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PAH Standard of Care from Galie PAH: Standard of Care Nazzareno Galiè Istituto di Cardiologia Università di Bologna [email protected] TF 7 Therapy ‐ Standard of Care Questions A. Do we have additional information on the role of rehabilitation in PAH patients? B. Should first-line combination therapy be the gold standard of severe WHO FC IV PAH (and what about other FC)? C. How can we modify the current treatment algorithm including the new approved drugs? D. Should we adapt the treatment algorithm to the different PAH types and to different countries (country organization)? 1st WHO PH Geneva 1973 PH Classification 1950-1998 (1st WHO PH Geneva 1973) 1. Primary Pulmonary Hypertension 2. Secondary Pulmonary Hypertension 3. Associated Pulmonary Hypertension PAH time course of Treatments „50 „80 „90 „00 „09 „10 Tolazoline, Hydralazine, Acetylcholine, Phentolamine, Isoproterenol, Diazoxide, Nitrates,… Calcium Channel Blockers in vasoreactive pts Calcium Channel Blockers Vasoreactivity – NO test Definition ↓ mPAP > 10, < 40 mmHg abs; CO =/↑ Baseline NO 10 ppm mPAP = 58 mm Hg mPAP = 25 mm Hg Rich S et al. N Engl J Med 1992, 32:76-81 ~ 10% Treatment Algorithm before 1998 Pulmonary Arterial Hypertension Oral anticoagulants Supportive Therapy and Exercise Limitation Diuretics General Measures Birth Control Oxygen(Iia) Psychological Assistance Digoxin Infections Prevention Acute Vasoreactivity Test Vasoreactive Non-vasoreactive NYHA Class I-IV ??????? Oral CCB (I C) New Engl J Med 1996; 334:296-301 Published RCTs in PAH 1. Rubin, Epoprostenol in PPH. Ann Intern Med 1990 2. Barst, Epoprostenol in PPH. N Engl J Med 1996 3. Badesch, Epoprostenol scleroderma PAH. Ann Intern Med 2000 2nd WHO PH Evian 1998 Treatment Algorithm …1998 - 2003 Pulmonary Arterial Hypertension Oral anticoagulants Supportive Therapy and Exercise Limitation Diuretics General Measures Birth Control Oxygen(Iia) Psychological Assistance Digoxin Infections Prevention Acute Vasoreactivity Test Vasoreactive Non-vasoreactive NYHA Class I-IV NYHA Class III-IV Oral CCB (I C) Epoprostenol Published RCTs in PAH 1. Rubin, Epoprostenol in PPH. Ann Intern Med 1990 2. Barst, Epoprostenol in PPH. N Engl J Med 1996 3. Badesch, Epoprostenol scleroderma PAH. Ann Intern Med 2000 4. Channick, Bosentan in PAH. Lancet 2001 5. Langleben, Terbogrel in PPH. Am J Cardiol 2002 6. Simonneau, Treprostinil in PAH. Am J Respir Crit Care Med 2002 7. Galié, Beraprost in PAH. J Am Coll Cardiol 2002 8. Olschewski, Inhaled Iloprost in PH. N Engl J Med 2002 9. Rubin, Bosentan in PAH. N Engl J Med 2002 10. Barst, Beraprost in PAH. J Am Coll Cardiol 2003 11. Sastry, Sildenafil in IPAH. J Am Coll Cardiol 2004 12. Humbert, Bosentan + Epoprostenol in PAH. Eur Respir J 2004 13. Barst, Sitaxsentan. Am J Respir Crit Care Med 2004 14. Galié, Sildenafil in PAH. N Engl J Med 2005 3rd WSPAH Venice 2003 Approved Drugs for PAH Bosentan Bosentan Epoprostenol iv Epoprostenol iv Iloprost inhal Iloprost inhal Sildenafil Sildenafil Treprostinil sc Treprostinil sc PAH treatment algorithm - 2004 Pulmonary Arterial Hypertension Oral anticoagulants (IIa C) Supportive