Medications for Pulmonary Hypertension
For treatment-naive patients with pulmonary arterial hypertension (PAH) WHO functional class II-III, initial combination therapy with ambrisentan 10 mg daily plus tadalafil 40 mg daily is the preferred first-line treatment, as this significantly delays clinical failure and improves exercise capacity compared to monotherapy. 1
Treatment Algorithm by Risk Stratification
Low-to-Intermediate Risk Patients (WHO FC II-III)
Initial combination therapy with ambrisentan plus tadalafil should be started immediately rather than monotherapy, as this approach has proven superior in delaying clinical failure 2, 1. The specific dosing is:
- Ambrisentan: Start at 5 mg once daily, increase to 10 mg once daily when tolerated 2, 1
- Tadalafil: 40 mg once daily 1, 3
This combination improved 6-minute walk distance by 49 meters versus 24 meters with monotherapy (p<0.001) 1.
High-Risk Patients (WHO FC IV)
Intravenous epoprostenol must be included in the initial combination therapy for high-risk patients, as it is the only agent that has reduced 3-month mortality in this population 2, 1. This should be prioritized over other prostacyclin analogues given the mortality benefit 2.
Alternative Monotherapy Options (When Combination Not Feasible)
Phosphodiesterase-5 Inhibitors
Sildenafil 20 mg three times daily is FDA-approved and improved 6-minute walk distance by 45-50 meters (p<0.001) 2, 1, 4. However, the durability of effect up to one year has only been demonstrated with 80 mg three times daily, and up-titration to 40-80 mg three times daily is frequently needed in clinical practice 2.
Critical contraindication: Sildenafil is absolutely contraindicated with nitrates or nicorandil due to risk of profound, potentially fatal systemic hypotension 1, 4.
Endothelin Receptor Antagonists
Bosentan (dual endothelin receptor antagonist): Start 62.5 mg twice daily for 4 weeks, then increase to 125 mg twice daily maintenance 1. This improved 6-minute walk distance by 44 meters (p<0.001) but requires monthly liver function monitoring due to 11% incidence of elevated transaminases (>3x upper limit normal) 1.
Ambrisentan (endothelin type A receptor-selective): 5-10 mg once daily, which increased 6-minute walk distance by 36.1 meters (p=0.0001) and has lower hepatic toxicity with only 3.1% incidence of elevated transaminases 2, 1.
Sequential Combination Therapy for Treatment Failure
If inadequate clinical response occurs (defined as no improvement or worsening WHO functional class, decline in 6-minute walk distance, or clinical worsening events such as hospitalization) 1, add a second agent from a different drug class:
- Macitentan can be added to stable PDE5 inhibitor or inhaled prostanoid therapy 1
- Treprostinil (IV, subcutaneous, or inhaled) can be added to stable endothelin receptor antagonist or PDE5 inhibitor therapy 1
After inadequate response to double combination therapy, triple combination therapy should be attempted 2. Consider lung transplant evaluation after inadequate response to initial therapy 1.
Critical Drug Interactions to Avoid
Absolute contraindications 1:
- PDE5 inhibitors + nitrates/nicorandil (risk of fatal hypotension)
- Bosentan + cyclosporine
- Bosentan + glibenclamide
- Riociguat + PDE5 inhibitors 2
Interactions requiring monitoring 1:
- Bosentan + sildenafil
- Bosentan + warfarin (requires dose adjustment)
- Bosentan + simvastatin/atorvastatin
Important Caveats for Secondary Pulmonary Hypertension
For PH due to left heart disease: PAH-specific drugs are NOT recommended until robust long-term data are available, as trials with epoprostenol and bosentan were terminated early due to increased adverse events 2. Optimal treatment of the underlying cardiac disease should be the primary focus 2.
For PH due to lung disease (COPD, interstitial lung disease): Sildenafil should only be considered for patients with "out-of-proportion" pulmonary hypertension (where PH severity exceeds what would be expected from airflow limitation) who have failed or are not candidates for other therapies 5, 6. This is not FDA-approved for this indication and most studies are small and short-duration 5.