Treatment of Pulmonary Arterial Hypertension
All patients with pulmonary arterial hypertension should be promptly referred to a specialized center for comprehensive evaluation and risk stratification, followed by initiation of combination therapy targeting multiple biological pathways for most treatment-naïve patients. 1, 2
Initial Assessment and Risk Stratification
Before initiating therapy, systematic evaluation is essential using WHO functional class, 6-minute walk distance, echocardiographic findings (right ventricular function), BNP/NT-proBNP levels, and hemodynamic parameters from right heart catheterization. 1 This multiparametric assessment categorizes patients into low-risk (estimated 1-year mortality <5%), intermediate-risk (5-10%), or high-risk (>10%) groups, which directly determines treatment intensity. 1, 2
Right heart catheterization is mandatory to confirm the diagnosis before starting PAH-specific therapy, demonstrating mean pulmonary artery pressure >20 mm Hg, pulmonary capillary wedge pressure ≤15 mm Hg, and pulmonary vascular resistance ≥3 Wood units. 1, 3
Vasoreactivity Testing
Acute vasoreactivity testing during right heart catheterization must be performed in all patients with idiopathic PAH, heritable PAH, and drug-induced PAH to identify the approximately 10% who may respond to calcium channel blockers. 1, 2 A positive response is defined as a reduction in mean pulmonary artery pressure ≥10 mm Hg to reach an absolute value ≤40 mm Hg with increased or unchanged cardiac output. 1, 2
Treatment Algorithm Based on Risk Stratification
Vasoreactive Patients (≈10% of idiopathic PAH)
High-dose calcium channel blockers are the first-line treatment for vasoreactive patients, using long-acting nifedipine (120-240 mg daily), diltiazem (240-720 mg daily), or amlodipine (up to 20 mg daily). 2 Verapamil should be avoided due to negative inotropic effects. 2
Critical caveat: These patients require close monitoring with repeat assessment at 3-6 months. If they fail to achieve or maintain WHO functional class I or II, PAH-specific therapy must be added immediately. 2
Non-Vasoreactive Patients: Low or Intermediate Risk (WHO FC II-III)
Initial oral combination therapy with ambrisentan (an endothelin receptor antagonist) plus tadalafil (a phosphodiesterase-5 inhibitor) is the recommended first-line treatment for most treatment-naïve patients with low or intermediate risk. 1, 2 This dual-pathway approach has proven superior to monotherapy in delaying clinical failure and improving progression-free survival. 2, 3
Alternative initial combination strategies include:
- An endothelin receptor antagonist plus a phosphodiesterase-5 inhibitor 1, 2
- An endothelin receptor antagonist plus riociguat (soluble guanylate cyclase stimulator) 2
Monotherapy is now considered suboptimal for most patients and should only be used when combination therapy is not feasible due to contraindications, intolerance, or patient preference. 1, 2
High-Risk Patients (WHO FC IV)
Continuous intravenous epoprostenol is the strongly recommended first-line therapy for high-risk patients, as it is the only treatment proven to reduce 3-month mortality in this population. 1, 2, 4 Initial combination therapy should include IV prostacyclin analogues (epoprostenol or treprostinil) plus oral agents targeting the endothelin and nitric oxide pathways. 1, 2
Alternative parenteral prostacyclin options include:
- IV treprostinil 2
- Subcutaneous treprostinil 2
- Inhaled prostacyclins (less preferred for high-risk patients) 2
Supportive and General Measures
Diuretics and Fluid Management
Diuretics are indicated for all PAH patients with clinical signs of right ventricular failure and fluid retention (peripheral edema, ascites, elevated jugular venous pressure). 1, 2 Careful monitoring of electrolytes and renal function is essential, as aggressive diuresis can reduce cardiac preload and worsen hemodynamics. 2
Oxygen Therapy
**Continuous long-term oxygen therapy is recommended when arterial oxygen pressure is consistently <60 mm Hg (8 kPa)**, with the goal of maintaining oxygen saturation >90%. 1, 2, 5
Anticoagulation
