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MEDICAL THERAPY

Diagnostic and treatment approaches to PAH due to recurrent pulmonary thromboembolism. MEDICAL THERAPY. Prof. Dr. Orhan Arseven Istanbul University Istanbul Medical Faculty Department of Pulmonary Disease. Chronic thromboembolic pulmonary Hypertension( CTEPH ).

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MEDICAL THERAPY

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  1. Diagnostic and treatment approaches to PAH due to recurrent pulmonary thromboembolism MEDICAL THERAPY Prof. Dr. Orhan Arseven Istanbul University Istanbul Medical Faculty Department of Pulmonary Disease

  2. Chronic thromboembolic pulmonary Hypertension(CTEPH) Symptomatic CTEPH may affect 3.6% of patients within 2 yr after a first episode of symptomatic PE Pengo V,Lensing AW,et al.N.Engl.J Med 2004;350:2257-64 %0.1-0.5 !Tapson VF,et al.Proc Am Thorac Soc 2006;3(7):564-7. Auger VR,et al. Clin Chest Med. 2007 Mar;28(1):255-69 Progressif pulmonary vascular remodelling Generalized hypertensive pulmonary arteriopathy Dartevelle P, Fadel E, et al. N. Engl J Med;2001;345:1465-72

  3. Progression of pulmonary hypertension Pre-clinic Symptomstable Progressive deterioration PVR Exercise >3 Mo - < 2 years PAP Rest Thereshold of Symptom Level RV disfunction Cardiac output Time / Severity

  4. CTEPH…….Prognosis • Related with right ventricular disfunction 5 Years survey : PAB > 40mmHg……………. %30 PAB > 50mmHg……………. % 10 Riedel M, et al.Chest 1982;81:151-158 Lewzcuk J,Pizko P,et al.Chest 2001;119:818-21

  5. CTEPH therapy Pulmonary endarterectomy (PEA) • Effective and often curative in patients • with severe CTEPH • But : ~ 50 %Inoperabl • Poor candidacy for PEA surgery (PH due to • concomitant small-vessel arteriopathy ) Skoro-sajer N, et al. J Thromb Haem 2007;5:483-489.

  6. Medical therapy : When is appropriate ? • Where PEA is not suitable due to distal thromboembolic • disease • 2. “ Therapeutic bridge “ to PEA • In high risk patient due to extremely poor hemodinamics • 3. Persistant or residual PH after PEA • 4. When surgery is contrindicated due to significant comorbidity

  7. 2004 ACCP practice guideline on CTEPH Medical therapy : • Inoperabl CTEPH…… “ May be considered “ • Benefit small and weak • Recommendation ……… C Doyle RL,McCrory D, et al:Surgical treatments/interventions for pulmonary artery Hypertension. ACCP evidence-based clinical practice quidelines.Chest 2004;126;63S-71S.

  8. Medical therapy • Anticoagulants • Diuretics • Dijitalis • Calcium canal blockers • Life-long anticoagulation Hoeper MM,Mayer E, simonneau G, Rubin L. Circulation 2006;113:2011-2020.

  9. Targets of therapy Symptomatic benefit Control of disease Improvement in QOL Increase in lifetime Slide courtesy of Marius Hoeper

  10. Medical therapy • Prostacyclin analog ( epoprostenol, iloprost ) • Endotelin receptor antagonist ( bosentan ) • Phosphodiesterase-5 inhibitör ( Sildenafil ) IPAH / CTEPH !

  11. Updated ACCP Guidelines Chest 2007;131:1917-28

  12. Pre-PEA “ Bridging “ therapy • Therapeutic bridge between : • CTEPH diagnosis and PEA • High risk patients : • Class IV ( NYHA ) • mPAP > 50 mmHg • Cardiac index < 2.0 L.min /m2 • PVR > 1.000 dyn.s.cm-5 What is the optimal medical therapy period ?

  13. Post-PEAtherapy • Persistan PH after surgery 10-15 % • Auger WR, Kerr KM, et al. Cardiol Clin 2004;22:453-466 • Probably distal thromboembolic pathology ! • Postoperative PVR > 500dynes.sec.cm-5 • There is no guide available!

  14. Medical therapy : Evidence to date • Data from clinical trials : • Limited • Based on preliminary trial findings • Randomized , controlled trials !

