The Case of Marco Nazzareno Galiè, M.D. DIMES
Disclosures Consulting fees and research support from Actelion Pharmaceuticals Ltd, Bayer HealthCare, Eli Lilly and Co, GlaxoSmithKline and Pfizer Ltd
Clinical history 45 YO male CV risk factor: smoker (1 pack/day) Dyspnoea on exercise, WHO FC II Echocardiogram: RV dilatation
Question 1: which further investigation would you require? 1.ECG 2.PFT+DLCO and arterial blood gases 3.Chest radiograph 4.HRCT 5.All the above
Question 1: which further investigation would you require? 1.ECG 2.PFT+DLCO and arterial blood gases 3.Chest radiograph 4.HRCT 5.All the above
Echocardiographic probability of pulmonary hypertension in symptomatic patients with a suspicion of pulmonary hypertension according with PTRV & additional signs 6 www.escardio.org Eur Heart J 2015, Eur Respir J, 2015
Diagnostic Algorithm for Pulmonary Hypertension 7 Eur Heart Speaker J 2015, Eur Respir J, 2015
Comprehensive clinical classification of pulmonary hypertension 8 www.escardio.org Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015
Clinical history 45 YO male CV risk factor: smoker (1 pack/day) Dyspnoea on exercise, WHO FC II Echocardiogram: RV dilatation Local hospital admission: normal coronary angiography > discharge Persisting dyspnoea, new admission in your hospital
Clinical Evaluation WHO FC III Height: 168 cm Weight: 71 kg (BMI = 25) JVP < 8 cmh20 BP = 130/80 mmhg HR = 94 b/min SaO2 = 90 % in room air Left parasternal systolic murmur, increased P2 6MWD = 479 m; B 5; Sat. 94% > 74%; HR 86 > 122 bpm
ECG/chest X-ray
Echocardiogram - PSP = 80 mmhg - PFO - Congenital Heart diseases were escluded
Spirometry/arterial blood gases FVC 85 % FEV1 91 % FEV1/FVC 88 FEF25% 125 % FEF50% 149 % FEF75% 72 % ph 7.46 pco2 27 po2 64 SatO2 93 DLCO 90 %
HRTC No parenchymal lung diseases
Question 2: which further investigation would you require? 1.Right heart catheterization 2.Right and left heart catheterization 3.CT pulmonary angiography 4.Cardiac Magnetic Resonance Imaging 5.Perfusion lung scan
Question 2: which further investigation would you require? 1.Right heart catheterization 2.Right and left heart catheterization 3.CT pulmonary angiography 4.Cardiac Magnetic Resonance Imaging 5.Perfusion lung scan
Diagnostic Algorithm for Pulmonary Hypertension 17 Speaker Eur Heart J 2015, Eur Respir J, 2015
Perfusion lung scan
CT Pulmonary Angiography Moderate dilatation of the main PA (3.8 cm)
Blood tests and immunology Immunology screening: negative Thrombophilia screening: negative Hepatitis serology: negative HIV test: negative Thyroid blood tests: normal BMPR2: negative Diagnosis: Idiopathic Pulmonary Arterial Hypertension
Question 3: which further investigation would you require? 1.Right heart catheterization 2.Right and left heart catheterization 3.Right heart catheterization and vasoreactivity 4.Cardiac Magnetic Resonance Imaging 5.3D-Echocardiography
Question 3: which further investigation would you require? 1.Right heart catheterization 2.Right and left heart catheterization 3.Right heart catheterization and vasoreactivity 4.Cardiac Magnetic Resonance Imaging 5.3D-Echocardiography
Treatment Algorithm for Pulmonary Arterial Hypertension 23 Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015
Right Heart Catheterization Baseline NO (25 ppm) HR (b/min) 94 86 RAP (mmhg) 5 3 PAP s/d/m (mmhg) 120/51/77 103/39/63 PAWP (mmhg) 8 7 SAP s/d/m (mmhg) 134/82/102 119/81/98 CO (L/min) 3.7 3.9 CI (L/min/m2) 2.0 2.1 PVR (UR) 18.6 14.4 SVR (UR) 26.2 24.4 SA O 2 % 90 96 SP O 2 % 58.7 65
Question 4: which is the further management? 1.Calcium channel blocker therapy 2.Endothelin receptor antagonist (ERA) monotherapy 3.Phosphodiesterase type-5 inhibitors (PDE-5i) monotherapy 4.ERA + PDE-5i initial combination 5.Other
