Current Therapeutic Approaches for Adults With WHO Group 1 Pulmonary Arterial Hypertension

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 1^1,2).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

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

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.

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 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