  15. Prostacyclin analogs • Oral Beraprost sodium • - Minimal survival benefit • - Placebo controlled trial lacking • - Is not approved for CTEPH • Nagaya N, et al. Hearth 2002;87:340-5 • Ono F, et al. Chest 2003;123:1583-8 • Ono F, et al. Circ J 2003;67:375-8 • I.V. Epoprostenol • Aerosolized Iloprost …Randomized controlled

  16. I.V. Epoprostenol… Bridging treatment • 6 wk before PEA n= 12 Severe CTEPH • Significant improvements in PVR , cardiac output • But not mPAP • BNP marked decreased after treatment : • - İmproved right-heart function • - excellent post-PEA outcome • İt is not clear whether this was as a result of preoperative • epoprostenol treatment , a succesful surgical procedure or • both ? Nagaya N,et al. Chest 2003;123:338-343

  17. I.V. Epoprostenol… Bridging treatment Use during the preoperative period : • Unclear whether the potential benefits • outweight the risk of disease progression • during the delay to surgical interventions

  18. Aerosolized Iloprost CTEPH, PAH Failed to show significant benefical effect in the CTPEH : n= 203 ( 101: inhaled iloprost……. 33 CTEPH) 12 weeks… 6MWD increased 58.8m in IPAH 12 m in CTEPH Olschewski H, et al. N Engl J Med2002;347:322-9.

  19. Aerosolized Iloprost …. AIR study Randomised controlled • Immediately before PEA ….. No significant effect • on mPAP, PVR, CI • Postoperative iloprost inhalation….. Benefical effect on • PVR , mPAP • ( Benefit of surgery ! ) • - Reduce reperfusion injury, • - improve early outcome after PEA Kramm T,et al.Ann Trorac Surg 2003;76:711-718

  20. Treprostinil sodium • IV. Epoprostenol….. Short half-life( 1 to 2 minute ) • Continuous infusion…. Permanently inplanted IV catheter • Catheter releated thrombosis, infections, sepsis,malfunctions • Treprostinil sodium … Subcutaneous • Comparable acute hemodynamic effects • Vachieri JL, et al. Expert Rev Cardiovasc Ther 2004;2: 183-191 • Stable at room temparature and neutral pH • Longer half life ( 3 to 6 h ) mean 4.6 h Simonneau G, et al. Am J Respir Crit Care Med 2002; 15: 800-4.

  21. Treprostinil sodium Lang I, et al. Chest 2006;129:1636-43 n= 99 PAH ( 23 = CTEPH ) NYHA class : II-IV Followed up 26.2 + 17.2 months 6MWD: 305+11 to 445+12 p=0.0001 NYHA class : 3.20+0.04 to 2.1+0.1 p=0.0001 Survival88.6 % at 1 year, 70.6 % at 3 year

  22. Treprostinil sodium - CTEPH • n= 25 inoperabl CTEPH • WHO func. Class : III or IV • 6MWD < 380 m • At least one hospitalization for right heart decomp. • within the prior 6 months • Min. 12 Months (12-33 Mo.) treatment • Control: Historical group of 31 patients at their centers • with inoperabl CTEPH Skoro-sajer N, et al. J Thromb Haem 2007;5:483-489

  23. CHANGE OF HAEMODYNAMYIC VARIABLES

  24. Kaplan-Meier survival estimates 25 inoperabl CTEPH

  25. Endothelin receptor antagonists • Plasma concentrations of endothelin are increased • in patients with CTEPH • Pulmonary endothelin type B receptors are • increased on vascular smooth muscles cells • Endothelin mediated pulmonary vascular remodelling • has been demostrated in a canine model of CTEPH Bauer M, et al.Circulation 2002;105:1034-6 Reesink HJ, et al.Eur Respir J 2004;24: 110s. Kim H, et al.Eur Respir J 2000;15:640-48.

  26. KTEPH - Bosentan NYHA Class improved : 70 % 6MWD significantly improved ( p=0.01 ) proBNP signif.

  27. Endothelin receptor antagonists • Inoperabl CTEPH n= 16 • 6 mo. Bosentan therapy • NYHA Class improved : 70 % • 6MWD significantly improved • (p=0.01 ) Bonderman D, et al. Chest 2005;128:2599-2603

  28. Endothelin receptor antagonists Prospective, multicenter, open-label trial n=19 3 mo. bosentan therapy …. Mixt CTEPH PVR 914+329 to 611+ 220 dyn.s.cm-5 p<0.001 6 MWD 340+ 102 to 413+ 130 m p= 0.009 Significant improv. : ProBNP levels , mPAP, CO, CI, SVR Hooper MM, et al. Chest 2005; 128:2363-67

