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2008 Post Conference Update: CHEST
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Epidemiology
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PAH Registries: Functional Class at Diagnosis Indicates Delayed Diagnosis Frost AE. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. % Patients NYHA Functional Class III-IV at Diagnosis N=2967 N=2364N=1009N=578N=187N=674 Percent (%)
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Survival of Geriatric Patients with IPAH Uzunpinar A. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331. N = 20, IPAH patients >65 years. Percent (%) Survival 100 90 80 70 60 50 40 30 20 10 0 Year 1 Year 2 Year 3 Time Expected Survival (NIH) Actual Survival
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Prevalence of Resting PH in Patients Referred for Stress Echocardiography Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. N = 2,306 adults referred for stress echocardiography. RSVP >35 mmHg 11.9% RVSP <35 mmHg 88.1%
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Diagnostic and Outcomes Markers
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BNP Predictive Value For Adverse Outcomes Garcia-Badillo EV. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. 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
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Biomarker Predictors of Clinical Worsening In Bosentan-treated Patients Vizza CD. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331. *P = 0.0006. † P = 0.09. Clinical worsening vs no clinical worsening. ET-1 (pg/mL) BNP (pg/mL) † *
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Clinical and Hemodynamic Predictors of Survival in PAH Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. Concordance index (C statistic) 0.8 0.7 0.6 0.5 P<0.005 P<0.001 NS Other Clinical factors RHC Age, Sex, WHO Class ECHO & PFTs
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Doppler Echo Overestimates PAH in Patients with Scleroderma-related Lung Disease Chan KM. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. Percent (%)
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PAH in Obese Patients: BMI Correlates With Worsening Hemodynamics Kaw R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. N = 1600, patients undergoing right heart catheterization for suspected PH. *p < 0.05 versus comparator. 70 60 50 40 30 20 10 0 RA MeanPA SystolicPA DiastolicPA MeanPCWP Mean mmHg BMI 3030≤BMI>35BMI≥35 * * * * * * * ** * * * *
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Clinical Pharmacology
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No Pharmacokinetic Interactions Between Ambrisentan and Tadalafil Spence R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. C max AUC Ambrisentan+5.0%-12.5% 4-hydroxymethyl ambrisentan +5.8%-14.5% Tadalafil+0.6%+0.2% N = 26, healthy volunteers. Comparison versus single-agent/metabolite.
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Sitaxsentan and Acencoumarol Interactions Pulido T, et al. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. N = 50. Dose adjustments of 1.6 – 2.0 mg required to reach INR target. 3.0 2.5 2.0 1.5 1.0 0.5 2 Duration (weeks) INR 6 10 14 18 22 2630 34 384246 5054 58 62667074 7882 86 90 94 98 102 106 110
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Short-term Clinical Trials
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Tadalafil for PAH: Change in 6MWD at 16 Weeks Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. N = 405 *p = 0.05; † p = 0.03; ‡ p = 0.0004 vs. placebo. † * ‡ 70 60 50 40 30 20 10 0 048 1216 placebo 2.5 mg 10 mg 20 mg 40 mg Weeks Change in 6-Minute Walking Distance (m)
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Tadalafil for PAH: Change in WHO Functional Class at 16 Weeks Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. P = NS for all comparisons. Percent (%) n = 82 n = 80n = 79 20.7 25.6 23.8 36.6 22.8 63.4 52.4 62.5 45.1 67.1 15.9 22 13.8 18.3 10.1 0% 20% 40% 60% 80% 100% Placebo2.5 mg10 mg20 mg40 mg ImprovedNo ChangeWorsened
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Long-term Clinical Trials
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ARIES-E: Survival With Long-term Ambrisentan Therapy Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. 0 20 40 60 80 100 0.00.51.01.5 2.0 Years Survival (%) ABS 2.5 mg 5 mg 10 mg At Risk: n=383 n=334 n=315 n=298 n=255 2 Year = 88%1 Year = 94%
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ARIES-E: Change in 6MWD Over 2 Years With Ambrisentan Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Change in 6MWD (m) Years -20 -10 0 10 20 30 40 50 60 0.00.250.51.0 1.5 2.0 70 2.5 mg, n = 93 5 mg, n = 186 10 mg, n = 96
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TRIUMPH-1: Long-term Inhaled Treprostinil Plus Oral Therapy 6MWD Improvements Over Time Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Baseline Month 6Month 12Month 18 Month 24 349 377 380 383 399 N = 206 Subjects received either bosentan (n = 143) or sildenafil ( n = 63) in addition to inhaled treprostinil up to 72 µg four times daily Total 6-Minute Walk Distance (meters)
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Long-term Inhaled Treprostinil Plus Oral Therapy: Change in NHYA Functional Class Over Time Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. *p < 0.05 NYHA Unchanged (%)NYHA Worsened (%)NYHA Improved (%) Month 12 N=93 Month 9 N=121 Month 6 N=160 Month 3 N=197 Change from Baseline 80 70 60 50 40 30 20 10 0 * * * *
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SUPER-2: Sildenafil Open-label Extension Clinical Outcomes at 3 Years Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Improved 6MWD Worsened 6MWD Discontinued/ Lost Died Percent (%) N = 259
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SUPER-2: Long-term Sildenafil Change in Functional Class at 3 Years Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. N = 259 Improved 2 Classes Improved 1 Class Worsened 1 Class UnchangedDC/LostDied Percent (%)
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Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. NNYA Functional Class Pre- and Post-Transition (6 months of therapy) N = 30 60 50 40 30 10 20 0 Percentage of Patients (%) NYHA CLASS I II III IV Pre-transition Post-transition
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Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Discontinuation of Treprostinil Over Time (Excluding Death) N = 30 1.0 0.8 0.6 0.4 0.2 0 01224364860 Time (Months) Proportion of Patients Remaining on SC TRE
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Adverse Effects of PAH Therapies
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Epoprostenol-related Thrombocytopenia Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. Platelet count drop >50,000 noted in red Platelet count at Baseline Platelet count at 2-4 months Platelet count at 8-12 months 450 400 350 300 250 200 150 100 50 0
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ARIES- 3: Long-term Ambrisentan Following Bosentan or Sitaxsentan Failure for LFT Abnormalities Feldman JP. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. N = 226, Subset analysis among 26 patients forced to discontinue alternative ERA therapy for LFT abnormalities. 25 20 15 10 0 No LFT Abnormalities ALT/AST >3X AND 5xULN 1 (4%) 5 Number of Patients 25 (96%)
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ARIES-1 & 2: 6MWD of Patients Experiencing Edema Versus No Edema Shapiro SL. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. PlaceboAmbrisentan AllNoYes -120 -100 -80 -60 -40 -20 0 20 40 60 Change in 6MWD (m) p = 0.032 AllYes -9 -55 +34 +39 +19 Edema
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Expanding Populations
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PH Inhibits Stress Echo Exercise Duration Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331. Exercise duration, mins 6 1014 182 100 80 60 40 20 0 No PH (8.6±3 mins) Ex - PH (7.4±3 mins) P<0.0001 Percentage (%) Patients
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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.
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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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