Contreversies in the management of PH What is controversial in treatment? Service de Pneumologie et Réanimation National reference center for pulmonary hypertension Université Paris Sud Hôpital Antoine Béclère, Clamart, APHP, France Inserm U 999
Disclosures Gerald Simonneau -has acted as a consultant and on advisory boards for Actelion Bayer, Eli Lilly, GSK, Novartis, Pfizer -has received lecture fees/honoraria from Actelion Bayer, Eli Lilly, GSK, Novartis, Pfizer -and has received research grants from Actelion, Bayer, Eli Lilly, GSK, Novartis, Pfizer, United Therapeutics
Updated classification of Pulmonary Hypertension (4 th PH World Symposium Dana Point, CA 2008) 1. Pulmonary Arterial Hypertension (PAH) 3. PH due to lung disease and/or hypoxemia 1.Pulmonary veno-occlusive disease and/or capillary Hemangiomatosis 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 2. PH due to left-heart disease 5. PH with unclear or multi- factorial mechanisms Simonneau G, et al. J Am Coll Cardiol 2009
Endothelial dysfunction in PAH Humbert, Sitbon, Simonneau. N Engl J Med 2004
PAH therapy: What are the ressources today? le Lung transplantation iv epoprostenol More therapies available - PGI 2 analogues (3) - ERA (2) - PDE5 inhibitors (2) Improving clinical outcome 1 drug Less complex therapies (oral, inh) 1990 s Today
4 th WS,PAH Evidence-based Treatment Algorithm ( JACC2009 ) Oral anticoagulants (E/B) - IPAH Diuretics ( E/A ) Oxygen* ( E/A ) Digoxin ( E/C ) Supervised rehabilitation ( E/B ) VASOREACTIVE Supportive therapy and general measures Expert referral ( E/A ) Acute vasoreactivity test (A for IPAH) (E/C for ( APAH Avoid excessive physical exertion ( E/A ) Birth control ( E/A ) Psychological and social support ( E/C ) Infection prevention ( E/A ) WHO Class I-IV Nifedipine, amlodipine, diltiazem ( B ) Sustained response (WHO ( I-II YES NO Nifedipine, amlodipine, diltiazem ( B ) NON-VASOREACTIVE GUIDELINES FOR INITIAL THERAPY Strength of Recommendation WHO Class II WHO Class III WHO Class IV Ambrisentan Ambrisentan, Bosentan Epoprostenol IV Bosentan Iloprost inh, A Sildenafil Epoprostenol IV Sildenafil, B Tadalafil Treprostinil SC, Tadalafil Iloprost inhaled C Beraprost Treprostinil SC E/B Ambrisentan, Bosentan, Sildenafil E/C Sitaxsentan, Tadalafil NA Treprostinil inh+, Treprostinil inh+ Iloprost IV Iloprost IV, Treprostinil IV Treprostinil IV Initial combination therapy Sequential combination therapy INADEQUATE CLINICAL RESPONSE *To maintain O 2 at 92% +NDA in review PDE-5 I + ( B ) Prostanoids + ( B ) + ( B ) ERA INADEQUATE CLINICAL RESPONSE AS (E/B) and/or lung transplant ( E/A )
Evaluation of specific PAH therapies in different PAH subgroups Idiopathic Héritable Drugs and toxins Associated with other diseases: -Connective tissue diseases -HIV infection -Portal hypertension -Systemic to pulmonary shunts -Schistosomiasis -Chronic hemolytic anemias
Evaluation of specific PAH therapies in different PAH subgroups 85% of patients included in RCTs are idiopathic, heritable, drugs induced PAH or PAH associated with CTD No RCTs in PAH associated with HIV infection, portal hypertension or shistosiomasis Only one RCT in Eisenmenger syndrome and PAH associated with Sickle cell disease
Circulation,2006
A Hemodynamic Study of Pulmonary Hypertension in Sickle Cell Disease Florence Parent, Dora Bachir, Jocelyn Inamo, François Lionnet, Françoise Driss Gylna Loko, Anoosha Habibi, Soumiya Bennani, Laurent Savale, Serge Adnot, Bernard Maitre, Azzedine Yaïci, Leila Hajji, Dermot S. O Callaghan,Pierre Clerson, Robert Girot, Frederic Galacteros and Gerald Simonneau New Engl J Med 2011