Therapy and Exercise Limitation Diuretics (I C) General Measures (IIa C) Birth Control Oxygen(IIa C) Psychological Assistance Digoxin (IIb C) Expert Referral Infections Prevention Acute Vasoreactivity Test Vasoreactive Non-vasoreactive NYHA Class I-IV NYHA Class III NYHA Class IV Epoprostenol (I A) Oral CCB (I C) Endothelin R Antagonists Bosentan (IIa B) Bosentan (I A) Treprostinil (IIa B) Sustained Response or Iloprost iv (IIa C) (NYHA I-II) Prostanoid Analogues Iloprost inh (I A) Treprostinil (IIa B) No improvement Yes No or deterioration: Beraprost (IIb B) Combination or Therapy ? (IIa B) Continue CCB PDE-5 inhibitors Sildenafil (IA) BAS (IIa C) or and/or Continuous IV prostacyclin Lung Transplant (I C) Epoprostenol (I A) Galiè N, et al. Eur Heart J 2004; 25:2243-2278. Terbogrel STEP Treprostinil Sildenafil AIR Sildenafil STRIDE2 ARIES Epoprostenol SUPER PHIRST BREATHE1 BREATHE2 COMBI EARLY Epoprostenol SERAPH TRIUMPH ALPHABET STRIDE1 BREATHE5 PACES Epoprostenol Bosentan Beraprost 1990 1996 2000 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘08 ‘09 ‘10 Monotherapy Monotherapy and/or Sequential Combination Upfront Combination N.Galiè, M.Palazzini, A.Manes, Eur Heart J 2010 Approved Drugs for PAH Ambrisentan Ambrisentan Bosentan Bosentan Epoprostenol iv Epoprostenol iv Iloprost inhal Iloprost inhal Sildenafil Sildenafil Sitaxentan Tadalafil Tadalafil Treprostinil sc, iv, inhal Treprostinil sc CURRENT OPINION Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses • Medline search from January 1990 to April 2010 • 25 RCTs, 3839 patients Study % StudyID All Cause Mortality RR (95% CI) %Weight ID RR (95% CI) Weight Prostacyclin Analogues ProstacyclinRubin-1990 Analogues 0.36 (0.04, 3.00) 4.90 Rubin-1990Barst-1996 0.360.06 (0.04,(0.00, 3.00)0.96) 4.902.74 Barst-1996Badesch-2000 0.060.79 (0.00,(0.22, 0.96)2.77) 2.7413.72 Badesch-2000Simmoneau-2002 0.790.92 (0.22,(0.38, 2.77)2.21) 13.7228.03 Simmoneau-2002Galiè-2002 0.921.00 (0.38,(0.06, 2.21)15.65) 28.032.88 Galiè-2002Olschewski-2002 1.000.25 (0.06,(0.03, 15.65)2.22) 2.884.62 Olschewski-2002Barst-2003 0.250.47 (0.03,(0.04, 2.22)5.01) 4.623.88 Barst-2003McLaughlin-2010 0.470.35 (0.04,(0.01, 5.01)8.45) 3.882.14 McLaughlin-2010McLaughlin-2006 0.35(Excluded) (0.01, 8.45) 2.140.00 McLaughlin-2006HoeperSubtotal-2006 (I-squared = 0.0%, p = 0.682) (Excluded)0.62 (0.34, 1.12) 0.00 62.91 Subtotal (I-squared = 0.0%, p = 0.682) 0.62 (0.34, 1.12) 62.91 Endothelin Receptor Antagonists EndothelinRubin-2002 Receptor Antagonists 0.24 (0.02, 2.60) 3.84 Rubin-2002Barst-2004 0.241.54 (0.02,(0.06, 2.60)37.19) 3.842.15 Barst-2004Galiè-2008 1.540.99 (0.06, 37.19)15.58) 2.152.87 Galiè-2008Channick-2001 0.99(Excluded) (0.06, 15.58) 2.870.00 RR = - 44% Channick-2001Galiè-2006 (Excluded)(Excluded) 0.00 Galiè-2006Barst-2006 (Excluded)(Excluded) 0.00 Barst-2006Subtotal (I-squared = 0.0%, p = 0.597) (Excluded)0.60 (0.12, 2.86) 0.008.86 P = 0.016 Subtotal (I-squared = 0.0%, p = 0.597) 0.60 (0.12, 2.86) 8.86 Phosphodiesterase Type 5 Inhibitors PhosphodiesteraseSastry-2004 Type 5 Inhibitors 0.39 (0.02, 8.73) 2.27 Sastry-2004Galiè-2005 0.391.01 (0.02,(0.11, 8.73)9.55) 2.274.32 Galiè-2005Galiè-2008 