What are the treatment options for pulmonary hypertension using an inhaler, such as iloprost (prostacyclin analog) or treprostinil (prostacyclin analog)?

Inhaled Prostacyclin Therapy for Pulmonary Arterial Hypertension

For patients with WHO Functional Class III pulmonary arterial hypertension who remain symptomatic on stable doses of an endothelin receptor antagonist or PDE5 inhibitor, add inhaled treprostinil or inhaled iloprost as combination therapy to improve exercise capacity and functional status. 1

Clinical Context and Patient Selection

When to Use Inhaled Prostacyclins

Add-on therapy for inadequate response to oral agents:

• Patients in WHO FC III with disease progression despite treatment with one or two classes of oral PAH medications should receive inhaled prostacyclin therapy 1
• Inhaled treprostinil improves 6-minute walk distance (6MWD) when added to stable doses of an ETRA or PDE5 inhibitor (Grade 2C recommendation) 1
• Inhaled iloprost improves WHO functional class and delays time to clinical worsening when added to stable doses of an ETRA or PDE5 inhibitor (Grade 2B recommendation) 1

Alternative for WHO FC IV patients unable to manage parenteral therapy:

• For treatment-naive WHO FC IV patients who cannot or will not manage parenteral prostanoid therapy, use inhaled prostacyclin in combination with an ETRA 1
• This represents a compromise when IV epoprostenol (the preferred therapy for FC IV) is not feasible 1

Inhaled Treprostinil: Dosing and Administration

Initial Dosing Protocol

• Start with 3 inhalations (18 mcg) four times daily (every 6 hours) 1, 2
• Titrate upward to achieve optimal effect, targeting 9 inhalations (54 mcg) four times daily 1
• The four-times-daily dosing schedule is more convenient than iloprost's 6-9 times daily requirement 3, 4

FDA-Approved Indications

• Treatment of PAH (WHO Group 1) to diminish symptoms associated with exercise 2
• Approved for patients with NYHA Functional Class II-IV symptoms 2
• Studied in idiopathic/heritable PAH (58%), PAH with congenital shunts (23%), and PAH with connective tissue disease (19%) 2

Clinical Evidence

• Inhaled treprostinil demonstrates pronounced pulmonary selectivity with minimal systemic vasodilatory effects 4
• In the pivotal trial with 253 patients, inhaled treprostinil improved physical capacity with excellent tolerability 4
• Patients transitioning from inhaled iloprost to inhaled treprostinil maintained clinical status while reducing daily treatment time by 1.4 hours 3

Inhaled Iloprost: Dosing and Administration

Dosing Requirements

• Administer 2.5-5 mcg per inhalation, 6-9 times daily 1
• Maximum daily dose: 45 mcg (median effective dose: 30 mcg/day) 1
• Each inhalation session takes approximately 15 minutes with jet nebulizers or 5 minutes with ultrasound nebulizers 1

Clinical Evidence

• The AIR trial (203 patients with PAH and CTEPH) demonstrated that 17% of iloprost-treated patients achieved the combined endpoint of ≥10% improvement in 6MWD plus NYHA functional class improvement versus 5% with placebo (p=0.007) 1
• Mean increase in 6MWD was 36 meters overall (p=0.004) and 59 meters in the IPAH subgroup 1
• Significant improvements in NYHA functional class (p=0.05), quality of life (p=0.05), and dyspnea index (p=0.05) 1
• The STEP trial showed improved exercise capacity when inhaled iloprost was added to bosentan (p<0.051) 1

Hemodynamic Effects

• Hemodynamic variables significantly improved when measured after iloprost inhalation but were largely unchanged when measured before inhalation 1
• This reflects the relatively short duration of action (approximately 60 minutes) requiring frequent dosing 1, 5
• Acute inhalation produces more potent pulmonary vasodilation than inhaled nitric oxide 1

Comparative Considerations: Treprostinil vs. Iloprost

Practical Advantages of Treprostinil

• Dosing frequency: 4 times daily versus 6-9 times daily for iloprost 1, 3, 4
• Treatment time: Significantly reduced daily treatment burden (1.4 hours saved per day when transitioning from iloprost) 3
• Duration of action: Longer-lasting effects due to stable prostacyclin analogue properties 4

When Iloprost May Be Preferred

• More extensive long-term safety data in European guidelines 1
• Approved in Europe since 2004 with established clinical experience 1
• May be considered when treprostinil is not available or not tolerated 1

Common Adverse Effects and Management

Inhaled Treprostinil

• Cough (74% of patients), headache (44%), and nausea (30%) are most common 3
• Most adverse events are mild and transient 3
• Only 3 patients discontinued due to adverse events in the transition study 3

Inhaled Iloprost

• Cough, flushing, and jaw pain are most frequent side effects 1
• Headache, flushing, and jaw pain occur significantly more frequently than placebo 5
• Increased airway reactivity noted in some pediatric patients 1
• Generally well-tolerated with mild, transient adverse effects 1

Critical Safety Considerations

Infrastructure Requirements

• Prostanoid therapies require proper infrastructure and specialty center care 1
• Patients must be able to manage complex delivery systems and comply with frequent dosing 1
• Family support is paramount for successful inhaled prostanoid therapy 1
• Centers without proper infrastructure should refer patients to experienced pulmonary hypertension centers 1

Monitoring Requirements

• Regular clinical assessment every 3-6 months to evaluate functional class, exercise capacity, and disease progression 6
• Management by a pulmonary hypertension specialist is recommended 6
• Avoid abrupt cessation of therapy as this can lead to rebound pulmonary hypertension with clinical deterioration and potential death 1, 6

When Inhaled Therapy Is Insufficient

Escalate to parenteral prostacyclin therapy when:

• Patients in WHO FC III show evidence of rapid disease progression or markers of poor clinical prognosis despite inhaled prostacyclin plus oral agents 1
• IV epoprostenol should be added to improve WHO FC, 6MWD, and cardiopulmonary hemodynamics 1
• IV treprostinil is an alternative to improve 6MWD and hemodynamics 1

For WHO FC IV patients:

• IV epoprostenol is the therapy of choice based on improved survival in randomized studies and extensive clinical experience 1
• Inhaled prostacyclins should only be used in FC IV patients who cannot manage parenteral therapy, and must be combined with an ETRA 1