Sickle Cell Disease patients screened n=403 Sickle Cell Disease patients included n=385 Doppler Echocardiograph screening Tricuspid Regurgitant Jet Velocity (TRJV) TRJV < 2.5 m/sec Group 1 No Pulmonary Hypertension n=289 (75%) TRJV 2.5 m/sec n=96 patients (25%) Pulmonary Hypertension suspected Right-heart catheterization Group 2 Pulmonary Hypertension excluded n=72 (19%) Group 3 Pulmonary Hypertension confirmed n=24 (6.2%)
Hemodynamics in different PH Subgroups No of Patients (Percentage) Pre-capillary PAH 11 (2.9%) Post-capillary PH 13 (3.3%) No PH on RHC 72 (18.7%) mpap (mm Hg) 28 4 32 7 19 3 spap (mm Hg) 43 7 45 8 28 4 dpap (mm Hg) 15 5 22 6 12 3 RAP (mm Hg) 5 2 13 5 7 2 PCWP (mm Hg) 10 3 21 5 11 3 CO (L/min) 8.2 1.6 9.1 2.1 8.4 2.1 PVR (dyn.s.cm -5 ) 178 55 104 26 72 26 Parent et al;new Engl J Med 2011
14 Machado R Blood Prepublished online April 28, 2011 Machado R Effects of Sildenafil in PAH associated with Sikle cell disease The walk-phasst study was a double-bind, placebo controlled trial of 16 weeks to test safety and efficacy of sildenafil in PAH patients with SSD The NIH stopped the study,due to safety concerns when 33 patients had completed the trial sildenafil treated patients were likely to have more likely sickle cell pain crisis (35%) compared to placebo-treated patients (14%). Furthermore,there was no evidence of treatment-related improvement at time of study Machado R et al Blood 2011 (in press)
Rationale for combination therapy Malignant nature of PAH requires aggressive approach Successfully employed in chronic heart failure, HIV, cancer Combination therapy PAH pathogenesis = several pathways Sequential or up-front? Potential for synergistic effects and added benefit for the patient
Sequential combination therapy in PAH What is the evidence? Current therapy Added therapy Patients (n) Study duration Primary endpoint Primary EP met Secondary EP met Step Bosentan Iloprost 67 12STEP 1 weeks 6MWD No TTCW PACES 2 Epoprostenol Sildenafil 267 16 weeks 6MWD Yes TTCW PHIRST 3 Naïve or bosentan Tadalafil 405 (206) 16 weeks 6MWD Yes / (No) TTCW, (No) TRIUMPH-1 4 Bosentan or sildenafil Treprostinil (inhaled) 235 12 weeks 6MWD Yes No FREEDOM-C 5 Bosentan and/or sildenafil Treprostinil (oral) 354 16 weeks 6MWD No No McLaughlin VV, Am J Respir Crit Care Med 2006 Simonneau G,. Ann Intern Med 2008. Galiè N Circulation 2009. McLaughlin V, J Am Coll Cardiol 2010;. www.clinicaltrials.gov identifier NCT00325442
% change Effect of up-front combination therapy BREATHE-2: bosentan & epoprostenol 6-MWD (m) TPR change from baseline (%) Baseline (mean and 95% CI) Placebo + epo (n = 10) Bos + epo (n = 19) 0-20 Placebo + epo (n = 10) 0-20 Bos + epo (n = 19) Week 16 (median and 95% CI) Placebo + epo (n = 10) Bos + epo (n = 19) -60-20 20 60 100 140-40 -60-80 Baseline Wk 16-40 -60-80 Baseline Wk 16 6-MWD (m) Humbert M, et al. Eur Respir J 2004;
PVR (d.s.cm -5 ) Effect of up-front combination therapy Cumulative survival BREATHE-2: 2000 1500 Epo + bosentan combination therapy (n = 23) p = 0.0001 Epoprostenol monotherapy (n = 46) -48 ± 17% -29 ± 17% 1 0.8 0.6 0.4 Epo + bosentan combination therapy (n=23) P=0.07 1000 500 0.2 0 Epoprostenol monotherapy (n=46) 0 Baseline 3-month Baseline 3-month 12 24 36 48 60 144 720 84 96 108120 132 Time (months) Kemp K, et al. J Heart Lung Transpl. 2011 In press.
