Pulmonary arterial hypertension (PAH), or Group 1 pulmonary hypertension (PH) in the World Health Organization (WHO) classification, is a rare disease. In the United States, the largest registry of PH patients, Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry™; ClinicalTrials.gov identifier: NCT00370214), estimates the incidence of PAH among adults to be 2.3 cases for every 1 million people; prevalence is 12.4 cases for every 1 million. 1 The prevalence of PAH is higher in women (78%; female:male ratio, 3.6:1).2 Although all races can be affected by PAH, patients are predominantly White (73%); 12% are African American, 9% Latino, 3% Asian, and 3% other or unknown (Figure 11,2).2

PAH is characterized by progressive occlusion of lung arterioles and small arteries with fibro-proliferative changes, leading to right ventricular failure and death.3,4 Furthermore, PAH is associated with connective tissue disease, portal hypertension, congenital heart disease, and schistosomiasis (Table 1).3 Shortness of breath, fatigue, chest pressure, and bluish color to the lips and skin are among the common symptoms of PAH.5

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Prompt diagnosis and treatment are essential for optimal management of PAH. However, the nonspecificity of symptoms — which are often indistinguishable from other lung or heart diseases, particularly at early stages of PAH — and the complexity of the diagnostic assessment often delay establishing a differential diagnosis. Despite having several therapies available, there is no cure, and most patients with PAH experience progression and die of the disease.6 The rare nature of PAH presents clinical challenges to physicians, who might be unfamiliar with symptoms that should raise clinical suspicion to trigger prompt referral for diagnosis and treatment.

Over the past 2 decades, expansion of PAH therapeutic options has resulted in an evolving treatment strategy, including updates to evidence-based treatment guidelines.7

The incidence and prevalence of PAH are increasing, and diagnosis is often delayed. What does this mean for clinical management?

Reporting of these increases is based on a cohort of 50,529 patients in Ontario, Canada, with PH, identified from hospitalizations and emergency department visits, using data collected by ICES.8 The annual incidence of adult PH increased from 24.1 cases for every 100,000 people in 2003 to 28.7 cases for every 100,000 in 2012; the annual prevalence increased from approximately 100 cases for every 100,000 people in 1993 to 127 cases for every 100,000 in 2012.8

An accurate differential diagnosis is critical for effective treatment, given that treatment options have proven effectiveness only in Group 1 PAH and Group 4 PH. Prompt referral to a PH center of excellence is vital for optimal PAH management. PH centers are equipped with a coordinated team of cardiologists, pulmonologists, and internists to expedite a diagnostic workup, rule out a non-PAH cause, and diagnose and manage comorbidities, including sleep apnea and chronic obstructive pulmonary disease.3,4 The diagnosis of PAH is complex and involves a series of imaging studies and diagnostic tests (Figure 2).

“We suggest that, whenever possible, all PAH patients be evaluated promptly at a center with expertise in the diagnosis of PAH, ideally before the initiation of therapy.”
(Ungraded consensus-based statement7)

“We suggest also that contributing causes of PH (eg, sleep apnea and systemic hypertension) in patients with PAH be treated aggressively.”
(Ungraded consensus-based statement7)

Lack of awareness by community physicians or inconsistent use of a diagnostic algorithm may result in diagnostic delay or misdiagnosis.9,10 As many as 55% of patients initially classified as having PAH and receiving PAH-targeted therapy were reclassified as non-PAH after referral to a tertiary care center.11 Indeed, approximately 3 of 4 patients eventually given an accurate diagnosis of PAH either had advanced symptoms or were initially given a misdiagnosis, with inappropriate treatment started.9,11,12

The clinical impact of misdiagnosis is significant, given that the treatment of PAH is potentially hazardous for patients with Group 2, 3, or 5 PH. 

Biomarkers offer a potential solution for a more accurate and less-invasive PAH differential diagnosis. Although several biomarkers have been investigated, only brain natriuretic peptide (BNP) and the N-terminal prohormone of BNP (NT-proBNP) are extensively used in routine practice and clinical trials to identify patients with early disease or to assess response to treatment.13,14 Given these limitations and challenges, it is critical to initiate prompt treatment with available options and strategies once PAH has been accurately diagnosed.

What are the options and strategies for treating PAH?

Evidence supporting targeted treatment of PH is available only for PAH or chronic thromboembolic pulmonary hypertension (Group 4) PH. For other PH classes, there are no data on treatment effectiveness and, for some therapies, there is evidence of harm. Consequently, it is critical to establish a correct diagnosis and initiate approved treatment for the specific group.

