Diagnosis, Treatment, and Clinical Management of Pulmonary Arterial Hypertension in the Contemporary Era: A Review

Abstract

Importance: Pulmonary arterial hypertension (PAH) is characterized by severe remodeling of the distal pulmonary arteries, increased pulmonary vascular resistance, and right ventricular dysfunction that promotes heart failure. Once regarded as largely untreatable, evidence-based decision making now guides clinical management of PAH and improves outcomes. However, misconceptions regarding the approach to PAH in the modern era are common and associated with substandard clinical care.

Observations: The clinical profile of PAH has changed substantially since its original description. Patients are older at diagnosis than previously reported; disease severity appears greater in men compared with women; and patients with PAH in association with connective tissue disease are identified as a particularly high-risk subgroup. Risk stratification scales for PAH are now available at point of care, which inform treatment goals, including a 6-minute walk distance of greater than 440 m, peak volume of oxygen consumption of greater than 15 mL/min/kg, right atrial area of less than 18 cm2, cardiac index of greater than 2.5 L/min/m2, and absent or low symptom burden with routine physical activity. At present, 14 therapies targeting 6 PAH-specific molecular intermediaries are used clinically. Recent landmark trial data have demonstrated the critical importance of initial combination therapy in treatment-naive patients. These findings underscore a global shift in PAH that couples early disease detection with aggressive pharmacotherapy. Indeed, recent longitudinal data from patients receiving combination therapy show that the 3-year survival rate in PAH may be as high as 84% compared with 48% from the original National Institutes of Health registry on idiopathic PAH (1980-1985). Despite these gains, incomplete clinical evaluation and misdiagnosis by referring clinicians is common and associated with inappropriate therapy.

Conclusions and relevance: Compared with the original clinical experience, PAH has evolved into a contemporary and treatable disease characterized by improved survival and a high standard for defining therapeutic success. However, underawareness among clinicians regarding the importance of early and accurate PAH diagnosis persists and is a potentially reversible cause of adverse outcome in this disease.

Figure 1. Classification of pulmonary hypertension subgroups

Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mmHg measured by right heart catheterization supine at rest. Patients meeting this criterion are classified further according to co-morbid left heart disease causing left atrial hypertension, parenchymal or hypoxic lung disease, chronic thrombembolic pulmonary hypertension (CTEPH), or other predisposing diseases associated with pulmonary vascular remodeling. In the case of CTEPH, in situ thrombotic and fibrotic remodeling of subsegmental pulmonary arterioles occurs in most patients as a maladaptive response to prior luminal pulmonary embolism. By contrast to these forms of pulmonary hypertension, pulmonary arterial hypertension (PAH) is characterized by a plexogenic, hypertrophic, and fibrotic vasculopathy affecting distal pulmonary arterioles that occurs primarily due to interplay between genetic and molecular factors and requires meeting the following additional cardiopulmonary hemodynamic criteria: pulmonary vascular resistance (PVR) >3.0 Wood units and pulmonary artery wedge pressure (PAWP) ≤15 mmHg. The most common forms of PAH in industrialized countries are idiopathic PAH, heritable PAH due primarily to a mutation in the gene for bone morphogenetic protein receptor-2, and PAH in association with connective tissue disease (CTD) or congenital heart disease. LV, left ventricle; HIV, human immunodeficiency virus; PH, pulmonary hypertension; COPD, chronic obstructive pulmonary disease; HD, hemodialysis.

Figure 2

A. The effect of sequential combination therapy of selexipag as monotherapy or as addition to endothelyn receptor antagonists and/or phosphodiesterase type5 inhibitors on the outcome. In the GRIPHON study patients were randomised to receive selexipag or placebo. Kaplan–Meier curves for the primary composite end point of death (from any cause) or a complication related to pulmonary arterial hypertension (disease progression or worsening of pulmonary arterial hypertension that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or the need for lung transplantation or balloon atrial septostomy) up to the end of the treatment period in the selexipag and placebo groups. A significant treatment effect in favor of selexipag versus placebo was observed (hazard ratio, 0.60; 99% CI, 0.46 to 0.78; P<0.001 with the use of a one-sided log-rank test). Reproduced with permission from Sitbon et al. B. The effect of initial combination therapy with ambrisentan plus tadalafil on pulmonary arterial hypertension (PAH) outcome in treatment-naive patients on clinical outcome. In the AMBITION trial, treatment-naive PAH patients were randomized to receive monotherapy standard of care with the selective endothelin-A receptor antagonist ambrisentan (10 mg daily) or the phosphodiesterase-type V inhibitor tadalafil (40 mg daily), or combination therapy with both drugs. The primary end-point included first event of clinical failure, which was a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. The pooled monotherapy condition refers to all patients randomized to receive either ambrisentan alone or tadalafil alone. Reproduced from Galiè, et al.

Figure 3. Evidence-based treatment algorithm for pulmonary arterial hypertension (PAH) patients

CCB: calcium channel blockers; DPAH, drug-induced PAH; HPAH, heritable PAH; IPAH, idiopathic PAH; i.v., intravenous; PCA: prostacyclin analogues; WHO-FC: World Health Organization Functional Class. ^bInitial combination with ambrisentan plus tadalafil has proven to be superior to initial monotherapy with ambrisentan or tadalafil in delaying clinical failure. ^cIntravenous epoprostenol should be prioritized. ^dConsider also balloon atrial septostomy. Adapted with permission from Galiè N, et al.^,