4 th WS,PAH Evidence-based Treatment Algorithm ( JACC2009 ) Oral anticoagulants (E/B) - IPAH Diuretics ( E/A ) Oxygen* ( E/A ) Digoxin ( E/C ) Supervised rehabilitation ( E/B ) VASOREACTIVE Supportive therapy and general measures Expert referral ( E/A ) Acute vasoreactivity test (A for IPAH) (E/C for ( APAH Avoid excessive physical exertion ( E/A ) Birth control ( E/A ) Psychological and social support ( E/C ) Infection prevention ( E/A ) WHO Class I-IV Nifedipine, amlodipine, diltiazem ( B ) Sustained response (WHO ( I-II YES NO Nifedipine, amlodipine, diltiazem ( B ) NON-VASOREACTIVE GUIDELINES FOR INITIAL THERAPY Strength of Recommendation WHO Class II WHO Class III WHO Class IV Ambrisentan Ambrisentan, Bosentan Epoprostenol IV Bosentan Iloprost inh, A Sildenafil Epoprostenol IV Sildenafil, B Tadalafil Treprostinil SC, Tadalafil Iloprost inhaled C Beraprost Treprostinil SC Iloprost IV Iloprost IV, Treprostinil IV E/B Treprostinil IV Ambrisentan, Bosentan, Sildenafil E/C Sitaxsentan, Tadalafil NA Treprostinil inh+, Treprostinil inh+ Sequential combination therapy Initial combination therapy INADEQUATE CLINICAL RESPONSE *To maintain O 2 at 92% +NDA in review PDE-5 I + ( B ) Prostanoids + ( B ) + ( B ) ERA INADEQUATE CLINICAL RESPONSE AS (E/B) and/or lung transplant ( E/A )
AMBITION STUDY A randomised, multicenter study of first-line AMBrisentan and Tadalafil combination therapy in subjects with pulmonary arterial hypertension To compare 2 treatment strategies upfront combo (amb+tad) vs mono (amb or tad) Event-driven trial Primary objective: time to clinical failure Secondary objectives: compare the changes in other clinical measures safety and tolerability 6MWT at peak and trough level
Classification of Pulmonary Hypertension (4 th PH World Symposium Dana Point, CA 2008) 1. Pulmonary Arterial Hypertension Prostanoids, ERA, PDE5i 7 drugs approved 2. Pulmonary hypertension due to left heart disease 3. Pulmonary hypertension due to lung diseases and / or hypoxia Oxygen therapy if needed In out of proportion PH: Which role for PAH therapy? 4. Chronic thromboembolic pulmonary hypertension Treatment of left heart failure In out of proportion PH: Which role for PAH therapy? Surgery when possible In non operable forms: Which role for PAH therapy? Simonneau G, et al. J Am Coll Cardiol 2009
. 2 Pulmonary hypertension due to left heart disease Systolic dysfunction Diatolic dysfunction Valvular diseases Represents probably the most frequent group 2 categories: -Passive post-capillary Pulmonary hypertension -Mixed pre and post-capillary pulmonary hypertension Which definition??