1.010.41 (0.11, 9.55)1.49) 4.3212.95 Galiè-2008Simonneau-2008 0.410.07 (0.11,(0.00, 1.49)1.15) 12.952.68 Simonneau-2008Galiè-2009 0.070.51 (0.00,(0.05, 1.15)5.53) 2.683.83 Galiè-2009Singh-2006 0.51(Excluded) (0.05, 5.53) 3.830.00 Singh-2006Subtotal (I-squared = 0.0%, p = 0.696) (Excluded)0.40 (0.16, 1.01) 0.0026.05 Subtotal (I-squared = 0.0%, p = 0.696) 0.40 (0.16, 1.01) 26.05 Thromboxane synthase inhibitor ThromboxaneLangleben-2002 synthase inhibitor 1.66 (0.07, 39.30) 2.18 Langleben-2002Subtotal (I-squared = .%, p = .) 1.66 (0.07, 39.30) 2.18 Subtotal (I-squared = .%, p = .) 1.66 (0.07, 39.30) 2.18 Heterogeneity between groups: p = 0.788 HeterogeneityOverall (I-squared between = 0.0%, groups: p = 0.908)p = 0.788 0.56 (0.35, 0.90) 100.00 Overall (I-squared = 0.0%, p = 0.908) 0.56 (0.35, 0.90) 100.00 .00342 1 292 .00342 1 292 Favors Treatments I Favors Controls 4th WSPH Dana Point 2008 Galiè.N et al Eur Heart J and Eur Respir J, 2009 Areas of Algorithm Improvement • Upfront combination therapy • Place for new drugs (Imatinib, Macitentan Riociguat, Selexipag) • Transplantation indication • RV assistance • Indications for complications • Definition of expert center/Country organization Areas of Algorithm Improvement • Upfront combination therapy • Place for new drugs (Imatinib, Macitentan Riociguat, Selexipag) • Transplantation indication • BAS indication • RV assistance • Indications for complications • Definition of expert center/Country organization Areas of Algorithm Improvement • Upfront combination therapy • Place for new drugs (Imatinib, Macitentan Riociguat, Selexipag) • Transplantation indication • BAS indication • RV assistance • Indications for complications • Definition of expert center/Country organization Combination Strategies Drug B Drug A Sequential Combination Inadequate response Drug A+B Upfront Combination BREATHE-2 Epoprostenol + bosentan 6-MWD (metres) TPR change from baseline (%) Mean and 95% CI Placebo + epo (n=10) Bos + epo (n=19) Placebo/epo (n=10) 0 0 Bos/epo (n=19) -20 -20 Median and 95% CI -40 Placebo/epo -40 Bos/epo change % -60 -60 -60 -40 -20 0 20 40 60 80 100 140 -80 -80 Baseline Wk 16 Baseline Wk 16 Metres 29 of 32 patients completed at week 16 Humbert M, et al. Eur Respir J 2004; 24:353-9. Effect of up-front combination therapy BREATHE-2: bosentan & epoprostenol Epo + bosentan Epoprostenol combination therapy monotherapy 1 (n = 23) (n = 46) Epo + bosentan 0.8 2000 p = 0.0001 combination therapy (n=23) -48 ± 17% -29 ± 17% 0.6 1500 ) P=0.07 5 - 0.4 1000 Cumulative survival Cumulative 0.2 PVR (d.s.cm PVR Epoprostenol 500 monotherapy 0 (n=46) 0 12 24 36 48 60 72 84 96 108120132144 0 Baseline 4-month Baseline 3-month Time (months) Kemp K, et al. J Heart Lung Transpl. In press. Up-front triple combination therapy in PAH Epoprostenol Epoprostenol + bosentan Epo + bosentan + sildenafil monotherapy combination therapy combination therapy (n=46) (n=23) (n=11) 2000 2000 2000 1600 1500 1500 ) ) 5 5 5) - - - 1200 1000 1000 2 diapo trithérapie à compléter(d.s.cm 800 PVR (d.s.cm PVR PVR (d.s.cm PVR PVR 500 500 400 0 0 0 Baseline 4-mo.
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