PAH Risk Stratification

Definition

PAH risk stratification is the systematic, multiparameter assessment of prognosis and treatment-response in pulmonary arterial hypertension, used to guide initial therapy selection and escalation decisions. The 2022 ESC/ERS guidelines use a 3-strata model at diagnosis (low/intermediate/high risk) and a 4-strata model at follow-up (low/intermediate-low/intermediate-high/high risk), with achieving and maintaining low-risk status as the primary treatment target.

Key Concepts

Risk Strata and Parameters

• 3-strata model at diagnosis and initial treatment planning: Low / Intermediate / High. (sources/PHT-ESC-2022, rating: very high)
• 4-strata model at follow-up: Low / Intermediate-Low / Intermediate-High / High. Sub-stratification within the intermediate range was added in 2022 to better guide escalation decisions. (sources/PHT-ESC-2022, rating: very high)
• Core risk parameters (at each assessment):
  • WHO functional class (WHO-FC I/II = low; III = intermediate; IV = high)
  • 6-minute walking distance (6MWD: >440 m = low; 165–440 m = intermediate; <165 m = high)
  • NT-proBNP/BNP (NT-proBNP <300 ng/L = low; 300–1100 = intermediate; >1100 = high)
  • Echocardiographic findings (RAP, RV/RA size and function, pericardial effusion)
  • RHC haemodynamics (RAP, CI, SVI, mixed venous O₂ saturation)
  • (sources/PHT-ESC-2022, rating: very high)

Low-Risk Target Haemodynamics

• RAP <8 mmHg
• Cardiac Index (CI) ≥2.5 L/min/m²
• Stroke Volume Index (SVI) ≥38 mL/m²
• Mixed venous O₂ saturation >65%
• (sources/PHT-ESC-2022, rating: very high)

Treatment Algorithm Based on Risk

• Low-to-intermediate risk at diagnosis: Initial combination ERA + PDE5i — Class I/B (ambrisentan + tadalafil or macitentan + tadalafil). (sources/PHT-ESC-2022, rating: very high)
• Intermediate risk with severe haemodynamic impairment (RAP ≥20 mmHg, CI <2.0 L/min/m², SVI <31 mL/m², and/or PVR ≥12 WU): Initial triple therapy including i.v./s.c. prostacyclin may be considered. (sources/PHT-ESC-2022, rating: very high)
• High risk at diagnosis: Initial triple therapy including parenteral prostacyclin; early lung transplantation evaluation. (sources/PHT-ESC-2022, rating: very high)
• Escalation trigger: If intermediate-high or high risk at reassessment (3–6 months) → add parenteral prostacyclin or escalate to lung transplantation. (sources/PHT-ESC-2022, rating: very high)
• Follow-up reassessment: Every 3–6 months — repeat WHO-FC, 6MWD, NT-proBNP, echocardiography; RHC as clinically indicated. (sources/PHT-ESC-2022, rating: very high)

REVEAL Lite 2 and the High-Risk Tier — ZENITH Evidence

• REVEAL Lite 2 risk score: 6-variable noninvasive composite tool (WHO-FC, systolic BP, heart rate, 6MWD, NT-proBNP, renal function); scores 1–14; higher = greater 1-year mortality risk; validated in GRIPHON post-hoc; changes in REVEAL Lite 2 score predict long-term outcomes
• Score ≥9 = high risk: Operationalized as the enrollment threshold in ZENITH; represents WHO FC III/IV patients with high 1-year mortality risk despite stable maximum tolerated double/triple therapy
• ZENITH trial (NEJM 2025): Sotatercept add-on in REVEAL Lite 2 ≥9 patients (n=172) — primary composite HR 0.24 (P<0.001); stopped early for efficacy; PAH hospitalization reduced from 50% to 9.3%; REVEAL Lite 2 score improved significantly at week 24 with sotatercept (sources/sotatercept-zenith-nejm-2025, rating: very high)
• Clinical implication (ZENITH): REVEAL Lite 2 ≥9 serves as both a risk marker and an evidence-based indication threshold for sotatercept escalation; achieving REVEAL Lite 2 ≤7 at reassessment represents a meaningful treatment response endpoint
• REVEAL Lite 2 is distinct from (but complementary to) the ESC 3/4-strata model; REVEAL Lite 2 ≥9 approximately corresponds to ESC high-risk or advanced intermediate-high risk
• HYPERION trial (NEJM 2025): Used REVEAL Lite 2 ≥6 OR COMPERA 2.0 ≥2 (intermediate or higher risk) as enrollment threshold — extending sotatercept evidence to intermediate-risk patients with early-disease PAH; majority had COMPERA 2.0 intermediate-low (64%) and REVEAL Lite 2 intermediate (51%), confirming benefit across the intermediate-risk tier (sources/sotatercept-hyperion-nejm-2025, rating: very high)
• COMPERA 2.0 as a complementary risk tool: 4-strata tool (1=low; 2=intermediate-low; 3=intermediate-high; 4=high); based on WHO-FC, 6MWD, and NT-proBNP; score ≥2 = actionable risk threshold for sotatercept add-on in early PAH; distinct from REVEAL Lite 2 (6-variable tool including systolic BP, HR, renal function)

