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

Transcription

1 PAH in Registry to Evaluate Early and Long-Term PAH Disease Management Ioana R. Preston, MD Co-Director, Pulmonary Hypertension Center Tufts Medical Center, Boston, MA

2 Background

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 Additional cohort of 500+ newly diagnosed patients

5 Where do REVEAL patients come from? Data lock: August 10, 2009 Data lock: August 30, 2010

6 Characteristics of PAH patients enrolled in the REVEAL

7 When were REVEAL patients diagnosed? *33 patients were diagnosed before 1990

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 Includes both newly and previously diagnosed patients

9 WHO Group Subgroup at Enrollment Badesch et al. CHEST 2010 PPHN 0.0% PVOD 0.4% PCH <0.1% FPAH 2.7% Drugs/ Toxins 10.5% HIV 4.0% Other 5.5% CHD 19.5% APAH 50.7% IPAH 46.2% Portal HT 10.6% CVD/CTD 49.9% N=2525 N=1280

10 APAH-CTD Chung et al., CHEST 2010 SLE MCTD RA 52 SSc 399 Unknown Limited Cutaneous Disease Diffuse Cutaneous involvement

11 Mean Age and Gender Distribution at Enrollment Badesch et al. CHEST 2010 (Table 1 excerpt) Age at Enrollment (years) n=2525 Percent Female n=2525

12 Patients Meeting or Not Meeting Traditional PAH Criteria Badesch et al. CHEST 2010 (Table 6 excerpt) p = p = p < p <0.001 p < 0.001

13 RHC Parameters at Diagnosis Badesch et al. CHEST 2010 (Table 2 excerpt) Mean RAP (mmhg) n=2298 Fick or Thermodilution CI n=1868

14 Percent of Patients 47.0% 49.0% 42.0% Medication Use in REVEAL at Enrollment Badesch et al CHEST 2010 (Table 4 excerpt) n = Any ETRA Any PDE-5 Inhibitor Any Prostacyclin 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).

15 How are patients enrolled in REVEAL being treated? Badesch et al. (Updated 2011 All REVEAL Previously Diagnosed Patients) ETRA 478 (19%) 315 (13%) (9%) 345 (10%) PDE5I (14%) 397 (16%) 300 (12%) PGI 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 Percent PAH-specific Medications at Enrollment Badesch et al. CHEST 2010 (Table 4 excerpt) ETRA PDE-5 Inhibitor Monotherapy Combination Therapy

17 Concomitant Medications Badesch et al. CHEST 2010 (Table 5 excerpt)

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 First PAH-specific therapy

19 Delay Predictors (part I of II) Brown et al., CHEST 2011 (table 5) Adjusted Logistic Regression of Factors Associated with a Time to Disease Recognition > 2 years Adjusted OR 95% CI Adjusted P Value Age at Initial Symptoms, y < 36y < to <46y to <56y to <65y Comorbid Conditions History of obstructive airway disease <0.001 Sleep apnea <0.001

20 COMPARISONS WITH OTHER REGISTRIES

21 How Does REVEAL Compare? Frost et al., CHEST 2010 Enrollment Intervals Sophia n=1180 Scottish n=374 French n=674 NIH PPH n=187 PHC n=578 REVEAL n=

22 Percent of Patients Characteristics of the Registries Frost et al. CHEST 2010 (taken from Fig. 1) 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 Female Patients (% of cohort) Characteristics of the Registries Frost et al. CHEST 2010 (taken from Fig. 2)

24 Mean Age of IPAH/FPAH Patients, Years Characteristics of the Registries Frost et al. CHEST 2010 (taken from Fig. 3)

25 Characteristics of the Registries Frost et al. CHEST 2010 (taken from Fig. 3)

26 Characteristics of the Registries Frost et al. CHEST 2010 (taken from Fig. 3)

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) DLCO, % predicted (No.) 41.2±16.3 (272) 53.3±19.5 (62) <0.001 DLCO 32% predicted, No. (%) 83 (30.5) 9 (14.5) 0.01