Question 4: which is the further management? 1.Calcium channel blocker therapy 2.Endothelin receptor antagonist (ERA) monotherapy 3.Phosphodiesterase type-5 inhibitors (PDE-5i) monotherapy 4.ERA + PDE-5i initial combination 5.Other
Treatment Algorithm for Pulmonary Arterial Hypertension 27 Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015
Risk assessment in pulmonary arterial hypertension 28 Eur Heart J 2015, Eur Respir J, 2015
Question 5: which is your initial therapeutic strategy? 1.Prostacyclin analogue monotherapy 2.Endothelin receptor antagonist (ERA) monotherapy 3.Phosphodiesterase type-5 inhibitors (PDE-5i) monotherapy 4.ERA + PDE-5i initial combination 5.Other
Treatment Algorithm for Pulmonary Arterial Hypertension 30 Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015
Time-course of completed RCTs in PAH (39): Therapy Strategy Epoprostenol SSc Epoprostenol IPAH Epoprostenol IPAH Bosentan Terbogrel Treprostinil AIR BREATHE1 ALPHABET STRIDE2 Sildenafil COMBI BREATHE2 STRIDE1 SUPER SERAPH Beraprost STEP Sildenafil BREATHE5 ARIES -1/2 EARLY PACES PHIRST FREEDOM M TRIUMPH FREEDOM C2 IMATINIB PATENT Iversen IMPRES SELEXIPAG AMBITION FREEDOM C1 GRIPHON VARDENAFIL COMPASS 2 SERAPHIN 90 96 00 01 02 03 04 05 06 08 09 10 11 12 13 14 8919: PAH patients in RCTs 50/million: PAH prevalence CTs on monotherapy vs placebo or vs monotherapy (21) CTs on monotherapy and/or sequential combination vs placebo (16) CTs on initial combination vs monotherapy (2) Modified from Galiè N, et al. Eur Heart J 2010;31(17):2080-6.
Current evidence from RCTs in PAH shows that Monotherapy is able to reduce short-term mortality (meta-analysis) and improve longterm outcomes (SERAPHIN and GRIPHON) in incident and prevalent PAH patients Sequential combination therapy is able to improve short term (meta-analysis) and longterm (SERAPHIN and GRIPHON) outcomes in prevalent PAH patients Initial combination therapy is able to improve long-term outcomes compared with monotherapy (AMBITION) in treatment-naive incident PAH patients. Initial combination is superior to monotherapy in head to head comparison
AMBITION Galie N et al, et al. New Engl J Med 2015; 379(9):834 44.
AMBITION primary endpoint: Time to Clinical Failure (Death, Hospitalization, Disease Progression, Uns. Clin Resp) Initial Combination vs pooled Initial Monotherapy Ambrisentan + Tadalafil Ambrisentan or Tadalafil Galie N et al, et al. New Engl J Med 2015; 379(9):834 44.
4/6-month results: % change comparison AMBITION - BONSAI Ambrisentan + Tadalafil (19) Joint - INTENTION Bosentan + Sildenafil (23) BRAND NEW Macitentan + Sildenafil (12) RAP (%) -17-36 - 16 mpap (%) -33-21 - 29 CI (%) +56 +63 + 54 PVR (%) -61-60 - 57 PA-SO 2 (%) +17 +25 + 14 6MWD (%) +25 + 42 + 34
Question 5: which is your initial therapeutic strategy? 1.Prostacyclin analogue monotherapy 2.Endothelin receptor antagonist (ERA) monotherapy 3.Phosphodiesterase type-5 inhibitors (PDE-5i) monotherapy 4.ERA + PDE-5i initial combination 5.Other
Haemodynamics, functional and exercise capacity Baseline ERA + PDE-5i 6 Mo ERA + PDE-5i 24 Mo HR (b/min) 94 73 70 RAP (mmhg) 5 5 5 PAP s/d/m (mmhg) 120/51/77 98/29/56 98/29/45 PWP (mmhg) 8 8 8 BP s/d/m (mmhg) 134/82/102 95/61/75 100/61/75 CI (L/min/m2) 2.0 3.0 3.5 PVR (UR) 18.6 9.6 7.6 SVR (UR) 26.2 13.8 13.5 ART O 2 % 90 93 94 PA O 2 % 58.7 68 70 6mwd meters 479 573 630 WHO-FC 3 1 1
Key messages An appropriate diagnostic strategy allows to clarify the precise clinical diagnosis which is crucial for the patient management In patients with pulmonary arterial hypertension the risk stratification needs to be assessed in order to establish the most appropriate treatment strategy Initial combination with an ERA and a PDE-5i appears to be a suitable strategy in newly diagnosed, intermediate risk and treatmentnaive patients with pulmonary arterial hypertension