What are the treatment options for pulmonary hypertension?

Treatment of Pulmonary Hypertension

For treatment-naïve pulmonary arterial hypertension (PAH) patients at low or intermediate risk, initial oral combination therapy with ambrisentan plus tadalafil is recommended as it has proven superior to monotherapy in delaying clinical failure. 1, 2

Initial Assessment and Risk Stratification

Before initiating therapy, all patients require comprehensive evaluation to guide treatment intensity:

• Right heart catheterization is mandatory to confirm diagnosis, establish hemodynamic severity, and guide therapeutic decisions 3
• Vasoreactivity testing must be performed in patients with idiopathic, heritable, or drug-induced PAH to identify the approximately 10% who may respond to calcium channel blockers 1, 2
• Risk stratification using WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, and echocardiographic parameters determines whether patients are low, intermediate, or high risk 1

Treatment Algorithm Based on Vasoreactivity and Risk

Vasoreactive Patients (Approximately 10% of Idiopathic PAH)

• High-dose calcium channel blockers are first-line therapy for patients demonstrating acute vasoreactivity during right heart catheterization 1, 2, 3
• Long-acting nifedipine, diltiazem, or amlodipine are preferred; verapamil should be avoided due to negative inotropic effects 2
• Patients must be closely monitored and if they fail to improve to WHO functional class I or II within 3-6 months, PAH-specific therapy must be added 2

Non-Vasoreactive Patients: Treatment by Risk Category

Low or Intermediate Risk (WHO FC II-III)

• Initial oral combination therapy with ambrisentan plus tadalafil is the preferred approach as it significantly delays clinical failure compared to monotherapy 1, 2
• Alternative initial monotherapy options include endothelin receptor antagonists (bosentan, macitentan, ambrisentan) or phosphodiesterase-5 inhibitors (sildenafil, tadalafil), though these are less preferred 1, 2

High Risk (WHO FC IV)

• Continuous intravenous epoprostenol should be prioritized as it is the only therapy proven to reduce 3-month mortality in high-risk PAH patients 1, 2, 4
• Initial combination therapy including intravenous prostacyclin analogues is recommended 1
• These patients should be managed at specialized pulmonary hypertension centers 1, 3

Sequential Combination Therapy

For patients with inadequate clinical response to initial therapy:

• Addition of a third class of PAH therapy is recommended for patients remaining symptomatic or deteriorating on dual therapy 1
• For patients on stable doses of PDE5 inhibitors or inhaled prostanoids, macitentan can be added to improve 6-minute walk distance, WHO functional class, and delay clinical worsening 1
• For patients on background ambrisentan therapy, addition of tadalafil improves exercise capacity 1
• The combination of riociguat and PDE5 inhibitors is contraindicated due to risk of severe hypotension 1, 2

Supportive Care Measures

Essential Supportive Therapies

• 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
• **Continuous long-term oxygen therapy is recommended when arterial blood oxygen pressure is consistently <8 kPa (60 mmHg)** or to maintain saturations >90-91% 1, 3
• Oral anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, though evidence is based on observational data 1, 3
• Supervised exercise rehabilitation should be considered for physically deconditioned patients already on medical therapy 1, 3

Critical Lifestyle Modifications

• Pregnancy must be avoided in all PAH patients due to 30-50% maternal mortality risk 1, 2
• When pregnancy occurs, care at a specialized pulmonary hypertension center with multidisciplinary approach including high-risk obstetrics and cardiovascular anesthesiology is mandatory 1
• High altitude exposure should be avoided, and supplemental oxygen (3-4 L/min) should be used during air travel to maintain saturations >91% 1
• Non-essential surgery should be avoided, and when necessary, performed at pulmonary hypertension centers with specialized anesthesiology support 1
• Immunization against influenza and pneumococcal infection is recommended 1, 2

Monitoring and Treatment Goals

Follow-up Strategy

• Regular assessments every 3-6 months for stable patients should include WHO functional class, 6-minute walk distance, BNP/NT-proBNP, and echocardiography 2, 3
• More frequent monitoring is required for patients with advanced disease or after treatment changes 2

Treatment Targets

• The primary goal is achieving and maintaining low-risk status, typically WHO functional class I-II 1, 3
• A 6-minute walk distance >440 meters is an important treatment target for most patients, though lower values may be acceptable in elderly patients or those with significant comorbidities 1, 2
• Near-normal BNP/NT-proBNP levels and preserved right ventricular function on echocardiography are additional goals 1

Advanced and Rescue Therapies

Lung Transplantation

• Eligibility for lung transplantation should be considered after inadequate response to initial monotherapy or combination therapy 1
• Referral for transplantation should occur soon after inadequate response is confirmed on maximal combination therapy 1, 3

Balloon Atrial Septostomy

• BAS may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 1, 3
• This procedure should only be performed at specialized centers with expertise 1

Treatment for Other Pulmonary Hypertension Groups

Group 2 (PH Due to Left Heart Disease)

• PAH-specific therapies are NOT recommended as they have not proven safe or effective and may cause harm 2, 3, 5
• Treatment should focus on optimizing the underlying cardiac condition 2, 3

Group 3 (PH Due to Lung Disease)

• Long-term oxygen therapy is the primary treatment as it slows PH progression in hypoxemic patients 6
• PAH-specific vasodilators are NOT recommended as they may worsen gas exchange by inhibiting hypoxic pulmonary vasoconstriction 6
• Treatment should focus on optimizing the underlying lung disease 6

Group 4 (Chronic Thromboembolic PH)

• Pulmonary endarterectomy is the treatment of choice when feasible 2, 3, 5
• For inoperable patients, riociguat has proven efficacious 5
• Evaluation of operability must be performed by a multidisciplinary expert team 7

Critical Pitfalls to Avoid

• Never combine riociguat with PDE5 inhibitors due to contraindication 1, 2
• Do not use sildenafil for PAH (20 mg three times daily) concurrently with sildenafil for erectile dysfunction or other PDE5 inhibitors 8
• Avoid conventional vasodilators (ACE inhibitors, ARBs, beta-blockers) in PAH unless specifically required for comorbidities, as they lack proven benefit 3
• Do not apply PAH-specific therapies to Group 2 or Group 3 PH outside of clinical trials, as they may cause harm 2, 3, 5, 6
• All PAH patients should be managed at or in consultation with specialized pulmonary hypertension centers to ensure appropriate diagnosis, risk stratification, and treatment escalation 1, 3