This document discusses the importance and evolution of systematic risk assessment tools for pulmonary arterial hypertension (PAH). It outlines several validated tools that stratify patients into risk groups for mortality based on factors like functional class, biomarkers, exercise capacity and hemodynamics. Ongoing work aims to improve risk prediction by incorporating additional variables and phenotypes. Risk tools can help objectively guide treatment decisions and are useful for balancing patient groups in clinical trials. While imperfect, risk assessment should continue alongside clinical judgment to optimize PAH patient care.

1. The Case for Systematic Risk
Assessment in PAH
H. James Ford MD
Associate Professor of Medicine
Director, Pulmonary Hypertension Program
University of North Carolina at Chapel Hill

2. Disclosures
• Consulting—United Therapeutics, Altavant, Acceleron/Merck,
Polarean

3. Validated Risk Assessment Tools in Medicine
• CHA₂DS₂-VASc Score for Atrial Fibrillation Stroke Risk
• Wells’ Score for DVT/PE risk
• Maddrey’s Discriminant Function for Alcoholic Hepatitis Prognosis
• Many more……
• Ideal tools:
• Utilize as few input variables as possible
• Utilize noninvasive metrics
• Can easily be used by non-experts
• Have a strong concordance in predicting the outcome of interest
(morbidity/mortality)

4. Why Use Systematic Risk Calculators?
• They are an important tool in the toolbox, a crucial piece of the puzzle
• They impart objectivity into the patient assessment
• They are ever-evolving to improve, and as such they are a work in progress
• They compel us to improve our prognosticating ability
• Current PAH guidelines recommend regular interval multi-parametric risk
assessment, with goal of achieving low risk status.
• Disclaimers
• There are shortcomings/opportunities for improvement
• There are discrepancies

5. Historical Perspective
REVEAL 1.0
2010
REVEAL 2.0
2019
REVEAL Lite 2
2021
European 3-
strata
2015
Enhanced 3-
strata
European 4-
strata
2022
Later validated in:
• Swedish registry (n = 530)
• Comparative, Prospective Registry of Newly Initiated Therapies for
Pulmonary Hypertension (COMPERA;multinational, n = 1,588)
• French registry (FPHR; n = 1,017)
Initially developed from expert opinion
REVEAL registry, US-based (2,555 prevalent, 960 incident), 2006-2009

6. Emergence of Therapies vs Risk Assessment Tools

7. Case Study
• 42 y/o female with SSc-PAH
• Diagnostic RHC: mPAP 46, RA 12, CI
2.2, PVR 10.6 WU, SVO2 59%
• 6 MWT 385 meters
• Functional Class 2
• Pro BNP 1375
• Creatinine 0.7
• BP 105/65
• HR 100
• No syncope, no pericardial effusion on
echo.
• RA mildly dilated on echo
• Risk assessment of this patient?
• A) Low
• B) Intermediate
• C) High
• D) need more information

8. Why Use Risk Assessment Tools?
• Anchor treatment and treatment escalation decisions to real world
outcomes data
• Gestalt is imperfect
• Ability to detect more subtle trends towards clinical worsening

9. Clinician Gestalt vs Model-Derived Risk
Simons JE. Adv Ther. 2019; 36
• 90 physicians
• 623 patients
• Mean age 56.4 yrs
• Abbreviated
ERS/ESC:
• FC, 6mWD, BNP, RAP,
CI, SvO2
• Scored 1 - 3

10. Clinician Gestalt vs Model-Derived Risk
• Retrospective chart review
• COMPERA, noninvasive French and
REVEAL 2.0
• Telephone interview with providers
• US based
• 153 patient charts, 38 physicians
• Factors associated with
incongruency:
• Less frequent echo
• Higher patient physical activity
• Systemic hypertension
• Autoimmune disease

