Registry to Evaluate Early and Long-Term PAH Disease Management
PAH in
Ioana R. Preston, MD
Co-Director, Pulmonary Hypertension Center Tufts Medical Center, Boston, MA
What is REVEAL?
•
Multi-center, observational, US-based
longitudinal registry
•
All consecutive PAH patients meeting inclusion
criteria are enrolled
•
Data collection occured retrospectively, and
prospectively for 7 years
•
Enrollment = first visit to an enrolling institution
during the enrollment phase
•
Diagnosis = time of diagnostic RHC at or
before the date of enrollment
What patients were eligible to enroll in
REVEAL?
•
PAH (WHO Group I) with documentation of:•
Mean pulmonary pressure of >25 mmHg at rest or >30 mmHg with exercise•
PCWP ≤18 mmHg at rest or LVEDP ≤18 mmHg•
PVR ≥240 dynes·sec·cm-5•
3 months or older at time of diagnosis•
Consecutive enrollment of both newly and previously diagnosed patients for 3515 consented patients•
Enrollment of first 2977 completed September 11, 2007Where do REVEAL patients come from?
Data lock: August 10, 2009Data lock: August 30, 2010 183 300 452 202 246 53 24 52 5 6 300 64 8 38 33 31 52 55 54 72 69 278 280 264 131 66 101 96
Characteristics of PAH patients enrolled
in the REVEAL
When were REVEAL patients diagnosed?
What are the characteristics of WHO Group I PAH
patients at US PAH centers?
Badesch et al. CHEST 2010
•
Baseline report focuses on adult patients with traditional hemodynamics (n=2525)•
Data are presented as most recent at time of enrollment unless noted otherwise• Target population for generalizability is adult patients being seen at US PAH centers
IPAH 46.2% APAH 50.7% FPAH 2.7% PCH <0.1% PVOD 0.4% PPHN 0.0% Othe r 5.5% Drugs/ Toxins 10.5% HIV 4.0% Portal HT 10.6% CVD/CTD 49.9% CHD 19.5% N=2525 N=1280
WHO Group Subgroup at Enrollment
APAH-CTD
Chung et al., CHEST 2010
110 52 28 52 251 77 71 399 SLE MCTD RA Unknown Limited Cutaneous Disease Diffuse Cutaneous involvement SSc
Mean Age and Gender Distribution at Enrollment
Badesch et al. CHEST 2010 (Table 1 excerpt)
Age at Enrollment (years)
n=2525
Percent Female
Patients Meeting or Not Meeting Traditional PAH Criteria
Badesch et al. CHEST 2010 (Table 6 excerpt)
p = 0.014
p < 0.001
p <0.001
p < 0.001 p = 0.023
RHC Parameters at Diagnosis
Badesch et al. CHEST 2010 (Table 2 excerpt)
Mean RAP (mmHg)
n=2298
Fick or Thermodilution CI
Medication Use in REVEAL at Enrollment
Badesch et al CHEST 2010 (Table 4 excerpt)
47.0% 49.0% 42 .0 % 0 10 20 30 40 50 60
Any ETRA Any PDE-5 Inhibitor Any Prostacyclin
Per cent of Pat ient s n = 2438
• Total n = 2438 adult patients meeting the traditional hemodynamic definition (PCWP <15
mmHg) enrolled between March 2006 and September 2007 (excluding those in a blinded clinical trial).
1147
1194
How are patients enrolled in REVEAL being treated?
Badesch et al. (Updated 2011 – All REVEAL Previously Diagnosed Patients)
PGI
300 221 244 345 315 (13%) (10%) (9%) (14%) (12%)PDE5I
397 (16%)ETRA
(19%) 478 Note: 184 (7%) of patients were not on a PGI, PDE5I, or ETRA, of whom 88 were on CCBs for the treatment of PAH. N = 2484PAH-specific Medications at Enrollment
Badesch et al. CHEST 2010 (Table 4 excerpt)
0 5 10 15 20 25 30 35
ETRA PDE-5 Inhibitor
Monotherapy
Combination Therapy
Pe
rcen
Concomitant Medications
Delayed Recognition of PAH
Brown et al., CHEST 2011
•
Delay defined as >2 yrs from symptoms to:•
RHC diagnosis meeting REVEAL entry criteria or•
Being told by a physician they have PAH orDelay – Predictors (part I of II)
Brown et al., CHEST 2011 (table 5)
Adjusted OR 95% CI Adjusted P Value
Age at Initial Symptoms, y
< 36y 3.07 2.03-4.66 <0.001
36 to <46y 1.85 1.20-2.84 0.005
46 to <56y 1.72 1.13-2.61 0.012
56 to <65y 2.07 1.34-3.20 0.001
Comorbid Conditions
History of obstructive airway disease 1.93 1.50-2.47 <0.001
Sleep apnea 1.72 1.33-2.22 <0.001
COMPARISONS WITH OTHER
REGISTRIES
1980 1985 1990 1995 2000 2005 2010 REVEAL PHC NIH PPH French Scottish Sophia n=578 n=2967
How Does REVEAL Compare? Frost et al., CHEST 2010
n=1180
n=374
n=674
n=187
Characteristics of the Registries
Frost et al. CHEST 2010 (taken from Fig. 1)
Per cen t o f Pati en ts
• REVEAL NIH is defined by applying the NIH registry criteria (IPAH or FPAH, PCWP ≤ 12mmHg) • REVEAL FCC is defined by applying the FrR criteria (≥18 years of age, PCWP ≤ 15)
