What is the recommended treatment for pulmonary hypertension?

Treatment of Pulmonary Hypertension

For patients with pulmonary arterial hypertension (PAH), initial oral combination therapy with ambrisentan and tadalafil is recommended as first-line treatment for most patients, as this approach has proven superior to monotherapy in delaying clinical failure and improving outcomes. 1

Initial Assessment and Risk Stratification

Before initiating therapy, comprehensive risk stratification is essential to determine treatment intensity 2, 1:

• Low-risk patients (estimated 1-year mortality <5%): WHO functional class I-II, 6-minute walk distance >440m, no signs of right ventricular failure 2
• Intermediate-risk patients (estimated 1-year mortality 5-10%): WHO functional class III, moderately impaired exercise capacity, signs of RV dysfunction without failure 2
• High-risk patients (estimated 1-year mortality >10%): WHO functional class III-IV with progressive disease, severe RV dysfunction or failure 2

Vasoreactivity testing during right heart catheterization is mandatory for all PAH patients to identify the approximately 10% who may respond to calcium channel blockers 2, 1. A positive response is defined as a fall in mean pulmonary artery pressure of at least 10 mmHg to ≤40 mmHg with increased or unchanged cardiac output 2.

Treatment Algorithm Based on Vasoreactivity and Risk

For Vasoreactive Patients (~10% of idiopathic PAH)

High-dose calcium channel blockers are the treatment of choice for patients demonstrating acute vasoreactivity 2, 1:

• Preferred agents: long-acting nifedipine, diltiazem, or amlodipine (verapamil should be avoided due to negative inotropic effects) 1
• Patients must achieve WHO functional class I or II within 3-6 months; if not, additional PAH-specific therapy must be added 2, 1

For Non-Vasoreactive Patients (Majority)

Treatment is stratified by risk assessment 1, 3:

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

• Initial oral combination therapy with ambrisentan and tadalafil is the recommended first-line approach 1, 3
• This combination has demonstrated superiority over monotherapy in delaying clinical failure 1

High-Risk Patients (WHO FC IV):

• Continuous intravenous epoprostenol should be prioritized as it is the only treatment proven to reduce 3-month mortality in high-risk PAH patients 1, 3, 4
• This is particularly critical for patients with clinical evidence of right ventricular failure 2

Sequential Combination Therapy

For patients with inadequate response to initial therapy (failure to achieve or maintain low-risk status), sequential addition of therapies from different drug classes is recommended 3:

• Add prostacyclin analogues (inhaled or parenteral) to oral combination therapy 1
• Consider triple combination therapy with endothelin receptor antagonist, phosphodiesterase-5 inhibitor, and prostacyclin pathway agent 3

Supportive Care Measures

Diuretics are indicated for all PAH patients with signs of right ventricular failure and fluid retention, with careful monitoring of electrolytes and renal function 1, 3:

Oxygen supplementation is recommended when arterial blood oxygen pressure is consistently <8 kPa (60 mmHg) or to maintain saturations >90% 1, 3

Oral anticoagulation should be considered specifically for patients with idiopathic PAH, heritable PAH, and anorexigen-induced PAH 1, 3

Supervised exercise rehabilitation should be considered for physically deconditioned patients already on medical therapy 1, 3

Immunization against influenza and pneumococcal pneumonia is recommended for all PAH patients 1

Monitoring and Treatment Goals

Regular follow-up assessments every 3-6 months are required for stable patients, with more frequent monitoring (every 3 months) after treatment changes 2, 3:

Assessment should include:

• WHO functional class 2
• 6-minute walk test with Borg dyspnea score 2
• Echocardiography every 6-12 months 2
• BNP/NT-proBNP levels 2
• Right heart catheterization should be considered at regular intervals 2

The treatment goal is achieving and maintaining low-risk status (WHO FC I-II, 6MWD >440m, preserved RV function) 2, 3. Achievement of intermediate-risk status should be considered inadequate for most patients and prompt treatment escalation 2.

Advanced Therapies

Lung transplantation should be considered early after inadequate clinical response on maximal medical therapy 1, 3:

Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy, but should only be performed at experienced centers 1, 3

Treatment for Other PH Groups

For Group 2 PH (left heart disease): Treatment focuses on optimizing the underlying cardiac condition; PAH-specific therapies are not recommended and may be harmful 1, 3

For Group 4 PH (chronic thromboembolic): Pulmonary endarterectomy is the treatment of choice when feasible, as it is potentially curative 2, 1, 3. Life-long anticoagulation with vitamin K antagonists (target INR 2.0-3.0) is mandatory 2. For inoperable patients, medical therapy with PAH-specific drugs may be considered, though evidence is limited 2.

Critical Pitfalls to Avoid

All PAH patients should be managed at specialized centers performing at least 50 PAH cases and receiving at least 2 new referrals monthly 2, 3

Pregnancy is contraindicated in PAH due to 30-50% maternal mortality risk; effective contraception is essential 1

The combination of riociguat with PDE-5 inhibitors is contraindicated due to risk of severe hypotension 1

Angiotensin-converting enzyme inhibitors, angiotensin-2 receptor antagonists, and beta-blockers are not recommended in PAH unless required for specific comorbidities 3

Avoid intubation when possible in patients with right ventricular failure, as positive pressure ventilation can precipitate cardiovascular collapse; if required, use lung-protective strategies and maintain preload 5

Never abruptly discontinue prostacyclin therapy in patients already receiving it, as this can lead to rapid clinical deterioration and death 5