Tyvaso® has been studied in TRIUMPH I, one of the largest trials for pulmonary arterial hypertension (PAH). View the results in the presentation below. The TRIUMPH I study assessed the efficacy and safety of Tyvaso in patients with PAH on background oral therapy with either a PDE-5 inhibitor or an ETRA.
One of the largest trials of an add-on therapy in pulmonary arterial hypertension (N=235)1,2
12-week, multicenter, randomized, double-blind, placebo-controlled trial of an inhalable prostanoid (Tyvaso) and a single oral PAH agent (a PDE-5 inhibitor or an ETRA)1
Patients had been receiving a single oral PAH agent for ≥3 months and continued on this medication throughout the study, regardless of treatment arm1
Nearly all patients were NYHA Class III severity (98%) with a baseline 6MWD between 200 m and 450 m1
All patients had a confirmed diagnosis of PAH that was idiopathic or familial (56%), secondary to connective tissue disease (33%), or secondary to HIV or previous anorexigen use (12%)1
Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2011.
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;55:1915-22.
Tyvaso is intended for oral inhalation only. Tyvaso is approved for use only with the Tyvaso Inhalation System
The safety and efficacy of Tyvaso have not been established in patients with significant underlying lung disease (such as asthma or chronic obstructive pulmonary disease) and in patients under 18 years of age. Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect
Tyvaso may increase the risk of bleeding, particularly in patients receiving anticoagulants
Study Design
ETRA=endothelin receptor antagonist; PDE-5=phosphodiesterase-5; TRIUMPH=TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension
Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2011.
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;55:1915-22.
Tyvaso is intended for oral inhalation only. Tyvaso is approved for use only with the Tyvaso Inhalation System
The safety and efficacy of Tyvaso have not been established in patients with significant underlying lung disease (such as asthma or chronic obstructive pulmonary disease) and in patients under 18 years of age. Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect
Tyvaso may increase the risk of bleeding, particularly in patients receiving anticoagulants
Results
Adding Tyvaso to oral monotherapy demonstrated additional improvements in 6MWD vs inhalable placebo plus oral monotherapy1
Primary endpoint: Peak 6MWD at 12 weeks
Patients receiving Tyvaso had a placebo-corrected median change from baseline in peak 6MWD of 20 meters at week 12 (p<0.001)1
Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2011.
In patients with low systemic arterial pressure, Tyvaso may cause symptomatic hypotension. The concomitant use of Tyvaso with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension
Hepatic or renal insufficiency may increase exposure to Tyvaso and decrease tolerability. Tyvaso dosage adjustments may be necessary if inhibitors of CYP2C8 such as gemfibrozil or inducers such as rifampin are added or withdrawn
Safety Results
Discontinuations due to adverse events were similar to placebo (6% Tyvaso vs 3% placebo)1
In a long-term, open-label extension of the TRIUMPH I trial (N=206), safety findings were qualitatively similar to those of the placebo-controlled phase2
Therapy was continued for a mean duration of 1 year
Serious adverse events included pneumonia (N=8) and hemoptysis (N=3)
The most common adverse event was cough, which occurred in 54% of patients receiving inhalable treprostinil as compared with 29% of patients receiving placebo. There were 11 serious adverse events reported in the inhalable treprostinil group, including 3 events of worsening pulmonary hypertension, 2 events of syncope, and 1 event of each of the following: anemia, abdominal pain, diabetes mellitus, diarrhea, gastric ulcer, and right ventricular failure1
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;55:1915-22.
Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2011.
In patients with low systemic arterial pressure, Tyvaso may cause symptomatic hypotension. The concomitant use of Tyvaso with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension
Hepatic or renal insufficiency may increase exposure to Tyvaso and decrease tolerability. Tyvaso dosage adjustments may be necessary if inhibitors of CYP2C8 such as gemfibrozil or inducers such as rifampin are added or withdrawn
Safety Results
Adverse Events in ≥4% of Patients Receiving Tyvaso and More Frequent* than Placebo1
Tyvaso [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2011.
The most common adverse events seen with Tyvaso in 4% of PAH patients and more than 3% greater than placebo in the placebo-controlled clinical study were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%)
Tyvaso should be used in pregnancy only if clearly needed. Caution should be exercised when Tyvaso is administered to nursing women
Conclusions
When Tyvaso was added to oral monotherapy (bosentan or sildenafil):
Improvement in 6MWD was shown1:
20 m median improvement in peak 6MWD at 12 weeks
14 m median improvement in trough 6MWD maintained at 12 weeks
More than half (52%) of patients receiving Tyvaso had a 6MWD improvement of greater than 20 m
No difference in time to clinical worsening between Tyvaso and placebo at 12 weeks
No change in Borg dyspnea score, NYHA functional class, or PAH signs and symptoms from baseline to week 12 compared with placebo
Twenty-three patients prematurely discontinued the study1:
In the placebo group: 1 patient died, 4 withdrew due to adverse events, and 5 patients withdrew consent; of these patients, 8 were receiving background bosentan
In the inhaled treprostinil group: 3 patients discontinued due to worsening pulmonary hypertension, 7 withdrew due to adverse events, and 3 withdrew consent; of these patients, 9 were receving background bosentan
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;55:1915-22.
The most common adverse events seen with Tyvaso in ≥4% of PAH patients and more than 3% greater than placebo in the placebo-controlled clinical study were cough (54% vs 29%), headache (41% vs 23%), throat irritation/ pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%)
Tyvaso should be used in pregnancy only if clearly needed. Caution should be exercised when Tyvaso is administered to nursing women
Indication
Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).
The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.
While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.
Important Safety Information for Tyvaso
Tyvaso is intended for oral inhalation only. Tyvaso is approved for use only with the Tyvaso Inhalation System
The safety and efficacy of Tyvaso have not been established in patients with significant underlying lung disease (such as asthma or chronic obstructive pulmonary disease) and in patients under 18 years of age. Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect
Tyvaso may increase the risk of bleeding, particularly in patients receiving anticoagulants
In patients with low systemic arterial pressure, Tyvaso may cause symptomatic hypotension. The concomitant use of Tyvaso with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension
Hepatic or renal insufficiency may increase exposure to Tyvaso and decrease tolerability. Tyvaso dosage adjustments may be necessary if inhibitors of CYP2C8 such as gemfibrozil or inducers such as rifampin are added or withdrawn
The most common adverse events seen with Tyvaso in ≥4% of PAH patients and more than 3% greater than placebo in the placebo-controlled clinical study were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%)
Tyvaso should be used in pregnancy only if clearly needed. Caution should be exercised when Tyvaso is administered to nursing women
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Why
Study Design
Study Design