Characteristics of the Registries
Frost et al. CHEST 2010 (taken from Fig. 2)
F emal e Pati en ts (% o f co h o rt)
Characteristics of the Registries
Frost et al. CHEST 2010 (taken from Fig. 3)
M ean A g e o f IP A H /F P A H Pati en ts, Y ear s
Characteristics of the Registries
Characteristics of the Registries
Characteristic features of
Non-IPAH patients
APAH-CTD
Chung et al., CHEST 2010
SSc-APAH (n=399)
SLE-APAH
(n=110) P Value
Pericardial effusion, No. (%) 0.03
None 181 (57.3) 66 (71.0)
Mild/Moderate 127 (40.2) 27 (29.0)
Severe 8 (2.5) 0 (0.0)
6-Min walk distance 288.0±115.1 (132) 324.3±121.3 (32) 0.12
BNP, pg/mL (No.) 552.2±977.8 (179) 263.8±338.8 (59) 0.004
DLCO, % predicted (No.) 41.2±16.3 (272) 53.3±19.5 (62) <0.001
APAH-CTD
APAH-CTD
APAH-CTD
APAH-PoPH
Krowka et al. CHEST 2011, (from table 3)
79% 51% 77% 54% 0 10 20 30 40 50 60 70 80 90 100
IPAH/FPAH (n=1059) PoPH (n=118) IPAH/FPAH (n=419) PoPH (n=56) Previously Diagnosed Newly Diagnosed
Percent
Female
(%
APAH-PoPH
Krowka et al. CHEST 2011, (taken from table 5)
0% 10% 20% 30% 40% 50% 60% 70%
Not on any of the above treatments Endothelin receptor antagonists Phosphodiesterase inhibitors Prostacyclin analogues, inhaled/oral Prostacyclin analogues, IV/SC
PoPH IPAH/FPAH
P 0.75
P 0.035
PAH Treatment of Previously Diagnosed Patients at Enrollment
P <0.001
P <0.001 P 0.19
APAH-PoPH
Childhood PAH
Barst et al. CIRC 2011
50% 34% 11% 5% Overall PAH IPAH/FPAH APAH-CHD Other PAH
Group I PAH subgroups at Enrollment, % 22% 51% 24% 4% WHO/NYHA FC I WHO/NYHA FC II WHO/NYHA FC III WHO/NYHA FC IV WHO/NYHA FC at Enrollment, % Overall PAH
Hemodynamics in Childhood PAH
Barst et al. CIRC 2011 (Table 2)
IPAH/FPAH APAH-CHD P Value
mRAP, mmHg mean±SD (n) 7±4 (116) 7±3 (74) 0.51 mPAP, mmHg mean±SD (n) 58±19 (121) 55±17 (77) 0.30 MAP, mmHg mean±SD (n) 73±17 (92) 68±14 (68) 0.044 mPCWP, mmHg mean±SD (n) 9±3 (121) 9±3 (77) 0.69
PVR index, Wood units*m2
mean±SD (n) 19±17 (104) 13±9 (63) 0.014
SVR index
Pediatrics – IPAH vs. APAH-CHD survival
Pediatrics – IPAH vs. FPAH survival from enrollment
Pediatrics revisited – Survival from diagnosis
Survival from Diagnosis
Survival from Diagnosis
Survival from Diagnosis
Gender revisited – Survival from Diagnosis
Functional Class change and survival
Functional Class change and survival
Functional Class change and survival
PREDICTORS OF OUTCOME IN
PAH
What Qualities Do We Want From an Ideal Prognostic Equation?
Benza et al., CIRC 2010
•
Practical• Applicable at any time in patient course
• Apply to all PAH patients
• Allow us to use the most recent information available even if all test were not conducted simultaneously
• Provide an estimate even if all tests were not conducted
•
Statistical• Should have good discrimination
Developed Predictive Model
Benza – CIRC 2010
“Integerized” Model to Create Risk Calculator
Validated Model and Calculator in Separate PAH Populations
Benza – Amendment 2 “New” Patients – In Preparation
Kane – 484 Consecutive Mayo Clinic PAH (Group 1) Patients 1995-2004 – (CHEST 2011)
Future Goals
Further Validation (International Patients)
Refine with Potential Additional Variables (?SV/PP, etc) Simplify with Fewer Variables
Multivariable Survival Model (part 1 of 2)
Multivariable Survival Model (part 2 of 2)
Risk Calculator
Benza et al., CHEST 2011
Risk Score Survival
(%) Low 1-7 7 is borderline! 95-100 Average 8 90-94 Moderatel y High 9 85-89 High 10-11 70-84 Very high 12-15 < 70
One Year Survival by Prognostic Equation Risk Strata Model Development Cohort
Benza et al., CIRC 2010
97.1% 0.5% 92.4% 1.0% 88.5% 1.9% 76.5% 2.5%
8.4% 14.1% 11.7% 1.1% 36.5% 47.1% 31.2% 12.8% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0%
ERA PDE5 Parenteral PGI2 Inhaled/Oral PGI2
Monotherapy Combination Therapy Per cen t Medications at Death
Farber et al., ACCP 2011
• 42.9% of patients overall were on parenteral prostacyclin at time of death • 56.1% of patients were on combination therapy at time of death
REVEAL Summary
•
Provides PAH data based on broadinstitutional, geographic, clinical, hemodynamic and demographic diversity
•
Allows characterization of disease and management at presentation in subsets of WHOgroup, gender, age, region and severity