29 APAH-CTD Chung et al., CHEST 2010 (figure 2A)

30 APAH-CTD Chung et al., CHEST 2010 (figure 3A)

31 APAH-CTD Chung et al., CHEST 2010 (figure 3B)

32 Percent Female (%) APAH-PoPH Krowka et al. CHEST 2011, (from table 3) % 77% % 54% 0 IPAH/FPAH (n=1059) PoPH (n=118) IPAH/FPAH (n=419) PoPH (n=56) Previously Diagnosed Newly Diagnosed

33 APAH-PoPH Krowka et al. CHEST 2011, (taken from table 5) PAH Treatment of Previously Diagnosed Patients at Enrollment Prostacyclin analogues, IV/SC P PoPH IPAH/FPAH Prostacyclin analogues, inhaled/oral P 0.75 Phosphodiesterase inhibitors P 0.19 Endothelin receptor antagonists P <0.001 Not on any of the above treatments P < % 10% 20% 30% 40% 50% 60% 70%

34 APAH-PoPH Krowka et al. CHEST 2011, (Figure 2)

35 Childhood PAH Barst et al. CIRC 2011 WHO/NYHA FC at Enrollment, % Overall PAH Group I PAH subgroups at Enrollment, % 24% 4% 22% 11% 5% 50% 34% 51% WHO/NYHA FC I WHO/NYHA FC II WHO/NYHA FC III WHO/NYHA FC IV Overall PAH IPAH/FPAH APAH-CHD Other PAH

36 Hemodynamics in Childhood PAH Barst et al. CIRC 2011 (Table 2) IPAH/FPAH APAH-CHD P Value mrap, mmhg mean±sd (n) mpap, mmhg mean±sd (n) MAP, mmhg mean±sd (n) mpcwp, mmhg mean±sd (n) PVR index, Wood units*m 2 mean±sd (n) SVR index mean±sd (n) 7±4 (116) 7±3 (74) ±19 (121) 55±17 (77) ±17 (92) 68±14 (68) ±3 (121) 9±3 (77) ±17 (104) 13±9 (63) ±15 (75) 17±10 (56) 0.002

37 Pediatrics IPAH vs. APAH-CHD survival Barst et al., CIRC 2011 (figure 2)

38 Pediatrics IPAH vs. FPAH survival from enrollment Barst et al., CIRC 2011

39 Pediatrics revisited Survival from diagnosis Barst et al., CIRC 2011

40 SURVIVAL IN REVEAL

41 Survival from Diagnosis Benza et al., CHEST 2011 (figure 2)

42 Survival from Diagnosis Benza et al., CHEST 2011 (figure 4)

43 Survival from Diagnosis Benza et al., CHEST 2011 (figure 3a)

44 Gender revisited Survival from Diagnosis Shapiro et al., CHEST 2012 (figure 2)

45 Functional Class change and survival Barst et al., ATS 2011 Poster (Figure 3)

46 Functional Class change and survival Barst et al., ACCP 2011 Poster

47 Functional Class change and survival Chung et al. ACR 2011 Poster

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 Should have good calibration

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 (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) Benza et al., CIRC parameters from etiology and physical exam

52 Multivariable Survival Model (part 2 of 2) Benza et al., CIRC parameters from diagnostic tests

53 Risk Calculator Benza et al., CHEST 2011 Risk Score Survival (%) Low is borderline! Average Moderatel y High High Very high < 70

54 One Year Survival by Prognostic Equation Risk Strata Model Development Cohort Benza et al., CIRC % 0.5% 92.4% 1.0% 88.5% 1.9% 76.5% 2.5% 49.5% 5.0%

55 Percent Medications at Death Farber et al., ACCP % 47.1% Monotherapy 40.0% 36.5% Combination Therapy 30.0% 31.2% 20.0% 10.0% 8.4% 14.1% 11.7% 12.8% 0.0% 1.1% ERA PDE5 Parenteral PGI2 Inhaled/Oral PGI2 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 Predicts outcome based on clinical variables