Vasoreactivity Testing

• Acute vasoreactivity testing: Recommended in IPAH, HPAH, DPAH (Class I). Positive response: mPAP reduction ≥10 mmHg to reach absolute mPAP ≤40 mmHg with unchanged or increased CO. (sources/PHT-ESC-2022, rating: very high)
• <10% of IPAH/HPAH/DPAH patients are vasoreactive; non-responders should NOT receive CCBs. (sources/PHT-ESC-2022, rating: very high)
• Positive responders treated with high-dose CCBs (nifedipine, diltiazem, amlodipine, felodipine); complete reassessment including RHC at 3–6 months. (sources/PHT-ESC-2022, rating: very high)

Contradictions / Open Questions

• 4-strata follow-up model not prospectively validated: The intermediate-low/intermediate-high sub-stratification is clinically pragmatic but based on expert consensus rather than prospective validation of hard outcome differences between these two sub-groups. (sources/PHT-ESC-2022, rating: very high)
• Low-risk threshold achievability varies by PAH subtype: SSc-PAH and PAH associated with liver disease consistently have worse haemodynamic profiles and lower rates of reaching low-risk status than IPAH; the same treat-to-target approach may not be equally effective or realistic across all PAH subtypes. (sources/PHT-ESC-2022, rating: very high)
• Sotatercept escalation threshold — ESC strata vs REVEAL Lite 2 ≥9 not directly mapped: The 2022 ESC guidelines recommend parenteral prostacyclin escalation or lung transplantation evaluation for intermediate-high/high risk; ZENITH used REVEAL Lite 2 ≥9 as the high-risk threshold for sotatercept eligibility. These risk frameworks are not identical, and the precise mapping between ESC strata and REVEAL Lite 2 thresholds for sotatercept initiation has not been prospectively validated. Updated ESC/ERS guidelines (post-ZENITH and post-HYPERION) will need to integrate REVEAL Lite 2 ≥9 (high-risk escalation) and REVEAL Lite 2 ≥6/COMPERA 2.0 ≥2 (intermediate-risk early treatment) into escalation and initiation recommendations. (sources/sotatercept-zenith-nejm-2025, rating: very high; sources/sotatercept-hyperion-nejm-2025, rating: very high)
• Simplified French risk score underperforms in older/comorbid PAH populations: HYPERION showed significant multicomponent improvement (P=0.003) and REVEAL Lite 2 ≤5 (P=0.04) but the simplified French risk score failed to reach significance — likely because the 6MWD >440m criterion is unachievable for older patients with more comorbidities regardless of drug response; fixed 6MWD thresholds in risk tools may systematically disadvantage older real-world PAH populations (sources/sotatercept-hyperion-nejm-2025, rating: very high)

Connections

• Related to concepts/pulmonary-hypertension — PAH treatment algorithm by risk tier
• Related to entities/CTEPH — CTEPH-specific risk stratification
• Related to entities/Sotatercept — ZENITH (REVEAL Lite 2 ≥9) and HYPERION (REVEAL Lite 2 ≥6/COMPERA 2.0 ≥2) as evidence-based treatment thresholds
• Related to sources/PHT-ESC-2022
• Related to sources/sotatercept-zenith-nejm-2025
• Related to sources/sotatercept-hyperion-nejm-2025

Sources

• sources/PHT-ESC-2022
• sources/sotatercept-zenith-nejm-2025
• sources/sotatercept-hyperion-nejm-2025