The Case of Lucia Nazzareno Galiè, M.D.

The Case of Lucia 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 18 YO female Volleyball player Dyspnoea on exercise, WHO FC III Withdrew from sport after a couple of presyncope and appearance of ankle edema General Cardiology visit

ECG and Echocardiogram No Congenital heart Diseases RV and PA dilatation; spap 45 mmhg

Question 1: how would you manage this patient? 1.Program a series of investigations according with the PH guidelines 2.Start PH approved medications 3.Send urgently the patient to a PH expert center for appropriate management 4.Program a perfusion/ventilation scan 5.Program a CT angiography

Risk assessment in pulmonary arterial hypertension 6 Eur Heart J 2015, Eur Respir J, 2015

Clinical history 18 YO female Volleyball player Dyspnoea on exercise, WHO FC III Withdraw from sport after a couple of presyncope and appearance of ankle edema General Cardiology visit Going back home while climbing stairs syncopal episode > ER of Expert PH Center

ER Clinical Evaluation JVP > 8 cmh20 Hepatomegaly and ankle edema BP = 95/75 mmhg HR = 110 b/min RR = 25 / min SaO2 = 90 % in room air Left parasternal systolic murmur, increased P2 TC 38

ECG

Question 2: which further investigation would you require? 1.Program a series of investigations according with the PH guidelines 2.Chest radiograph 3.HRCT and CT pulmonary angiography 4.Perfusion lung scan 5.D-dimer

Hemodynamic management of critically ill patients with right ventricular failure The basic principles of ICU management of patients with PH and RV failure include the treatment of triggering factors (such as anaemia, arrhythmias, infections or other co-morbidities), optimization of fluid balance (usually with i.v. diuretics. improvement of CO with inotropes (with dobutamine being the preferred inotrope to treat RV failure) and maintenance of systemic blood pressure with vasopressors, if necessary.

HRCT and CT pulmonary angiography

Clinical history Blood cultures negative Treated for non-specific infection Regression of fever and inflammatory signs Laboratory work-up for PH: negative

ECG/chest X-ray

No CHD Patent foramen ovale Pericardial effusion Echocardiogram

Right Heart Catheterization Baseline NO HR (b/min) 116 114 RAP (mmhg) 15 15 PAP s/d/m (mmhg) 85/42/62 86/41/60 PAWP (mmhg) 8 9 SAP s/d/m (mmhg) 81/63/70 81/63/70 CI (L/min/m 2 ) 1.9 1.9 PVR (UR) 17 17 SA O 2 % 92 94 SP O 2 % 54 55 WHO-FC IV IV 6MWD (meters) 0 0

Galie N et al Eur Heart J 2015, Eur Respir J, 2015 Risk assessment in pulmonary arterial hypertension 19

Question 3: which is your treatment strategy? 1.Inotropic drugs, diuretics and oxygen 2.Inotropic drugs, diuretics, oxygen and iv epoprostenol 3.Inotropic drugs, diuretics, oxygen and initial combination therapy including iv epoprostenol 4.Inotropic drugs, diuretics, oxygen and initial combination therapy 5.Balloon atrial septostomy

22 Recommendations for PAH supportive therapy www.escardio.org Galie N et al Eur Heart J 2015, Eur Respir J, 2015

Recommendations for efficacy of intensive care unit management, balloon atrial septostomy and lung transplantation for PAH (Group 1) 23 www.escardio.org Galie N et al Eur Heart J 2015, Eur Respir J, 2015

Treatment Algorithm for Pulmonary Arterial Hypertension 24 Galiè N. et al Eur Heart J 2015, Eur Respir J, 2015

ECG/Chest X-ray after one week

Initial Chest X-ray and after one week

PAH functional class IV precipitated by infection @ admission WHO FC IV JVP 15 cmh 2 O SaO 2 95% 3 l/mino 2 NT-proBNP 2000 ng/l @ discharge WHO FC III JVP < 8 cmh 2 O SaO 2 98% RA NT-proBNP 150 ng/l Thermostable iv epoprostenol 22 ng/kg/min Sildenafil 20 mg TID Macitentan 10 mg OD Furosemide 75 mg K canrenoate 25 mg OD

Right Heart Catheterization Baseline 3 months Epo+ Macitentan+ Sildenafil HR (b/min) 116 92 RAP (mmhg) 15 7 PAP s/d/m (mmhg) 85/42/62 87/41/55 PAWP (mmhg) 8 6 SAP s/d/m (mmhg) 81/63/70 97/53/69 CI (L/min/m 2 ) 1.9 3.5 PVR (UR) 17 7.9 SA O 2 % 92 95 SP O 2 % 54 70 WHO-FC IV II 6MWD (meters) 0 575

Survival in overall population admitted in ICU ICU mortality 41.3% Sztrymf B.Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension.

