What is the recommended treatment for pulmonary hypertension?

Treatment of Pulmonary Hypertension

For patients with pulmonary arterial hypertension (PAH, WHO Group 1), initial oral combination therapy with ambrisentan and tadalafil is the recommended first-line treatment for most patients with WHO Functional Class II-III disease, while continuous intravenous epoprostenol should be prioritized for high-risk WHO Functional Class IV patients as it is the only therapy proven to reduce mortality. 1, 2

Initial Assessment and Risk Stratification

Before initiating therapy, several critical steps must be completed:

• Perform vasoreactivity testing during right heart catheterization to identify the approximately 10% of idiopathic PAH patients who may respond to calcium channel blockers 1
• Risk stratify patients based on clinical evidence of right ventricular failure, WHO functional class, exercise capacity (6-minute walk distance), and hemodynamic parameters 1
• Confirm the specific WHO Group of pulmonary hypertension, as treatment strategies differ fundamentally between groups 1

Treatment Algorithm Based on Disease Severity

For Vasoreactive Patients (≈10% of idiopathic PAH)

• High-dose calcium channel blockers (long-acting nifedipine, diltiazem, or amlodipine) are recommended as first-line therapy 1
• Avoid verapamil due to negative inotropic effects 1
• Monitor closely: if patients do not improve to WHO Functional Class I or II, additional PAH-specific therapy must be instituted 1

For Non-Vasoreactive Patients with Low-Intermediate Risk (WHO FC II-III)

• Initial oral combination therapy with ambrisentan and tadalafil is superior to monotherapy in delaying clinical failure and should be the standard approach 1
• For patients unable to tolerate combination therapy, monotherapy with endothelin receptor antagonists (bosentan or ambrisentan) or phosphodiesterase-5 inhibitors can be considered 1

For High-Risk Patients (WHO FC IV)

• Continuous intravenous epoprostenol is strongly recommended as it has reduced 3-month mortality rates in high-risk PAH patients 1, 2
• Initial combination therapy including intravenous prostacyclin analogues should be implemented 1

Supportive Care Measures

These interventions are essential adjuncts to PAH-specific therapy:

• Diuretics are indicated for patients with signs of right ventricular failure and fluid retention 1
• Continuous long-term oxygen therapy is recommended when arterial blood oxygen pressure is consistently <8 kPa (60 mmHg) 1
• Oral anticoagulation should be considered in patients with idiopathic PAH, heritable PAH, and PAH due to anorexigens 1
• Supervised exercise rehabilitation should be considered for physically deconditioned patients 1
• Immunization against influenza and pneumococcal pneumonia is recommended 1

Treatment for Other WHO Groups

Group 2: PH Due to Left Heart Disease

• Focus treatment on optimizing the underlying cardiac condition 1
• PAH-specific therapies are NOT recommended as they have not shown benefit and may cause harm 1

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• Pulmonary endarterectomy (PEA) is the treatment of choice when feasible, as it is potentially curative 3, 1
• Life-long anticoagulation with vitamin K antagonists (target INR 2.0-3.0) is mandatory 3
• Medical therapy with PAH-specific drugs may be considered for: (1) inoperable patients, (2) pre-operative hemodynamic optimization, or (3) symptomatic residual/recurrent PH after PEA 3
• Bosentan has been studied in inoperable CTEPH patients, showing significant reduction in pulmonary vascular resistance but no change in 6-minute walk distance 3

Advanced Therapies

When maximal medical therapy fails:

• Lung transplantation should be considered soon after inadequate clinical response on maximal medical therapy 1
• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal therapy 1

Critical Pitfalls to Avoid

• Never combine riociguat with PDE-5 inhibitors (such as sildenafil or tadalafil) due to risk of severe hypotension 1
• Do not use sildenafil tablets 20 mg with sildenafil citrate tablets 25-100 mg or other PDE-5 inhibitors 4
• Avoid intubation when possible in patients with right ventricular failure, as positive pressure ventilation can worsen right ventricular function 5
• Do not give aggressive fluid boluses to hypotensive patients with right ventricular failure; instead use vasopressors and inotropes to avoid exacerbating right ventricular ischemia 5
• Never abruptly discontinue pulmonary vasodilators in patients already receiving them, as this may rapidly precipitate right ventricular failure and death 5
• Pregnancy is contraindicated in PAH due to 30-50% mortality risk 1

Monitoring and Follow-up

• Regular follow-up every 3-6 months for stable patients, more frequently for advanced disease 1
• Assessment should include WHO functional class, 6-minute walk distance, and echocardiographic evaluation 1
• Treatment goals include achieving WHO Functional Class I or II and a 6-minute walk distance >440 meters 1

Specialized Center Management

• All patients with PAH should be managed at specialized centers with expertise in pulmonary hypertension 1
• Referral centers should follow at least 50 patients with PAH or CTEPH and receive at least two new referrals per month 3
• Early consultation with a pulmonary hypertension specialist and transfer to a tertiary care center with invasive monitoring and mechanical support capabilities is advised for complex cases 5