PAH in. Registry to Evaluate Early and Long-Term PAH Disease Management

(1)

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

(2)

(3)

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

(4)

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, 2007

(5)

Where 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

(6)

Characteristics of PAH patients enrolled

in the REVEAL

(7)

When were REVEAL patients diagnosed?

(8)

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

(9)

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

(10)

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

(11)

Mean Age and Gender Distribution at Enrollment

Badesch et al. CHEST 2010 (Table 1 excerpt)

Age at Enrollment (years)

n=2525

Percent Female

(12)

Patients Meeting or Not Meeting Traditional PAH Criteria

p = 0.014

p < 0.001

p <0.001

p < 0.001 p = 0.023

(13)

RHC Parameters at Diagnosis

Mean RAP (mmHg)

n=2298

Fick or Thermodilution CI

(14)

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

(15)

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 = 2484

(16)

PAH-specific Medications at Enrollment

0 5 10 15 20 25 30 35

ETRA PDE-5 Inhibitor

Monotherapy

Combination Therapy

Pe

rcen

(17)

Concomitant Medications

(18)

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 or

(19)

Delay – 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

(20)

COMPARISONS WITH OTHER

REGISTRIES

(21)

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

(22)

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)

(23)

Characteristics of the Registries

F emal e Pati en ts (% o f co h o rt)

(24)

Characteristics of the Registries

M ean A g e o f IP A H /F P A H Pati en ts, Y ear s

(25)

Characteristics of the Registries

(26)

Characteristics of the Registries

(27)

Characteristic features of

Non-IPAH patients

(28)

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

(29)

APAH-CTD

(30)

APAH-CTD

(31)

APAH-CTD

(32)

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

(%

(33)

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

(34)

APAH-PoPH

(35)

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

(36)

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

(37)

Pediatrics – IPAH vs. APAH-CHD survival

(38)

Pediatrics – IPAH vs. FPAH survival from enrollment

(39)

Pediatrics revisited – Survival from diagnosis

(40)

(41)

Survival from Diagnosis

(42)

(43)

(44)

Gender revisited – Survival from Diagnosis

(45)

Functional Class change and survival

(46)

(47)

(48)

PREDICTORS OF OUTCOME IN

PAH

(49)

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

(50)

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

(51)

Multivariable Survival Model (part 1 of 2)

(52)

Multivariable Survival Model (part 2 of 2)

(53)

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

(54)

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%

(55)

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

(56)

REVEAL Summary

•

Provides PAH data based on broad

institutional, geographic, clinical, hemodynamic and demographic diversity

•

Allows characterization of disease and management at presentation in subsets of WHO

group, gender, age, region and severity

•

Describes functional and survival outcomes in PAH population and subsets