Post-capillary PH: Pathophysiology and definition Passive (Pure) Venous component Reactive -out of proportion (Mixed Pre & Post capillary) Arterial component Increased hydrostatic pressure Pulmonary vascular remodeling X X TPG 12 mmhg 1 dpap PCWP 8 mmhg² TPG > 12 mmhg 1 dpap PCWP > 8 mmhg² 1. Galiè N et al. Eur Respir J 2009 2. Chemla D et al. Eur Respir J 2002
72 year-old male,obese,systemic hypertension,diabetis and severe left diastolic dysfunction 4 March 2010 11 March 2010* RAP, mm Hg 32 12 PAPs/d-m, mmhg 110/45 73 56/25 32 PCWP, mmhg 40 22 TPG, mmhg 33 8 dpap PCWP 5 3 CI, L.min.m² 2,5 2,43 PVR, WU 5,9 1,4 * Second RH cath after one week of high doses of diuretics
3. PH withlungdiseases/hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed obstructive and restrictive pattern Represents also an important goup (10% of CLD) PH is generally mild or moderate Some rare cases(1%) have severe PH (Mean PAP>35mmHg) These patients generaly show moderate lung function impairement (disproportionate PH) and could benefit from Specific PAH treatment The effects of specific PAH therapies in this setting need to be properly evaluated
Mechanisms of Pulmonary hypertension in CTEPH Obstruction of proximal pulmonary arteries by organized fibrotic clots, surgically accessible Small vessel pulmonary vascular disease: Distal fibrotic clots surgically inaccessible. Pulmonary vascular remodeling in non- obstructed vascular bed (similar to IPAH)
J Am Coll Cardiol 2008;52:2127-34 Inclusion criteria: Symptomatic PH in WHO FC II to IV due to CTEPH - V/Q lung scan and pulmonary angiography Judged inoperable (distal lesions) OR Persistent or recurrent PH after PEA Operability assessed retrospectively
% of baseline PVR at week 16 (geometric means) BENEFIT STUDY co-primary endpoint: PVR 110% 100% 90% 80% Placebo n = 71 Bosentan n = 66 70% 60% Treatment effect: 24.1% (95% CI: 31.5, 16.0) p <0.0001; Wilcoxon Jaïs X, et al. J Am Coll Cardiol 2008; 52:2127-34
BENEFIT STUDY co-primary endpoint: 6-MWD 6-MWD Placebo (n = 73) Bosentan (n = 67) Baseline (mean SD, m) 344.5 82.6 340.0 85.3 Week 16 (mean SD, m) 345.3 109.5 342.9 106.5 Change from baseline (mean SD, m) 0.8 80.9 2.9 65.0 Treatment effect* (m) 2.2 (95% CI: 22.5, 26.8); p = 0.5449; Wilcoxon test *Treatment effect is expressed as a mean difference with related CIs Jaïs X, et al. J Am Coll Cardiol 2008;
Effects of sildenafil in CTEPH patients a 12-week RCT for persistent PH post PEA or de novo distal CTEPH Change from baseline Difference between treatments Sildenafil (n = 9) Placebo (n = 10) Difference (95% CI) p value Change in WHO class Improved >1 class Deteriorated >1 class 44% 0% 0% 20% 0.025 6-MWD (m) 17.9 0.4 17.5 (-23.9 to 58.8) 0.385 Borg dyspnoea index -0.7 0.2-0.9 (-2.4 to 0.6) 0.219 NT-proBNP (pg/ml) -355-77 -278 (-779 to -223) 0.240 RA (mmhg) -0.1-0.8-0.9 (-6.1 to 4.2) 0.713 mpap (mmhg) -5.8 0.4-6.2 (-12.4 to 0.1) 0.052 CI (L/min/m 2 ) -0.1-0.1 0.0 (-0.4 to 0.4) 0.994 PVR (dyn/s/cm 5 ) -179 18-197 (-389 to -6) 0.044 Suntharalingham J, et al. Chest 2008
Conclusion The effects of Prostanoids, ERA and PDE5 inhibitors have been properly evaluated in idiopathic, heritable, drugs induced PAH and PAH associated with CTD Data in other PAH subgroups are scarce and more informations are needed The role of o specific PAH treaments beyond PAH remains not established and RCTs are needed especially in PH associated with left heart disease, with chronic lung disease as well as in non operable CTEPH