What are the treatment options for pulmonary hypertension?

Treatment Options for Pulmonary Hypertension

Initial treatment of pulmonary hypertension should be guided by risk stratification, with initial combination therapy including an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE5i) recommended for low/intermediate risk patients, while high-risk patients should receive initial combination therapy including intravenous prostacyclin analogues. 1

Classification and Risk Assessment

Pulmonary hypertension (PH) is classified into five groups:

• Group 1: Pulmonary Arterial Hypertension (PAH)
• Group 2: PH due to left heart disease
• Group 3: PH due to lung diseases/hypoxia
• Group 4: Chronic thromboembolic PH (CTEPH)
• Group 5: PH with unclear mechanisms 1, 2

Risk stratification is crucial for treatment decisions:

Risk Category	Estimated 1-year Mortality	Key Features
Low risk	<5%	WHO FC I-II, 6MWD >440m, No RV dysfunction
Intermediate risk	5-10%	WHO FC III, 6MWD 165-440m, Moderate RV dysfunction
High risk	>10%	WHO FC IV, 6MWD <165m, Severe RV dysfunction

Treatment Algorithm Based on Risk

Low to Intermediate Risk Patients (WHO FC II-III)

1. First-line therapy: Initial combination therapy with ambrisentan and tadalafil is recommended over monotherapy 3, 1
2. If combination therapy is not tolerated, monotherapy options include:
   • ERAs: bosentan, macitentan, or ambrisentan
   • PDE5i: sildenafil or tadalafil
   • Soluble guanylate cyclase stimulator: riociguat (note: must not be combined with PDE5i) 3, 1

High Risk Patients (WHO FC IV)

1. First-line therapy: Continuous IV epoprostenol, IV treprostinil, or SC treprostinil 3, 1
2. IV epoprostenol should be prioritized as it has demonstrated reduced 3-month mortality 1
3. For patients unable to receive parenteral prostanoids: Consider inhaled prostanoid in combination with an ERA and PDE5i 3

Inadequate Response to Initial Therapy

1. For patients with unacceptable clinical status despite established monotherapy: Add a second class of PAH therapy 3
2. For patients with unacceptable or deteriorating clinical status despite dual therapy: Add a third class of PAH therapy 3, 1

Specific Medication Information

Prostacyclin Pathway Agents

• IV Treprostinil: Indicated for PAH to diminish symptoms associated with exercise in WHO Group 1 patients. Initial dose: 1.25 ng/kg/min, which can be reduced to 0.625 ng/kg/min if not tolerated. Dose should be increased by 1.25 ng/kg/min per week for the first four weeks, then 2.5 ng/kg/min per week thereafter 4
• IV Epoprostenol: First-line for high-risk patients, starting at 2 ng/kg/min with titration based on tolerance 1

Endothelin Receptor Antagonists (ERAs)

• Ambrisentan: Used in combination with tadalafil as first-line therapy 3, 1
• Bosentan: Started at 62.5 mg twice daily for 4 weeks, then 125 mg twice daily 1
• Macitentan: Alternative ERA option 1

Phosphodiesterase-5 Inhibitors (PDE5i)

• Tadalafil: Shown to increase 6-minute walk distance by 33m (placebo-corrected) at 40mg daily dosing 5
• Sildenafil: Dosed at 20 mg three times daily, improves exercise capacity, WHO functional class, and hemodynamic parameters 6

Special Considerations

Hepatic Insufficiency

• In patients with mild or moderate hepatic insufficiency, decrease the initial dose of treprostinil to 0.625 ng/kg/min 4
• Medications should be titrated slowly due to greater systemic exposure 1

Medication Precautions

• Riociguat must never be combined with PDE5i due to risk of severe hypotension 1
• Avoid abrupt withdrawal of prostacyclin therapy which can lead to rebound pulmonary hypertension 1, 4
• Monitor for liver function abnormalities with ERA therapy 1

Supportive Care and Lifestyle Modifications

• Avoid high altitude exposure and ensure supplemental oxygen during air travel to maintain saturations >91% 3, 1
• Pregnancy should be avoided due to high mortality risk 3, 1
• Incorporate palliative care services to address symptom burden and quality of life 3, 1
• Supervised exercise training is recommended for deconditioned patients 1
• Maintain current immunizations against influenza and pneumococcal pneumonia 3, 1

Advanced Therapies

• Lung transplantation should be considered for patients with inadequate response to maximal medical therapy 1
• Pulmonary endarterectomy is the treatment of choice for eligible CTEPH patients 1
• Atrial septostomy may be considered as a bridge to transplantation 1

Monitoring and Follow-up

• Regular assessments every 3-6 months including WHO FC, 6MWD, BNP/NT-proBNP levels, and echocardiography 1
• Management should occur at specialized centers with expertise in pulmonary hypertension 1, 7

By following this evidence-based approach to treatment based on risk stratification, patients with pulmonary hypertension can experience improved symptoms, exercise capacity, and potentially survival.