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2008 Post Conference Update: CHEST

2008 Post Conference Update: CHEST. Epidemiology. N=2967. N=2364. N=1009. N=578. N=187. N=674. PAH Registries: Functional Class at Diagnosis Indicates Delayed Diagnosis. % Patients NYHA Functional Class III-IV at Diagnosis. Percent (%).

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2008 Post Conference Update: CHEST

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  1. 2008 Post Conference Update:CHEST

  2. Epidemiology

  3. N=2967 N=2364 N=1009 N=578 N=187 N=674 PAH Registries: Functional Class at Diagnosis Indicates Delayed Diagnosis % Patients NYHA Functional Class III-IV at Diagnosis Percent (%) Frost AE. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

  4. Survival of Geriatric Patients with IPAH 100 90 80 70 60 Expected Survival (NIH) Percent (%) Survival 50 Actual Survival 40 30 20 10 0 Year 3 Year 2 Year 1 Time N = 20, IPAH patients >65 years. Uzunpinar A. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.

  5. RSVP >35 mmHg 11.9% RVSP <35 mmHg 88.1% Prevalence of Resting PH in Patients Referred for Stress Echocardiography N = 2,306 adults referred for stress echocardiography. Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

  6. Diagnostic and Outcomes Markers

  7. BNP Predictive Value For Adverse Outcomes Death Cardiogenic shock Inpatient heart failure Outpatient heart failure Ventricular dysfunction WHO Class IV WHO Class III WHO Class II WHO Class I Control N = 85 Garcia-Badillo EV. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

  8. Biomarker Predictors of Clinical Worsening In Bosentan-treated Patients * ET-1 (pg/mL) † BNP (pg/mL) *P = 0.0006. †P = 0.09. Clinical worsening vs no clinical worsening. Vizza CD. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.

  9. Clinical and Hemodynamic Predictors of Survival in PAH NS P<0.001 0.8 P<0.005 0.7 Concordance index (C statistic) 0.6 0.5 Age, Sex, WHO Class Other Clinical factors ECHO & PFTs RHC Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

  10. Percent (%) Doppler Echo Overestimates PAH in Patients with Scleroderma-related Lung Disease Chan KM. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

  11. PAH in Obese Patients: BMI Correlates With Worsening Hemodynamics BMI < 25 25≤BMI>30 30≤BMI>35 BMI≥35 * * 70 * 60 * * * * 50 * * 40 * mmHg * * 30 * 20 10 0 RA Mean PA Systolic PA Diastolic PA Mean PCWP Mean N = 1600, patients undergoing right heart catheterization for suspected PH. *p < 0.05 versus comparator. Kaw R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

  12. Clinical Pharmacology

  13. No Pharmacokinetic Interactions Between Ambrisentan and Tadalafil N = 26, healthy volunteers. Comparison versus single-agent/metabolite. Spence R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

  14. Sitaxsentan and Acencoumarol Interactions 3.0 2.5 2.0 INR 1.5 1.0 0.5 14 22 34 50 54 62 66 70 74 90 86 10 18 26 30 38 42 46 58 78 82 94 98 2 6 106 110 102 Duration (weeks) N = 50. Dose adjustments of 1.6 – 2.0 mg required to reach INR target. Pulido T, et al. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

  15. Short-term Clinical Trials

  16. Tadalafil for PAH: Change in 6MWD at 16 Weeks placebo 70 2.5 mg 60 10 mg 20 mg 50 40 mg 40 ‡ † Change in 6-Minute Walking Distance (m) 30 * 20 10 0 12 16 0 4 8 Weeks N = 405 *p = 0.05; †p = 0.03; ‡p = 0.0004 vs. placebo. Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  17. Tadalafil for PAH: Change in WHO Functional Class at 16 Weeks Improved No Change Worsened 100% 10.1 13.8 15.9 18.3 22 80% Percent (%) 60% 45.1 67.1 62.5 63.4 52.4 40% 20% 36.6 25.6 23.8 22.8 20.7 0% Placebo 2.5 mg 10 mg 20 mg 40 mg n = 82 n = 82 n = 80 n = 82 n = 79 P = NS for all comparisons. Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  18. Long-term Clinical Trials

