Foundational Pathways in PAH

Early diagnosis and treatment may improve long-term outcomes in PAH^1-3

The goal of PAH treatment is to achieve a low-risk status²
A risk assessment should be performed at diagnosis and follow-up²
- A low-risk status at diagnosis focuses on WHO FC I or II, 6MWD >440 m, BNP <50 ng/L, NT-proBNP <300 ng/L, RAP <8 mmHg, CI ≥2.5 L/min/m², SVI >38 mL/m², and SvO₂ >65%*
- A low-risk status at follow-up includes WHO FC I or II, 6MWD >440 m, BNP <50 ng/L, and NT-proBNP <300 ng/L

Guidelines recognize that focusing on multiple pathways is an effective treatment strategy²

The 3 foundational signaling pathways in PAH can be targeted by different drug classes^2,4:
- Nitric oxide pathway (PDE5is and sGC stimulators)^2,4
- Endothelin pathway (ERAs)^2,4
- Prostacyclin pathway (prostacyclin pathway agents)^2,4

Specific drug classes target the 3 foundational PAH pathways^2,4

Focusing on multiple pathways has been proven to have clinical benefits, depending on disease progression^2,3

In the 2020 ESC Guidelines for adult CHD,

Combination therapy is recommended in patients with PAH-CHD (Class I, Level A)⁵^†

Low- and intermediate-risk patients^‡

Initial oral combination (ERA and PDE5i) or sequential combination therapy (ERA and PDE5i and/or prostacyclin pathway agents) is recommended^2,3,5‖

High-risk patients^§

Initial combination therapy, including parenteral prostacyclin pathway agents (ERA and/or PDE5i and IV prostacyclin pathway agents), is recommended^2,3,5‖

Patients with PAH-CHD require multidisciplinary management with PAH specialists⁵

PAH support and tools

REVIEW THE RESOURCES

*Guidelines recommend taking into account as many factors as possible, but emphasize these parameters. The full list can be found in the comprehensive risk assessment in PAH table (Table 16 in the 2022 ESC/ERS Guidelines).²

^†A Class I recommendation is defined as evidence and/or general confirmation that a therapy or procedure is beneficial, useful, or effective. Level A evidence is defined as data derived from multiple randomized clinical trials or meta-analyses. A Class I, Level A is the highest recommendation possible.⁵

^‡In risk assessment at diagnosis, low-risk patients are defined as: absent for signs of right HF; no progression of PAH symptoms and clinical manifestations; no syncope; WHO FC I-II; a 6MWD of >440 m; CPET peak VO₂ >15 mL/min/kg (>65% predicted), VE/VCO₂ slope <36; BNP <50 ng/L, NT-proBNP <300 ng/L; echocardiography observations: RA area <18 cm², TAPSE/sPAP >0.32 mm/mmHg, no pericardial effusion; cMRI observations: RVEF >54%, SVI >40 mL/m², RVESVI <42 mL/m²; hemodynamic observations: RAP <8 mmHg, CI ≥2.5 L/min/m², SVI >38 mL/m², and SvO₂ >65%. Intermediate-risk patients are defined as: absent for signs of right HF; slow progression of PAH symptoms and clinical manifestations; occasional syncope; WHO FC III; a 6MWD range of 165 m to 440 m; CPET peak VO₂ range of 11 mL/min/kg to 15 mL/min/kg (35% to 65% predicted), VE/VCO₂ slope range of 36 to 44; BNP range of 50 ng/L to 800 ng/L, NT-proBNP range of 300 ng/L to 1100 ng/L; echocardiography observations: RA area range of 18 cm² to 26 cm², TAPSE/sPAP range of 0.19 mm/mmHg to 0.32 mm/mmHg, minimal pericardial effusion; cMRI observations: RVEF range of 37% to 54%, SVI range of 26 mL/m² to 40 mL/m², RVESVI range of 42 mL/m² to 54 mL/m²; hemodynamic observations: RAP range of 8 mmHg to 14 mmHg, CI range of 2.0 L/min/m² to 2.4 L/min/m², SVI range of 31 mL/m² to 38 mL/m², and SvO₂ range of 60% to 65%. High-risk patients are defined as: presenting with signs of right HF; rapid progression of PAH symptoms and clinical manifestations; repeated syncope; WHO FC IV; a 6MWD of <165 m; CPET peak VO₂ <11 mL/min/kg (<35% predicted), VE/VCO₂ slope >44; BNP >800 ng/L, NT-proBNP >1100 ng/L; echocardiography observations: RA area >26 cm², TAPSE/sPAP <0.19 mm/mmHg, moderate or large pericardial effusion; cMRI observations: RVEF <37%, SVI <26 mL/m², RVESVI >54 mL/m²; hemodynamic observations: RAP >14 mmHg, CI <2.0 L/min/m², SVI <31 mL/m², and SvO₂ <60%.²

^§In risk assessment at follow-up, low-risk parameters are defined as WHO FC I or II, 6MWD >440 m, BNP <50 ng/L, and NT-proBNP <300 ng/L. Intermediate-low risk parameters are defined as a 6MWD range of 320 m to 440 m, BNP range of 50 ng/L to 199 ng/L, and NT-proBNP range of 300 ng/L to 649 ng/L. Intermediate-high risk parameters are defined as WHO FC III, a 6MWD range of 165 m to 319 m, BNP range of 200 ng/L to 800 ng/L, and NT-proBNP range of 650 ng/L to 1100 ng/L. High-risk parameters are defined as WHO FC IV, a 6MWD <165 m, BNP >800 ng/L, and NT-proBNP >1100 ng/L. Each determinant (WHO FC, 6MWD, BNP, NT-proBNP) is assigned a point value: low (1), intermediate-low (2), intermediate-high (3), and high (4). The risk is calculated by adding up the points assigned and dividing by the number of determinants, rounding up when needed.²

^‖Initial combination therapy is not recommended in patients with cardiopulmonary comorbidities per the 2022 ESC/ERS Guidelines.²

Foundational Pathways in PAH

Early diagnosis and treatment may improve long-term outcomes in PAH1-3

Guidelines recognize that focusing on multiple pathways is an effective treatment strategy2

Combination therapy is recommended in patients with PAH-CHD (Class I, Level A)5†

PAH support and tools

Early diagnosis and treatment may improve long-term outcomes in PAH^1-3

Guidelines recognize that focusing on multiple pathways is an effective treatment strategy²

Combination therapy is recommended in patients with PAH-CHD (Class I, Level A)⁵^†