Oral anticoagulation should be considered in patients with idiopathic PAH, heritable PAH, and anorexigen-associated PAH, targeting an INR of 1.5-2.5. 1, 2 The evidence is strongest for idiopathic PAH, where retrospective data suggest survival benefit. 1, 2 Anticoagulation is not routinely recommended for other PAH subtypes (e.g., connective tissue disease-associated PAH, congenital heart disease-associated PAH). 2
Exercise and Rehabilitation
Supervised exercise rehabilitation should be considered for physically deconditioned PAH patients who are on stable medical therapy, as it improves exercise capacity and quality of life without adverse effects. 1, 2
Pregnancy
Pregnancy is contraindicated in PAH due to 30-50% maternal mortality risk. 2 Effective contraception counseling is mandatory for all women of childbearing age. 1, 2
Sequential Therapy and Treatment Escalation
For patients who fail to achieve or maintain low-risk status on initial therapy, sequential addition of agents from different drug classes is recommended. 1, 2 Treatment goals include:
- WHO functional class I or II 1, 2
- 6-minute walk distance >440 meters 1, 2
- BNP <50 ng/L or NT-proBNP <300 ng/L 1
- Absence of right ventricular failure signs 1, 2
Regular reassessment every 3-6 months is mandatory using the same multiparametric risk stratification approach. 1
Advanced and Rescue Therapies
Lung Transplantation
Lung transplantation should be considered early for patients with inadequate clinical response despite maximal medical therapy, particularly those remaining at high risk. 1, 2 Referral to a transplant center should occur before severe clinical deterioration. 2
Balloon Atrial Septostomy
Balloon atrial septostomy may be considered as a palliative or bridging procedure in carefully selected patients who are deteriorating despite maximal medical therapy, particularly as a bridge to transplantation. 1, 2 This procedure creates a right-to-left shunt to decompress the right ventricle but carries significant procedural risk. 2
Treatment for Other Pulmonary Hypertension Groups
Group 2 (PH Due to Left Heart Disease)
PAH-specific therapies are NOT recommended for Group 2 PH, as they have not demonstrated benefit and may worsen outcomes. 1, 2, 6 Treatment should focus on optimizing the underlying cardiac condition (heart failure management, valve repair/replacement). 1, 6
Group 3 (PH Due to Lung Disease)
PAH-specific therapies are NOT recommended for Group 3 PH. 1, 2 Treatment focuses on optimizing the underlying lung disease and providing supplemental oxygen when indicated. 7, 6
Group 4 (Chronic Thromboembolic PH)
Surgical pulmonary endarterectomy is the treatment of choice for operable CTEPH patients, performed in specialized centers with expertise in this procedure. 1, 2, 7 For inoperable or persistent/recurrent CTEPH, riociguat is the only approved targeted therapy. 7, 6 Balloon pulmonary angioplasty is emerging as an alternative for selected inoperable patients. 1
Critical Pitfalls to Avoid
Do not delay referral to a specialized PH center, as this results in inappropriate treatment initiation and worse outcomes. 1, 2 The complexity of diagnostic evaluation and rapidly evolving treatment options necessitate expert center involvement. 1
Do not use monotherapy as initial treatment for most PAH patients, as combination therapy has demonstrated superior outcomes in delaying clinical worsening and improving survival. 1, 2, 3
Do not combine riociguat with phosphodiesterase-5 inhibitors (sildenafil, tadalafil), as this combination is contraindicated due to risk of severe hypotension. 2
Do not use PAH-specific therapies in patients with Group 2 or Group 3 PH, as these medications can worsen pulmonary edema in left heart disease and impair gas exchange in lung disease. 1, 2, 6
Do not overlook the need for vasoreactivity testing in appropriate patients, as missing vasoreactive patients denies them the opportunity for simpler, effective therapy with calcium channel blockers. 1, 2