  19. ARIES-E: Survival With Long-term Ambrisentan Therapy 100 80 1 Year = 94% 2 Year = 88% 60 Survival (%) 40 ABS 2.5 mg 5 mg 10 mg 20 0 0.0 0.5 1.0 1.5 2.0 Years At Risk: n=383 n=334 n=315 n=298 n=255 Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  20. 2.5 mg, n = 93 5 mg, n = 186 10 mg, n = 96 ARIES-E: Change in 6MWD Over 2 Years With Ambrisentan 70 60 50 40 30 Change in 6MWD (m) 20 10 0 -10 -20 0.0 0.25 0.5 1.0 2.0 1.5 Years Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  21. Month 6 Month 12 Month 18 Month 24 Baseline TRIUMPH-1: Long-term Inhaled Treprostinil Plus Oral Therapy 6MWD Improvements Over Time 399 383 380 377 Total 6-Minute Walk Distance (meters) 349 N = 206 Subjects received either bosentan (n = 143) or sildenafil ( n = 63) in addition to inhaled treprostinil up to 72 µg four times daily Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  22. Long-term Inhaled Treprostinil Plus Oral Therapy: Change in NHYA Functional Class Over Time NYHA Unchanged (%) NYHA Worsened (%) NYHA Improved (%) 80 70 60 50 * Change from Baseline 40 * * 30 * 20 10 0 Month 3 N=197 Month 6 N=160 Month 9 N=121 Month 12 N=93 *p < 0.05 Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  23. SUPER-2: Sildenafil Open-label ExtensionClinical Outcomes at 3 Years Percent (%) Worsened 6MWD Discontinued/Lost Died Improved 6MWD N = 259 Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  24. SUPER-2: Long-term Sildenafil Change in Functional Class at 3 Years Percent (%) Improved 2 Classes Improved 1 Class Unchanged Worsened 1 Class DC/Lost Died N = 259 Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  25. Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil NNYA Functional Class Pre- and Post-Transition (6 months of therapy) 60 50 40 Pre-transition 30 Percentage of Patients (%) Post-transition 20 10 0 III II I IV NYHA CLASS N = 30 Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  26. Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil Discontinuation of Treprostinil Over Time(Excluding Death) 1.0 0.8 0.6 Proportion of Patients Remaining on SC TRE 0.4 0.2 0 0 12 24 36 48 60 Time (Months) N = 30 Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  27. Adverse Effects of PAH Therapies

  28. Epoprostenol-related Thrombocytopenia 450 400 350 300 250 200 150 100 50 0 Platelet count at Baseline Platelet count at 2-4 months Platelet count at 8-12 months Platelet count drop >50,000 noted in red Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

  29. ARIES- 3: Long-term Ambrisentan Following Bosentan or Sitaxsentan Failure for LFT Abnormalities 25 20 25 (96%) 15 Number of Patients 10 5 1 (4%) 0 No LFT Abnormalities ALT/AST >3X AND 5xULN N = 226, Subset analysis among 26 patients forced to discontinue alternative ERA therapy for LFT abnormalities. Feldman JP. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

  30. ARIES-1 & 2: 6MWD of Patients Experiencing Edema Versus No Edema p = 0.032 All Yes +39 60 +34 +19 40 20 0 -20 -1 -9 Change in 6MWD (m) -40 -60 -80 -100 -55 -120 All NoYes All NoYes Edema Edema Placebo Ambrisentan Shapiro SL. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.

  31. Expanding Populations

  32. PH Inhibits Stress Echo Exercise Duration 100 Ex - PH (7.4±3 mins) 80 No PH (8.6±3 mins) 60 Percentage (%) Patients 40 P<0.0001 20 0 2 18 10 14 6 Exercise duration, mins Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331.

  33. PAH in Sickle Cell Disease • 10% of sickle cell patients will have PAH/PH • Pathophysiology not necessarily related to occlusion • Soluble factors have been identified • Mixed PH (PAH combined with diastolic dysfunction) associated with 11-fold relative risk of mortality • Clinical trials of PAH medications in sickle cell have been slow to recruit Barst RJ, Machado RF, Mubarak KK. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session 15983.

  34. Summary: CHEST 2008 • Evidence suggests PAH treatment can be effective in wide range of patient types and ages • Tadalafil may provide a new choice in PDE-5 inhibitor class • Inhaled treprostinil in combination with oral therapy may provide an additional choice in prostacyclin class • Long-term data for ambrisentan, sildenafil show 2+ years of benefit in survival and time to clinical worsening

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