What are the treatment options for pulmonary hypertension?

Treatment of Pulmonary Hypertension

Initial Assessment and Classification

All patients with suspected pulmonary hypertension require right heart catheterization to confirm diagnosis (mean PAH ≥25 mmHg, PCWP ≤15 mmHg) and vasoreactivity testing must be performed in idiopathic, heritable, or drug-induced PAH to identify the ~10% who 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 treatment intensity 2.
• The five groups of pulmonary hypertension require fundamentally different treatment approaches, making accurate classification essential 1, 3.

Treatment Algorithm for Pulmonary Arterial Hypertension (Group 1)

For Vasoreactive Patients (~10%)

High-dose calcium channel blockers (long-acting nifedipine, diltiazem, or amlodipine) are first-line therapy for patients demonstrating acute vasoreactivity during right heart catheterization; verapamil should be avoided due to negative inotropic effects 1, 2.

• Patients must be closely monitored and if they fail to improve to WHO functional class I or II, additional PAH-specific therapy must be added 1.

For Non-Vasoreactive Patients

Treatment is determined by risk stratification:

Low or Intermediate Risk (WHO FC II-III)

Initial oral combination therapy with ambrisentan plus tadalafil is the recommended first-line treatment, as it has proven superior to monotherapy in delaying clinical failure 1, 3, 2.

• This combination should be started simultaneously, not sequentially 1, 2.
• For patients unable to tolerate combination therapy, monotherapy with endothelin receptor antagonists (bosentan or ambrisentan) or PDE-5 inhibitors may be considered 1.

High Risk (WHO FC IV)

Continuous intravenous epoprostenol must be prioritized as first-line therapy, as it is the only treatment proven to reduce 3-month mortality in high-risk PAH patients 1, 3, 2, 4.

• Initial combination therapy including intravenous prostacyclin analogues is recommended for all high-risk patients 1, 3.
• Epoprostenol is FDA-approved for PAH (WHO Group 1) to improve exercise capacity, with studies predominantly in NYHA Functional Class III-IV patients 4.

Supportive Care Measures (All PAH Patients)

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, 2.

• Continuous long-term oxygen therapy is indicated when arterial blood oxygen pressure is consistently <8 kPa (60 mmHg) or to maintain saturations >90% 1, 3, 2.
• Oral anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5 1, 3.
• Supervised exercise rehabilitation should be considered for physically deconditioned patients under medical therapy 1, 3.
• Immunization against influenza and pneumococcal pneumonia is recommended 1.
• Pregnancy is absolutely contraindicated in PAH due to 30-50% mortality risk 1.

Treatment for Other PH Groups

Group 2 (PH Due to Left Heart Disease)

PAH-specific therapies are NOT recommended for Group 2 PH; treatment must focus exclusively on optimizing the underlying cardiac condition 1, 3, 2.

• This is the most common form of pulmonary hypertension and requires management of the left heart disease itself 3.

Group 3 (PH Due to Lung Disease)

Long-term oxygen therapy is the only proven treatment that slows PH progression in COPD patients with hypoxemia 3, 5.

• PAH-specific therapies are NOT recommended for Group 3 PH as they may worsen gas exchange 1, 3, 5.
• Conventional vasodilators (calcium channel blockers, ACE inhibitors, ARBs) are contraindicated as they inhibit hypoxic pulmonary vasoconstriction and worsen ventilation-perfusion mismatch 3, 5.

Group 4 (Chronic Thromboembolic PH)

Pulmonary endarterectomy is the treatment of choice when feasible, performed in deep hypothermia with circulatory arrest 1, 3, 2.

• Operability assessment must be performed by a multidisciplinary expert team 3.
• For inoperable patients, riociguat (soluble guanylate cyclase stimulator) has proven efficacy 6.
• Oral anticoagulation targeting INR 2-3 is mandatory 3.

Monitoring and Treatment Goals

Regular assessments every 3-6 months for stable patients should include WHO functional class, 6-minute walk distance, BNP/NT-proBNP, and echocardiography 1, 2.

• The primary goal is achieving and maintaining low-risk status, typically WHO functional class I-II 1, 2.
• A 6-minute walk distance >440 meters is an important treatment target, though lower values may be acceptable in elderly patients with significant comorbidities 1, 2.
• Sequential combination therapy should be added in patients with inadequate response to initial therapy 3.

Advanced and Rescue Therapies

Lung transplantation should be considered soon after inadequate response to maximal medical therapy is confirmed 1, 3, 2.

• Referral for transplant evaluation should occur early, not as a last resort 2.
• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 1, 3, 2.

Critical Pitfalls to Avoid

Never combine riociguat with PDE-5 inhibitors (sildenafil, tadalafil) due to absolute contraindication and risk of severe hypotension 2, 7.

• Never use sildenafil 20 mg for PAH concurrently with sildenafil 25-100 mg for erectile dysfunction or other PDE-5 inhibitors 7.
• Never use nitrate medications in patients taking sildenafil, as blood pressure could drop to life-threatening levels 7.
• Avoid ACE inhibitors, ARBs, and beta-blockers in PAH unless specifically required for comorbidities, as they lack proven benefit 3, 2.
• All PAH patients must be managed at or in consultation with specialized pulmonary hypertension centers 1, 2.
• Avoid volume overload in right ventricular failure, as it worsens cardiac function 3.
• Do not use PAH-specific therapies in Groups 2 and 3 PH outside of clinical trials, as they may cause harm 1, 3, 5.