng/kg/min. In a subanalysis of the patients in the highest dose quartile, there was a 36-meter increase in the 6MW. The present study by Tapson and colleagues helps to confirm the implications of that pivotal study -- namely, that improvements are dose-dependent. Because of the small number of patients involved, the authors temper their conclusion with the statement that "the data... suggests that IV treprostinil is a safe and effective treatment option for patients with PAH." Nonetheless, this study provides a basis and rationale for using IV TRE in patients for whom an intravenous prostanoid is indicated.
Abstract
http://www.medscape.com/medline/abstract/16537868
This program was supported by an unrestricted educational grant from Actelion.
Chest
The Pulmonary Hypertension Journal Scan is the clinician's guide to the latest clinical research findings from JAMA, The New England Journal of Medicine, CHEST, and other journals of interest. Short summaries of feature articles include links to the article abstracts when available. (Access to full-text articles usually requires registration at the specific journal's Web site.)
Safety and Efficacy of IV Treprostinil for Pulmonary Arterial Hypertension: a Prospective, Multicenter, Open-Label, 12-Week Trial
Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al.
Chest. 2006:129;683-688
This paper reports the results of a prospective, open-label, multicenter study of intravenous treprostinil (TRE) as therapy for pulmonary arterial hypertension (PAH). TRE, which is a prostacyclin analogue, was originally approved as a continuous subcutaneous infusion for PAH. Although an effective form of therapy, the subcutaneous route is frequently hampered by severe infusion-related site pain. TRE has since received approval for administration as a continuous intravenous infusion. TRE has the advantage over epoprostenol, the only other form of IV therapy for PAH, in that it has a longer half-life, is stable at room temperature, and can be prepared every 48 hours rather than every 24 hours. Therefore, it is easier logistically for patient administration and adds a measure of safety through its longer half-life in the event of an unanticipated interruption.
This 12-week study, which was relatively small, included 16 patients with World Health Organization (WHO) functional class I PAH in whom IV prostanoid therapy was believed to be indicated. Of these 16 patients, 8 had idiopathic PAH, 6 had connective tissue disease, and 2 had congenital heart disease. Only 1 of the patients was on a specific PAH medication in the form of bosentan at baseline. Fourteen of the patients were WHO functional class III, and the remaining 2 were class IV. The mean pulmonary artery pressure of the group at baseline was 58 ± 15 mm Hg, right atrial pressure 12 ± 5 mm Hg, and the cardiac index was 1.7 ±0.4 L/min/m. In other words, this was a pretty sick group of patients. The 6-minute walk test (6MW) distance was the primary outcome measure. Patients were hospitalized for initiation of therapy, and the mean dose of IV TRE at discharge was 5 ng/kg/min. There were no specific guidelines for the uptitration of the drug, but at the end of the 12-week period, the mean dose was 41 ± 14 ng/kg/min in the 14 patients who completed the study. The 6MW distance increased by 82 meters, from 319 at baseline to 400 meters at 12 weeks. This was associated with a decrease in the Borg dyspnea score (4.3 to 2.5). Six of the 14 patients improved by at least 1 WHO functional class, and none of the remaining 8 had a deterioration in their WHO functional class.
Hemodynamic measures were also obtained, and these showed a 9% improvement in the mean pulmonary artery pressures, a 29% increase in the cardiac index, and a 33% reduction in pulmonary vascular resistance. One patient died from a subdural hematoma during the course of the study. A second patient was not included in the final analysis because he was hospitalized for urosepsis at an outside hospital and was therefore unable to complete the 12-week evaluation. Adverse events included the typical prostanoid side effects such as extremity pain, jaw pain, and gastrointestinal upset. There were no serious adverse events attributed to TRE. The mean systemic blood pressure decreased by 16.2 mm Hg, but only 1 patient reported any dizziness.
Although this was an open-label study involving a small number of patients, the results are most gratifying in that there was clear demonstration of the efficacy of IV TRE. The increase in the 6MW distance is especially remarkable and helps lay to rest any controversy arising from the pivotal study of subcutaneous TRE, in which an increase of only 16 meters was demonstrated. In that study, the mean dose at the end of the 12-week study period was only 9 ng/kg/min. In a subanalysis of the patients in the highest dose quartile, there was a 36-meter increase in the 6MW. The present study by Tapson and colleagues helps to confirm the implications of that pivotal study -- namely, that improvements are dose-dependent. Because of the small number of patients involved, the authors temper their conclusion with the statement that "the data... suggests that IV treprostinil is a safe and effective treatment option for patients with PAH." Nonetheless, this study provides a basis and rationale for using IV TRE in patients for whom an intravenous prostanoid is indicated.
Reference
Simonneau G, Barst RJ, Galie N, et al. 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. 2002;165:800-804.
Abstract
http://www.medscape.com/medline/abstract/16537868
This program was supported by an unrestricted educational grant from Actelion.
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