Treatment for PAH is best carried out in a PH center, taking a multidisciplinary approach. However, PAH treatment is complex. Despite approval of several therapies that interfere with the pathologic mechanisms of PAH (eg, endothelin, nitric oxide, and prostacyclin pathways), clinical outcomes in PAH remain poor. Although treatment guidelines and consensus recommendations have been developed by several professional organizations (eg, The European Society of Cardiology/European Respiratory Society Guidelines,13  American College of Chest Physicians CHEST Guideline,7 and the 6th World Symposium on Pulmonary Hypertension consensus recommendations6 ), selecting individualized appropriate treatment from among the more than a dozen drugs available can be challenging.

“We suggest collaborative and closely coordinated care of PAH patients involving the expertise of both local physicians and those with expertise in PAH care.”
(Ungraded consensus-based statement7)

“For treatment-naive PAH patients with WHO Functional Class I symptoms, we suggest continued monitoring for the development of symptoms that would signal disease progression and warrant the initiation of pharmacotherapy.”
(Ungraded consensus-based statement7)

Initial treatment is based on PAH functional class and mortality risk (Table 2).3,4 Low (II)-, intermediate (III)-, and high-risk (IV) classes are patients with, respectively, <5%, 5% to 10%, and >10% mortality risk based on predefined criteria, including clinical signs of right heart failure, progression of symptoms, plasma NT-proBNP level, imaging findings, and hemodynamics.13

Several agents have been approved by the US Food and Drug Administration (FDA) for PAH, with various delivery methods, including oral, intravenous, subcutaneous, and inhaled (Table 3).15,16

Treatment options and strategies recommended by the ESC/ERS guidelines include monotherapy or a combination of various treatment options, often with sequential addition of dual or tertiary therapy upon disease progression, including consideration of lung transplantation (Figure 3). Patients considered at low or intermediate risk of death within 1 year after diagnosis (WHO functional classes II and III) should be treated initially with combination therapy of an endothelin-receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor. Patients at high risk of death (WHO functional class IV) should be treated with continuous intravenous infusion of prostacyclin, alone or combined with an oral PDE5 inhibitor, or a combination of a PDE5 inhibitor and an ERA.4 Up-front treatment with dual or tertiary therapy in selected patients with moderate- or high-risk features has been proposed as a strategy to improve prognosis in these subsets of patients; however, studies to support this recommendation are limited.3 The prospective, multicenter, single-arm, open-label, phase 4 OPTIMA study (ClinicalTrials.gov Identifier: NCT02968901) demonstrated that oral combination therapy with macitentan and tadalafil led to significant improvement in cardiopulmonary hemodynamics, functional parameters, NT-proBNP level, and the risk profile in treatment-naive patients whose PAH was newly diagnosed.17 Findings of the OPTIMA study support early use of dual oral combination therapy with an ERA and a PDE5 inhibitor to manage PAH optimally.

 “In patients with PAH initiating therapy with IV epoprostenol, we suggest against the routine simultaneous initiation of bosentan.”
(Ungraded consensus-based statement7)

“For WHO FC III or IV PAH patients with unacceptable clinical status despite established PAH-specific monotherapy, we advise the addition of a second class of PAH therapy to improve exercise capacity. Such patients are ideally evaluated at centers with expertise in the evaluation and treatment of patients with PAH.”
(Ungraded consensus-based statement7)

“For WHO FC III or IV PAH patients with unacceptable or deteriorating clinical status despite established PAH-specific therapy with 2 classes of PAH pharmacotherapy, we suggest addition of a third class of PAH therapy.”
(Ungraded consensus-based statement7)

“In patients with PAH who remain symptomatic on stable doses of a PDE5I or an inhaled prostanoid, we suggest macitentan to improve 6MWD.”
(Ungraded consensus-based statement7)

In addition to pharmacotherapy, general measures and supportive therapy are recommended for patients with PAH.18

General measures include exercise as tolerated, routine vaccinations for preventing infection, counseling against smoking (and vaping), maintaining a normal body mass index, counseling on pregnancy and contraception, and offering psychological support.

Supportive therapy includes anticoagulation, diuretics, oxygen, cardiovascular and antiarrhythmic medications, and treatment of anemia and iron deficiency. Patients should be treated for any comorbidity known to be associated with or to exacerbate PAH. Women of childbearing age should be counseled regarding the risk of pregnancy to them, including death, and potential teratogenic effects on the fetus of medications used to treat PAH.18


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Reviewed February 2021