Management of Pulmonary Arterial Hypertension
For treatment-naïve adults with confirmed PAH and WHO functional class II-III symptoms, initiate combination therapy with ambrisentan and tadalafil rather than monotherapy, as this approach delays clinical worsening and improves outcomes. 1, 2
Initial Diagnostic Confirmation and Risk Stratification
Before initiating therapy, confirm PAH diagnosis with right heart catheterization demonstrating mean pulmonary artery pressure >20 mmHg, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance ≥3 Wood units. 3, 4 Perform ventilation-perfusion scanning to exclude chronic thromboembolic pulmonary hypertension, as a normal scan effectively rules out CTEPH. 1, 3
Screen all patients with unexplained PAH for connective tissue disease and HIV infection, as CTD-associated PAH represents the second most common cause of PAH after idiopathic disease. 1, 5 Systemic sclerosis accounts for 75% of CTD-associated PAH cases and carries worse prognosis than other forms. 5, 6
Assess WHO functional class at diagnosis, as this determines treatment intensity. 2 Establish baseline with 6-minute walk test, BNP/NT-proBNP levels, and echocardiographic parameters for right ventricular function. 1, 3
Vasoreactivity Testing and Calcium Channel Blocker Candidacy
Perform acute vasoreactivity testing during right heart catheterization only in patients with idiopathic, heritable, or drug-induced PAH using short-acting agents (IV epoprostenol, adenosine, or inhaled nitric oxide). 1, 2 A positive response is defined as a fall in mean pulmonary artery pressure ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output. 1, 2
For the small subset of vasoreactive patients (approximately 10-15%), initiate high-dose calcium channel blockers (long-acting nifedipine, diltiazem, or amlodipine) as first-line therapy. 2 Never use calcium channel blockers empirically without documented vasoreactivity, as this can cause harm. 3, 2
First-Line Pharmacotherapy for Non-Vasoreactive Patients
WHO Functional Class II-III
Initiate upfront oral combination therapy with ambrisentan (endothelin receptor antagonist) and tadalafil (PDE5 inhibitor) for treatment-naïve patients willing and able to tolerate combination therapy. 1, 2 This recommendation carries moderate quality evidence and represents a paradigm shift from sequential monotherapy. 1
If combination therapy is not feasible due to patient preference, cost, or tolerability concerns, acceptable monotherapy options include bosentan, macitentan, ambrisentan, riociguat, sildenafil, or tadalafil. 1 However, recognize that monotherapy provides inferior outcomes compared to initial combination therapy. 1, 6
For patients with SSc-associated PAH specifically, initial ERA-PDE5i combination therapy demonstrates significantly better survival compared to monotherapy (P=0.016 for ERA monotherapy, P=0.012 for PDE5i monotherapy). 6
WHO Functional Class III with Rapid Progression or Poor Prognosis
Initiate continuous IV epoprostenol, IV treprostinil, or subcutaneous treprostinil for patients with WHO FC III demonstrating evidence of rapid disease progression or poor prognostic features. 1 IV epoprostenol has the strongest evidence base for severe PAH, with proven mortality benefit. 7, 8
Start epoprostenol at 2 ng/kg/min and increase in 2 ng/kg/min increments every 15 minutes or longer until tolerance limits are reached. 7 Dose-limiting adverse events commonly include nausea, vomiting, hypotension, and headache. 7
If parenteral prostanoids are not immediately feasible, consider adding inhaled or oral prostanoid therapy to dual oral therapy. 1
WHO Functional Class IV
For WHO FC IV patients, initiate continuous IV epoprostenol, IV treprostinil, or subcutaneous treprostinil as first-line therapy. 1, 7 This represents the only treatment with proven mortality benefit in severe PAH. 8
If parenteral prostanoids cannot be initiated, use inhaled prostanoid in combination with an oral PDE5 inhibitor and oral endothelin receptor antagonist as triple therapy. 1
Sequential Therapy for Inadequate Response
Reassess patients every 3-6 months using WHO functional class, 6-minute walk distance, and BNP/NT-proBNP levels. 2 For WHO FC III or IV patients with unacceptable clinical status despite established monotherapy, add a second class of PAH therapy targeting a different biological pathway. 1
For patients with inadequate or deteriorating status despite dual therapy, add a third class of PAH therapy. 1 The addition of inhaled treprostinil to background ERA or PDE5i therapy improves 6-minute walk distance. 9 Titrate inhaled treprostinil up to 9 inhalations (54 mcg) every 6 hours as tolerated. 9
Selexipag (oral prostacyclin receptor agonist) provides an alternative for prostacyclin pathway activation without continuous infusion requirements. 9
Essential Supportive Care Measures
Administer diuretics for signs of right ventricular failure and fluid retention. 2 Provide supplemental oxygen to maintain arterial oxygen saturation >91%, particularly during high altitude exposure or air travel. 1
Consider oral anticoagulation targeting INR 1.5-2.5 for idiopathic PAH, heritable PAH, and anorexigen-associated PAH, though evidence is limited. 2
Counsel all patients to avoid pregnancy, as maternal mortality remains extremely high. 1 If pregnancy occurs, provide care at a specialized pulmonary hypertension center. 1
Maintain current immunizations against influenza and pneumococcal pneumonia. 1 Encourage participation in supervised exercise programs as part of integrated disease management. 1
Avoid non-essential surgery; when surgery is necessary, perform at a pulmonary hypertension center with expertise in perioperative management. 1
Advanced Therapies and Transplantation
Refer patients for lung transplantation evaluation early after inadequate clinical response on maximal medical therapy. 2, 8 Indicators for transplant evaluation include WHO FC III-IV despite maximal therapy, rapidly progressive disease, and hemodynamic deterioration. 2
Consider balloon atrial septostomy as a palliative or bridging procedure to transplantation in patients deteriorating despite maximal medical therapy. 2, 8 This technique requires expertise and should only be performed at specialized centers. 8
Incorporate palliative care services early in the management of PAH patients, particularly those with advanced disease or inadequate response to maximal pharmacotherapy. 1
Critical Management Pitfalls
Avoid abrupt withdrawal of epoprostenol or sudden large reductions in infusion rates, as this can precipitate acute decompensation. 7 Except in life-threatening situations, adjust infusion rates only under physician direction. 7
Never empirically use calcium channel blockers without documented acute vasoreactivity testing, as this approach can worsen outcomes. 1, 3, 2
Coordinate care between local physicians and specialized pulmonary hypertension centers for optimal outcomes. 1, 2 All PAH patients should have access to multidisciplinary teams with expertise in complex disease management. 1, 2
Recognize that CTD-associated PAH, particularly SSc-PAH, carries worse prognosis than idiopathic PAH, with 5-year survival of only 42% for SSc-PAH compared to >60% for idiopathic disease. 4, 6 This necessitates more aggressive initial therapy and closer monitoring. 6
All PAH-specific therapies carry pregnancy category X contraindications and require strict contraception counseling. 9