% change BREATHE-2: Initial dual combination therapy with epoprostenol and bosentan 6-MWD (m) TPR change from baseline (%) Baseline (mean and 95% CI) Placebo + epo (n = 10) Bos + epo (n = 18) Week 16 (median and 95% CI) Placebo + epo (n = 10) Bos + epo (n = 18) -60-20 20 60 100 6-MWD (m) 140 0-20 -40-60 -80 Placebo + epo (n = 10) Baseline Wk 16 0-20 -40-60 -80 Bos + epo (n = 18) Baseline Wk 16-23% -36% P=0.08 Humbert M, et al. Eur Respir J. 2004;24:353-9.

PVR (d.s.cm -5 ) Cumulative survival (%) Initial dual combination therapy with epoprostenol and bosentan Percent change in PVR from baseline to 1 st f-up evaluation (3 6 months) 2000 1500 Epo + bosentan combination therapy (n=23) Epoprostenol monotherapy (n=46) 100 80 Epoprostenol + bosentan (n = 23) 1000 60 40 p = 0.07 500 20 Epoprostenol (n = 46) 0 Baseline 4-month Baseline 3-month -48 ± 17% -29 ± 17% P=0.0001 0 0 24 48 72 96 Time (months) Kemp K, et al. J Heart Lung Transplant 2012;31:150 8.

Initial triple combination therapy: I.V. Epoprostenol + Bosentan + Sildenafil Initial triple combo therapy: i.v. epoprostenol + bosentan + sildenafil 19 incident (i.e. newly diagnosed) patients with Idiopathic (n=9) or Heritable (n=10) PAH Mean age 39 ± 14 years (18 63) NYHA FC III (n=8) or IV (n=11) Severe haemodynamics: CI < 2.0 L/min/m 2 or PVR > 1000 d.s.cm -5 Sitbon O, et al. Eur Respir J. 2014;43:1691 7.

Patients (n) 6MWD (m) Initial triple combination therapy: Effect on FC and 6MWD Prospective, observational analysis of idiopathic or heritable PAH patients (n = 19) treated with upfront combination therapy (epoprostenol, bosentan and sildenafil) FC I/II FC III FC IV 20 18 16 14 12 10 8 6 4 2 0 17 18 10 8 1 Baseline 4 months* Last visit* # 700 600 500 400 300 200 100 0 Baseline 4 months Last visit * * ** # # 32 ± 19 months *p < 0.01 versus baseline; ** p < 0.01 versus 4 months Sitbon O, et al. Eur Respir J. 2014;43:1691 7.

mpap (mmhg) Cardiac index (l/min/m 2 ) PVR (dyn s/cm 5 ) Initial triple combination therapy: Effect on haemodynamics 100 90 80 70 60 50 40 30 20 10 0 Baseline Month 4 Final followup visit # 5 4 3 2 1 0 Baseline Month 4 Final followup visit # 3500 3000 2500 2000 1500 1000 500 0 Baseline Month 4 Final followup visit # Baseline Month 4 Final follow-up # RAP (mmhg) 11.9 ± 5.2 4.9 ± 4.9* 5.2 ± 3.5* mpap (mmhg) 65.8 ± 13.7 45.7 ± 14.0* 44.4 ± 13.4* CI (l/min/m 2 ) 1.66 ± 0.35 3.49 ± 0.69* 3.64 ± 0.65* PVR (d.s.cm -5 ) 1718 ± 627 564 ± 260* 492 ± 209* # 32 ± 19 months *p < 0.01 versus baseline Sitbon O, et al. Eur Respir J. 2014;43:1691 7.

Initial triple combination therapy: Long-term outcome / survival Long-term follow-up (n=19) Median follow-up: 58.7 months (IQR: 52.5 70.0 months) Two patients underwent LT (after 3.8 and 41.4 months) 17 patients well and alive in NYHA FC I-II 7 patients with mpap < 35 mmhg (incl. one < 20 mmhg) Survival (n=19) 1-year 2-year 3-year 5-year Actual 100% 100% 100% 100% Expected* [95% CI] 75% [68%-82%] 60% [50%-70%] 49% [38%-60%] Transplant-free 94% 94% 94% 89% * according to the French equation (Humbert M, et al. Eur Respir J 2010) - Sitbon O, et al. Eur Respir J. 2014;43:1691 7.

Key messages High risk PAH patients should be treated in expert PH centers ICU treatment including iv inotropic support may be required according with the clinical and haemodynamic status Initial combination therapy including iv epoprostenol is the treatment of choice for these patients