11. REVEAL
Includes non-modifiable variables
Only modifiable variables
Inclusion of renal function

12. REVEAL Risk Tools
REVEAL 1.0 REVEAL 2.0 REVEAL Lite 2
Group 1 subgroup CTD/POPH/HPAH CTD/POPH/HPAH -------------
Demographics Male > 60 Male > 60 -------------
Comorbidities Renal insufficiency eGFR < 60 eGFR < 60
Functional class 1 vs 3 vs 4 1 vs 3 vs 4 1 vs 3 vs 4
Vital signs SBP<110, HR >92 SBP <110, HR >96 SBP <110, HR >96
6 MWD >440 m, < 165 m >440, 320-440, <165 m >440, 320-440, <165 m
All cause hospitalization in
last 6 months
-------- +1 -------------
Natriuretic peptides BNP < 50, > 180 BNP or NT pro BNP, 3
strata
BNP or NT pro BNP, 3
strata
Echocardiogram Pericardial effusion Pericardial effusion -------------
PFT DLCO >80% pred, < 32%
pred
DLCO < 50% predicted -------------
RHC/hemodynamics RAP > 20, PVR >32 WU RAP >20, PVR <5 -------------
C = 0.76
C = 0.74 C = 0.73

13. European 3 Strata Models
C = 0.64
Nonmodifiable factors not included

14. European 4-Strata (COMPERA 2.0)
C = 0.70

15. European 4-Strata (COMPERA 2.0)
Hoeper MM. Eur Respir J. 2022; 60(1)
Baseline First follow-up

16. 6th WSPH vs ERS/ESC 2022 Treatment
Algorithm
Humbert M. Eur Respir J. 2022

17. Case Study Revisited
• 42 y/o female with SSc-PAH
• Diagnostic RHC: mPAP 46, RA 12, CI 2.2, PVR
10.6 WU, SVO2 59%
• 6 MWT 385 meters
• Functional Class 2
• Pro BNP 1375
• Creatinine 0.7
• BP 105/65
• HR 100
• No syncope, no pericardial effusion on echo.
• RA mildly dilated on echo
• REVEAL 2.0 Risk
• High risk
• REVEAL Lite 2
• High risk
• ESC/ERS 3 strata table
• Intermediate Risk
• European 4 strata
• Intermediate-low risk
?

18. Role for Risk Assessment in Clinical Trials
(FREEDOM EV)
• FREEDOM-EV--placebo-controlled, event-driven study, randomized
690 PAH participants 1:1 to oral treprostinil (TRE) or placebo.
• Potential role for ensuring placebo and active treatment arms are
truly comparable
• In Freedom EV study, contemporary risk scores were therapy
responsive and early improvements predicted subsequent outcomes
(? Surrogate for clinical worsening)
• At baseline, treatment and placebo groups were imbalanced with
respect to systematic risk assessment (treatment arm was higher risk
status overall). White et al. Am J Respir Crit Care Med. 2020; 201: 707-717
Benza et al, JHLT, VOLUME 41, ISSUE 11, P1572-1580,

19. REVEAL 1.0, 2.0 and REVEAL Lite 2 in PATENT
1/2
• PATENT and extension trial:
riociguat vs placebo for PAH
• REVEAL Lite 2 and original RRS
scores at baseline and Week
12 were significantly
associated with survival and
CWFS in patients with PAH
receiving riociguat.
• Significantly increased
proportion of patients with
REVEAL Lite 2 Low risk status
at PATENT 1 and 2 week 12 (tx
group) and PATENT 2 week 12
(pbo group).
Benza et al. J Heart Lung Transplant. 2022 Mar;41(3):411-420.

20. What Needs to Improve?
• Inclusion of more nuanced phenotypes (including within the “IPAH”
tent)
• Age adjusted impacts on mortality
• Comorbidities
• Additional RV imaging parameters (TAPSE, CMRI)
• Racial/ethnic differences
• Genetics
• Inclusion of patient reported outcomes

21. Summary
• Risk assessment tools continue to evolve, with ever-improving discriminatory power and
risk group stratification
• Gestalt alone remains unreliable
• Opportunities to better balance clinical trial treatment and placebo arms, as well as use
risk calculators in serial reassessment as surrogates of clinical worsening/CWFS.
• Simpler tools make risk assessment easy and accessible in clinical practice
• Complex calculators should remain an important tool. Don’t just rely on simpler tools.
• An increasingly complex array of PAH therapy options likely in the future—tools needed
to aid clinicians in treatment choices (how many, which, when?)
• WE SHOULD NOT ABANDON THESE TOOLS, RATHER WORK TO CONTINUE TO IMPROVE
THEM