Medications are currently approved to treat PAH via multiple pathways
Approved medications are designed to specifically address under- or over-expression of naturally occurring substances that contribute to the pathology of pulmonary arterial hypertension (PAH). These substances support the lungs in different ways, depending on the pathway involved. Each class of medication available today addresses the imbalance of a single substance. Data suggest that treating multiple pathways improves exercise capacity, heart health, and other key measures of patient outcomes.1
Prostacyclin-class therapies2
- Induce vasodilation
- Inhibit platelet aggregation
- Inhibit smooth muscle cell proliferation
Available forms: 
PDE-5i therapies and sGCS2
- Induce vasodilation
- Inhibit proliferation
Available form:
ERA therapies2
- Prevent vasoconstriction
- Prevent proliferative effects
Available form:
Activin signaling therapy3,4
- Modulate vascular proliferation
Available form5:
Treating multiple pathogenic pathways is the current standard of care6
Current treatment guidelines stress the necessity of helping patients achieve low-risk status within the first year of diagnosis. To accomplish this goal, the guidelines recommend2:
- Treating multiple pathogenic pathways
- Conducting frequent follow-up, including risk assessments
- Striving toward and maintaining the treatment goal of low risk
- Escalating therapy when not at low risk
- Referring patients to PH expert centers
Baseline risk score guides initial treatment regimen
Guidelines advocate for an objective, multiparameter risk calculation upon diagnosis of PAH to establish the patient's baseline risk status. Guidelines recommend using patient risk status to guide treatment initiation involving combination therapy for appropriate patients.2
- Low- and intermediate-risk patients should receive therapies treating two pathways2
- Note that initial treatment using only one pathway is reserved for patients with cardiopulmonary comorbidities, with close, frequent follow-up required
- High-risk patients should receive a combination of therapies that includes a parenteral prostacyclin, either IV or subcutaneous2
Baseline Risk Status and Initial Therapy
In patients without cardiopulmonary comorbidities, it is recommended to perform a baseline risk assessment using a multiparameter, 3-strata treatment algorithm to determine risk status. Those patients at either low or intermediate risk are recommended to go on initial ERA and PDE-5i therapy. Patients at high risk are recommended to go on initial ERA and PDE-5i therapy and an IV or SC prostacyclin.
Baseline Risk Status and Initial Therapy
In patients with cardiopulmonary comorbidities, it is recommended to perform the 3-strata risk assessment treatment algorithm, and these patients are recommended to go on initial oral monotherapy with PDE-5i or ERA and have regular follow-up assessment, individualized therapy, and be referred to PH expert centers.
Frequently assess progress to low-risk with a 4-strata risk assessment
Prompt adjustments to the treatment plan are recommended for patients not at low risk, to help improve their risk status and outcomes.2
Following initial visit and treatment, the guidelines recommend checking a patient’s risk status frequently, every 3-6 months at follow-up. For patients not at low risk, escalate therapy by adjusting their medication regimen: switch from PDE-5i to sGCS or add a prostacyclin therapy. In patients with intermediate-high or high risk, consider adding intravenous or subcutaneous prostacyclin or evaluate them for potential lung transplantation.2
Follow-Up Risk Status and Therapy
While oral and inhaled forms of PCY-class medications are approved in the US, most of these are not available in Europe and were not included in the European Guidelines. Activin-signaling inhibitors were not approved at the time guidelines were published.
During follow-up visits, patients should be assessed using the 4-strata risk assessment treatment algorithm, which will group them into one of four risk strata:
- Low-risk patients are recommended to continue initial therapy
- Intermediate-low risk patients are recommended to add a prostacyclin or switch from PDE-5i to sGCs therapy
- Intermediate-high risk patients are recommended to add an intravenous or subcutaneous prostacyclin and/or evaluate for a lung transplantation
- High-risk patients are recommended to add an intravenous or subcutaneous prostacyclin and/or evaluate for a lung transplantation
- While oral and inhaled forms of PCY-class medications are approved in the US, most of these are not available in Europe and were not included in the European Guidelines. Activin-signaling inhibitors were not approved at the time guidelines were published
PAH pathophysiology is complex and multifaceted
PAH pathogenesis is described by a chronic over- or under-production of several naturally occurring substances present in the lungs.7
Imbalances in several pathways contribute to the progression of PAH
Naturally produced prostacyclins are potent vasodilators with antithrombotic, antiproliferative, and anti-inflammatory properties.7,8 Some patients with PAH have decreased levels of prostacyclin. These lower levels of prostacyclin are linked to increased pulmonary arterial pressure, disease severity, and disease progression.9,10
Overexpression of endothelin-1 in PAH is linked to arteriolar vasoconstriction, smooth muscle proliferation, and inflammation, and in PAH, is treated with endothelin receptor antagonists.2,7
Nitric oxide–class medications help address the under-expression of nitric oxide that causes vasoconstriction and smooth muscle proliferation in PAH.11
Activin-signaling inhibitors target the abnormal upregulation of activin signaling that contributes to smooth muscle proliferation in PAH. Modulating this pathway can help restore the balance between pro-proliferative and anti-proliferative signaling in the pulmonary vasculature.3-5