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TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension - TRIUMPH
Description:
The three main classes of medications used in pulmonary arterial hypertension (PAH) include prostacyclins (e.g., treprostinil, iloprost), endothelin receptor antagonists (e.g., bosentan), and phosphodiesterase (PDE) inhibitors (e.g., sildenafil). Although numerous trials have demonstrated the utility of the different agents as monotherapy in the treatment of PAH, very little data exist on the use of combination therapy. The current trial sought to study the safety and efficacy of inhaled treprostinil in PAH patients who were already on either bosentan or sildenafil.
Hypothesis:
Inhaled treprostinil would be superior to placebo as add-on therapy in patients with PAH who were receiving either bosentan or sildenafil.
Study Design
- Parallel
Patients Enrolled: 235
Mean Follow Up: 12 weeks
Mean Patient Age: 54 years
Female: 81
Patient Populations:
- Age 18-75 years
- Confirmed diagnosis of idiopathic or familial PAH, or associated with collagen vascular disease, HIV infection, anorexigen use
- NYHA class III/IV symptoms
- Baseline 6MWD of 200-450 m
- On bosentan 125 mg daily, or sildenafil ≥20 mg tid, for at least 3 months
Exclusions:
- Pregnant or nursing
- Any acute or chronic illness, other than that associated with PAH
- Changed or discontinued any PAH medication within 3 months
- Received other investigational medications, prostanoids, or PDE inhibitors (except sildenafil) within 30 days
Primary Endpoints:
- 6MWD at 12 weeks
Secondary Endpoints:
- Time to clinical worsening (death, transplantation, hospital stay due to worsening PAH, initiation of additional approved PAH-specific therapy)
- Borg dyspnea score
- NYHA functional class
- Through 6MWD at week 12
- Peak 6MWD at week 6
- Quality of life
- PAH signs and symptoms
Drug/Procedures Used:
Inhaled treprostinil or placebo was administered 4 times daily, using the OPTINEB nebulizer device. Patients were usually initiated at 3 breaths (18 mcg)/inhalation. If tolerated, this was increased to a goal of 9 breaths (54 mcg)/inhalation.
Concomitant Medications:
Bosentan (70%), sildenafil (30%)
Principal Findings:
A total of 235 patients were randomized, 115 to trepostrinil, and 120 to placebo. Baseline characteristics were fairly similar between the two arms. PAH was idiopathic or familial in more than one-half of the patients (56%). The majority of patients had New York Heart Association (NYHA) class III symptoms (98%). Baseline 6-minute walk distance (6MWD) was about 350 m. The mean dose of trepostinil used in the study was 50 mcg.
The peak 6MWD increased by 21.6 m in the trepostrinil group, as compared with 3.0 m in the placebo group, with a resultant 19.0 m treatment difference at 6 weeks (p = 0.0001), and 20.0 m at 12 weeks between the two groups (p = 0.0004). Patients in the lowest quartile for baseline 6MWD seemed to derive a greater benefit (treatment difference = 49 m). Patients who were on baseline bosentan seemed to derive a benefit of 25 m at 12 months (p = 0.0002), whereas patients on baseline sildenafil did not derive a statistically significant improvement at 12 weeks (9 m, p = NS).
Secondary endpoints such as Borg dyspnea score, NYHA functional class, and PAH signs and symptoms were similar between the two groups at the end of follow-up. There seemed to be an improvement in quality of life in both the global and physical scales. At week 12, there was also a significant difference in the N-terminal pro-brain natriuretic peptide (NT-proBNP) between the two arms, as compared with baseline (-187 pg/ml, p = 0.0014).
Clinical worsening, primarily to hospitalization for PAH, was similar between the two arms (3% vs. 5%, p = NS). A total of 13 patients in the treprostinil and 10 patients in the placebo arm discontinued treatment before the end of follow-up. Adverse events included a higher incidence of cough (54% vs. 29%), headache (41% vs. 23%), and flushing (15% vs. <1%) in="" the="" treprostinil="" arm="" vs.="" placebo,="" respectively.="" other="" adverse="" events="" such="" as="" nausea,="" diarrhea,="" and="" dizziness="" were="" similar="" between="" the="" two="" arms.="" there="" were="" no="" deaths="" in="" either="" arm,="" and="" one="" transplant="" in="" the="" placebo="" arm.="" in="" the="" treprostinil="" arm="" vs.="" placebo,="" respectively.="" other="" adverse="" events="" such="" as="" nausea,="" diarrhea,="" and="" dizziness="" were="" similar="" between="" the="" two="" arms.="" there="" were="" no="" deaths="" in="" either="" arm,="" and="" one="" transplant="" in="" the="" placebo="">
Interpretation:
The results of this trial indicate that in patients with predominantly NYHA class III symptoms due to PAH, the addition of inhaled prostacyclin, treprostinil, to either bosentan or sildenafil, is associated with a significant improvement in 6MWD at 12 weeks, as compared with placebo. This effect is observed as early as 6 weeks, and appears to be sustained until 12 weeks.
Most prior studies on combination therapy in PAH have utilized parenteral prostacyclins. This study highlights the utility of using inhaled treprostinil, as an addition to oral therapy, in patients with symptomatic PAH. Further long-term data are necessary.
References:
McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010;55:1915-1922.
Keywords: Phosphodiesterase Inhibitors, Epoprostenol, Follow-Up Studies, Purines, Headache, HIV Infections, Vasodilator Agents, Dizziness, Hypertension, Pulmonary, Prostaglandins I, Cough, Sulfonamides, Natriuretic Peptide, Brain, Nausea, Iloprost, Nebulizers and Vaporizers, Diarrhea, Vascular Diseases, Piperazines, Phosphoric Diester Hydrolases, Dyspnea, Sulfones, Urological Agents, Receptors, Endothelin, Quality of Life, Peptide Fragments, Collagen
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