What are the treatment options for pulmonary hypertension?

Treatment of Pulmonary Hypertension

Initial Assessment and Diagnosis

Right heart catheterization is mandatory before initiating any PAH-specific therapy to confirm diagnosis, establish hemodynamic classification, and guide treatment decisions. 1, 2

• Vasoreactivity testing must be performed during right heart catheterization in patients with idiopathic, heritable, or drug-induced PAH to identify the ~10% who may respond to calcium channel blockers 3, 1, 2
• Risk stratification using WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, and echocardiographic parameters determines treatment intensity (low, intermediate, or high risk) 2
• All patients should be evaluated at an expert pulmonary hypertension center before starting treatment, as therapeutic approaches differ fundamentally based on PH classification 1

Treatment Algorithm for Pulmonary Arterial Hypertension (WHO 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. 3, 1, 2

• Verapamil should be avoided due to negative inotropic effects 3
• Patients must be closely monitored and if they do not improve to WHO functional class I or II, additional PAH-specific therapy should be added 3

For Non-Vasoreactive Patients

Initial oral combination therapy with ambrisentan plus tadalafil is recommended for low or intermediate risk patients (WHO FC II-III), as it has proven superior to monotherapy in delaying clinical failure. 3, 1, 2

• Tadalafil 40 mg once daily is the evidence-based dose, improving exercise capacity by 33 meters (44 meters in treatment-naive patients) and reducing clinical worsening by 68% 4
• This combination is preferred over monotherapy with endothelin receptor antagonists or PDE-5 inhibitors alone 3, 2

For high-risk patients (WHO FC IV), continuous intravenous epoprostenol should be prioritized as first-line therapy, as it is the only treatment proven to reduce 3-month mortality in high-risk PAH patients. 3, 1, 2

• Epoprostenol is indicated for WHO FC III-IV symptoms and has established mortality benefit 5
• Initial combination therapy including intravenous prostacyclin analogs is recommended for all high-risk patients 3, 2
• Treprostinil (subcutaneous or intravenous) is an alternative prostacyclin analog, initiated at 1.25 ng/kg/min and titrated by 1.25 ng/kg/min per week for the first four weeks 6

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

Treatment for Other Pulmonary Hypertension Groups

Group 2 (PH Due to Left Heart Disease)

PAH-specific therapies are not recommended for Group 2 PH and may be harmful; treatment should focus on optimizing the underlying cardiac condition. 3, 1

Group 3 (PH Due to Lung Disease)

• Long-term oxygen therapy is recommended to maintain saturations >90% and has been shown to partially reduce PH progression 1
• PAH-specific therapies are generally not indicated 3

Group 4 (Chronic Thromboembolic PH)

Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice when feasible. 3, 1

• Anticoagulation targeting INR 2-3 is recommended 1

Monitoring and Treatment Goals

• Regular assessments every 3-6 months for stable patients (more frequently for advanced disease) 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
• Target 6-minute walk distance >440 meters for most patients, though lower values may be acceptable in elderly patients or those with significant comorbidities 2

Advanced and Rescue Therapies

• Lung transplantation should be considered after inadequate response to initial monotherapy or combination therapy, with referral soon after inadequate response is confirmed on maximal medical therapy 3, 1, 2
• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 3, 1, 2

Critical Pitfalls to Avoid

• Never start PAH-specific drugs empirically without confirming diagnosis and classification via right heart catheterization, as this can delay appropriate treatment and cause harm, particularly in Group 2 PH 1
• Never combine riociguat with PDE-5 inhibitors (such as sildenafil or tadalafil) due to contraindication and risk of severe hypotension 3, 2
• Avoid conventional vasodilators (ACE inhibitors, ARBs, beta-blockers) in PAH unless specifically required for comorbidities, as they lack proven benefit 1, 2
• Avoid abrupt cessation of prostacyclin infusion; interruptions for longer periods may require dose re-titration 6

Emergency Department Management

• ICU hospitalization is recommended for PH patients with heart rate >110 bpm, systolic blood pressure <90 mmHg, low urine output, or rising lactate 1
• In hypotensive patients with right ventricular failure, vasopressors and inotropes rather than fluid boluses are required to augment cardiac output and reduce risk of exacerbating right ventricular ischemia 7
• Intubation should be avoided if possible, as positive pressure ventilation worsens right ventricular function 7
• Patients on pulmonary vasodilators may rapidly develop right ventricular failure and death without these therapies; never discontinue these medications 7
• Early consultation with a pulmonary hypertension specialist and transfer to a tertiary care center with invasive monitoring and mechanical support capabilities is advised 7