The US REVEAL Registry

Transcription

1 Pulmonary Hypertension: Lessons from Contemporary Registries The US REVEAL Registry ESC August 30, 2010 Dave Badesch, MD University of Colorado

2 Disclosures Dr. Badesch has received grant/research support from Glaxo Wellcome, United Therapeutics / Lung Rx, Actelion / CoTherix, Encysive, Myogen / Gilead, Pfizer, Lilly / ICOS, Novartis and Bayer He has received honoraria for service on steering committees and advisory boards from Glaxo Wellcome / GlaxoSmithKline, Actelion / CoTherix, Gilead / Myogen, Encysive, Pfizer, United Therapeutics / Lung Rx, Lilly/ICOS, MondoBiotech / MondoGEN / Biogen IDEC, Bayer and Arena.

3 What is REVEAL? Multi-center, observational, US-based longitudinal registry All consecutive PAH patients meeting inclusion criteria are enrolled Data collection will occur retrospectively, and prospectively for 5 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 are the goals of REVEAL? To characterize the demographics and clinical course of the patient population diagnosed with WHO Group I PAH To evaluate differences in patient outcomes according to WHO Group I classification subgroup To compare patient outcomes in patients who do and do not meet prespecified hemodynamic criteria for the diagnosis of PAH To identify clinical predictors of short-term and long-term outcomes To assess the relationship between PAH medications (individually and in combination) and patient outcomes To report temporal trends in treatments and outcomes for newly diagnosed patients To collect timely and relevant data that will assist in the evolving research needs of the PAH community

5 Who is behind REVEAL? Steering Committee Michael McGoon (chair), David Badesch, Robyn Barst, Ray Benza, Greg Elliott, Hap Farber, Adaani Frost, Abby Poms Special Consultants Gary Raskob, Ted Liou Statistical support by ICON Dave Miller, Michelle Turner, Aimee Foreman, Jae Oh, Lori Parsons, Christy Guyan, Ginny Lai, Faith Beery, Rachel Condon Sponsored by Actelion Pharmaceuticals Shal Jacobovitz, Kathy Feldkircher, Prieya Wason, Sabrina Smith, Ansgar Conrad, Janette Nieva, Bob Garris

6 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

7 REVEAL Baseline Demographics Badesch et al.(chest 2009)

8 What are the characteristics of WHO Group I PAH patients at US PAH centers? Badesch et al. CHEST 2009 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 generalizaibility 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 2009 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 (Table 1)

10 Mean Age and Female Predominance Badesch et al. CHEST Age at Enrollment (years) Drugs/ Toxins PoPH CTD CHD IPAH 100% 80% 60% 40% 20% 0% Percent Female 90% 80% 84% 74% 50% Drugs/ Toxins PoPH CTD CHD IPAH (Table 1)

11 Diagnostic RHC Parameters Badesch et al. CHEST 2009 Mean RAP (mmhg) Fick or Thermodilution CI IPAH CHD CTD PoPh Drugs/ Toxins 0 IPAH CHD CTD PoPH Drugs/ Toxins (Table 2)

12 Percent PAH-specific Medications Badesch et al. CHEST Monotherapy Combination Therapy* * Includes combination with one oral therapy (defined as bosentan, sildenafil, ambrisentan, sitaxsentan and tadalafil), combination with Prostacyclin Analogue, and combination with more than one other therapy; *ETRA = Endothelin Receptor Antagonist, where N = 953 on bosentan, N = 106 on sitaxsentan, and N = 89 on ambrisentan; PDE-5 Inhibitor = Phosphodiesterase Inhibitor, where N = 1147 on sildenafil and N = 47 on tadalafil; Treprostinil use includes N=159 on IV, N=112 on SC, N=28 on inhaled, and N=9 on oral treprostinil. ETRA* Treprostinil Inhaled Iloprost IV Epoprostenol PDE-5 Inhibitor (Table 4)

13 9.7% 12.6% 19.7% Percent of Patients 47.0% 49.0% 42.0% Medication Use in REVEAL Badesch et al CHEST 09 (Table 4 excerpt) N = Any ETRA Any PDE-5 Inhibitor Any Prostacyclin IV Epoprostenol Inhaled Iloprost Treprostinil 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).

14 Concomitant Medications Badesch et al. CHEST 2009 Diuretic Warfarin Oxygen Digoxin Synthetic Thyroid Replacement Calcium Channel Blocker SSRI Other Antidepressants Aspirin Other Anti-inflammatory Statin Beta Blocker Psychotropic Drugs Corticosteroids ACE Inhibitor 0% 10% 20% 30% 40% 50% 60% 70% 80% (Table 5)

15 Patients Meeting or Not Meeting Traditional PAH Criteria Badesch et al. CHEST % 50% 40% p = p = p < PCWP 15 mmhg (n = 2525) 30% 20% p <0.001 PCWP mmhg (n = 239) 10% p < % Sleep Apnea Obese (BMI 30+) Hypertension Renal Insufficiency Diabetes - Overall (Table 6)

16 REVEAL Risk Score Calculator Benza et al. (Circ 2010 publication and ATS 2010 presentation)

17 1-Year Survival Benza et al. Circulation 2010

18 What Qualities Do We Want From an Ideal Prognostic Equation? Benza ATS 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

19 Multivariable Survival Model (part 1 of 2) Benza et al. Circulation 2010 Developed from stepwise multivariable Cox proportional hazards model Establishes 19 predictors of one-year survival 10 parameters from etiology and physical exam

20 Multivariable Survival Model (part 2 of 2) Benza et al. Circulation parameters from diagnostic tests 6MWD is very important and infrequently available at dx BNP and DLCO are very important and not collected at dx

21 One Year Survival by Prognostic Equation Risk Strata Model Development Cohort Benza ATS % ± 0.5% 92.4% ± 1.0% 88.5% ± 1.9% 76.5% ± 2.5% 49.5% ± 5.0%

22 Risk Calculator Benza ATS 2010 Multivariable model coefficients were replaced with integer values to create calculator Risk Calculator allows easy tabulation of risk score Not mentioned in Circ paper will be included in validation paper

23 REVEAL Prognostic Equation Simplified Risk Calculator NIH Equation Random Chance Assessing Discrimination in the Validation Cohort C-index Benza ATS

24 Characteristics of the Registries Frost et al. (CHEST 2010)

25 Characteristics of the Registries Frost et al. CHEST 10 Sophia n=1180 Scottish n=374 French n=674 NIH PPH n=187 PHC n=578 REVEAL n=

26 Characteristics of the Registries Frost et al. CHEST 10 (taken from Fig. 2)

27 Characteristics of the Registries Frost et al. CHEST 10 (taken from Fig. 3)

28

29 Characteristics of the Registries Frost et al. CHEST 10 (taken from Fig. 5)

30 The REVEAL Registry now 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 Can be applied to improve decisions regarding transplant

31 The REVEAL Registry will Provide long-term outcome data on PAH patients and subgroups Examine outcomes associated with different treatment strategies Monitor changes in management over time Generate testable hypotheses for additional studies