  29. Bosentan………BENEFIT study • n= 157 • Double-blind, placebo-controlled, multicenter study • Inoperable CTEPH , post-PEA • Significant improvements : • PVR( p < 0.001 ), cardiac index(p=0.0007). • Borg dyspnoea index(p=0.0386) • Significant decrease in NT-proBNP (p = 0.0028), • ( indicator of disease severity ) • No effect on exercise capacity (p = 0.5449) Lang I, et al. ESC Sept. 2007; FP 4505

  30. PDE-5 INHIBITION SUPER-1 trial :Oral sildenafil, PAH Large, multicentric, double blind, placebo controlled Sildenafil improved in 6MWD,mPAP and WHO functional class. Galie N, et al.N.Engl J Med 2005;353:2148-57. • n=12 CTEPH patients… Open label study …. • 6 mo follow-up ……Sildenafil 50 mg tid • 6 MWD increased from 312m to 366 m. • Comparable with BREATHE-1 ( Bosentan) • ( Rubin LJ, et al. N Engl J Med 2002;346:896-903 ) Ghofrani HA, et al. Am J Respir Crit care Dis 2003;167:1139-1141

  31. PDE-5 INHIBITION CI ………2.0 to 2.4 L min-1m-2 CVP ……..11 to 4.8 mmHg mPAP……..52.6 to 44.9mmHg Ghofrani HA, et al. Am J Respir Crit care Dis 2003;167:1139-1141

  32. Combination therapy

  33. CPETH - Combination therapy / safety ? • Generaly older than those with PAH • Comorbidity ( COPD , cardiac diseases ) • Drug – drug interactions • - Bosentan… Mild CYP3A4-inducing effect • Reduction in warfarin exposure…Hypocoagulability • Murphey LM, et al. Ann Pharmacother 2003;37: 1028-1031 • - Sildenafil , Citaxsentane ……. Hypocoagulability( warfarin ) • Widlitz AC, et al. Exp Rev Cardiovasc Ther 2005;3: 985-991

  34. CPETH - Combination therapy / safety ? Interaction during combination therapy ! • Sildenafil has inhibitory effect on hepatic CYP3A4 • Bosentan + Sildenafil : • Bosentan decreases the plasma concentration of sildenafil • But bosentan doesn’t decrease it’s efficiency Paul GA, et al. Br J Clin Pharmacol 2005;60:107-112

  35. Sildenafil added 406 ± 53 403 ± 80 392 ± 61 346 ± 66 Bosentan and sildenafil Bosentan started 6-MWD (m) 500 400 300 200 277 ± 80 100 n = 9 Before Sildenafil’ Beginning 3.Mo 3.Mo 6-12 Mo Hoeper MM, et al.Eur Respir J 2004; 24:1007-10.

  36. Combination therapy • BREATHE-2………..Bosentan + Epoprostenol • IPAH • Benefical effect • Humbert M, et al. Eur Respir J 2004; 24: 353-359. Goal- oriented therapy in PAH Bosentanand/oriloprost and/orsildenafil…….Historical control group * Survival benefits Hoeper MM, et al. Eur Respir J 2005;26: 868-863. CTEPH !!

  37. GOAL-ORIENTED THERAPY • 6 MWD > 380 m • VO2max>10.4 ml / min / kg • Peak sist.blood pressure • during exercise > 120 mm/Hg Hoeper MM, et al. Eur Respir J 2005;26: 868-863.

  38. Combination therapy • n=16 CTEPH ……….. Inhal. Iloprost • + • Bosentan • After 6 mo. • * 6MWD increased significantly • * NYHA Class improvemet…. 9/16 patients Seyfarth HJ, et al. Chest 2005;128: 709-13

  39. Limitations on current data • Majority of data : • * Small , uncontrolled • * Retrospective evaluations • * Unpublished clinical experience • * Primarly assessing PAH ( CPETH ? ) • * Heterogeneous populations • * Variable periods of time

  40. Future trials…. • Prospective, • Randomized, • Controlled …………..clinical trials ! • Selection of patients………those with similar stage ! • - > One year duration ( Not 3-4 mo.) • Long term mortality results • 6 MWD , other types of exercise testing / more complex • Assessment of vascular histopathology Rich S. The current treatment of pulmonary arterial hypertension. Chest 2006; 130: 1198-1202

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