1. Marius M Hoeper Therapeutic goals and algorithms

2. The evolution of goal-oriented therapy 1. The determination period

3. Change in 6MWD in clinical trials Bosentan Sildenafil +45 m Ambrisentan +31 m +51 m Tadalafil

4. Change in 6MWD and prognosis Sitbon O, et al. JACC 2002; 40:780-8 1.0 0.2 108 786348311913521 Subjects at risk (n) 7860352516821 <112m ≥112m ∆ 6MWD ≥ 112 m ∆ 6-MWD < 112 m 0.4 0.6 0.8 0 1224364860728496 Cumulative survival Time (months) 0

5. Prognostic importance of 6MWD after initiation of PAH therapy Sitbon O, et al. JACC 2002; 40:780-8  380 m Cumulative survival 1.0 Time (months) 0.8 0.6 0.4 0.2 0 01224364860728496108 < 380 m p = 0.0005 Subjects at risk (n) 6-MWD  380 m 6-MWD < 380 m 7854281686331 7871564128154

6. Cardiopulmonary exercise testing in PAH Wensel R et al. Circulation 2002; 106:319-24 Cumulative survival (%) 100 Time (years) 80 60 40 20 0 0123 Peak VO 2  10,4 ml/kg/min Peak VO 2 > 10,4 ml/kg/min Cumulative survival (%) 100 Time (years) 80 60 40 20 0 0123 Peak SBP  120 mmHg Peak SBP > 120 mmHg Several CPET variables of prognostic importance, including peak VO 2 and the peak systolic blood pressure (SBP) during exercise

7. Goal-oriented use of combination therapy: The original approach (2002) Diagnosis of PAH vasoreactivity test negative WHO FC III or IV Baseline examination, therapy and 2-6 monthly re-evaluation to assess treatment goals (6MWD >380 m, peak VO 2 >10,4 ml/min/kg, peak SBP >120 mmHg) Treatment goals not met Treatment goals met Addition of Sildenafil Treatment continued Addition of inhaled iloprost Treatment continued Transition from inhaled to IV PGI 2 Treatment continued Lung transplantation Treatment continued First-line Bosentan Hoeper MM et al. ERJ 2005; 26:858-63

8. Goal-oriented use of combination therapy in patients with PAH modified from Hoeper MM et al. ERJ 2005; 26:858-63 Historical control group 0.2 0.4 0.6 0.8 1.0 First-line bosentan Addition of sildenafil/iloprost 2002-2004 Historical control group 1999-2001 Expected survival Treatment group vs historical control group, p=0.011 Treatment group vs expected survival, p <0.001 for all time points Months Cumulative survival (IPAH) 061218243036 89836961464337 67644738312320 Treatment group Subjects at risk (n)

9. Functional class is one of the most powerful predictors of survival Sitbon O, et al. JACC 2002; 40:780-8

10. Functional class is one of the most powerful predictors of survival Sitbon O, et al. JACC 2002; 40:780-8

11. BNP/NT-proBNP prognostic markers in patients with PAH Nagaya N et al. Circulation 2000; 102:865-870 Fijalkowska A et al. Chest 2006; 129: 1312-21 NT-proBNP Baseline values and changes with therapy are of prognostic relevance

12. TAPSE – An indicator of RV function and prognosis Forfia PR et al. AJRCCM 2006; 174: 1034-41 TAPSE: Tricuspid annular plane systolic excursion

13. Galié N et al. Eur Heart J 2009; 30:2493-537

15. Prognostically important variables and treatment goals

16. The evolution of goal-oriented therapy 2. The validation period

17. Lack of association between change in 6MWD and clinical events in PAH Gabler NB et al. Circ 2012;126:349-56; Savarese G et al. JACC 2012;60:1192-201

18. Change in FC and survival in the REVEAL registry Barst RJ et al. Chest 2013;144:160-8

19. Prognostic impact of follow-up assessments in patients with IPAH IPAH, n=109, all treatment-naive at baseline, invasive follow-up assessment WHO-FC, 6MWD Hemodynamics (RA, PAPm, PVR, CI, SvO 2 ) Biomarkers (creatinine, BUN, uric acid, bilirubin, yGT, RDW, CRP, NT-proBNP) Nickel N et al., Eur Resp J 2012;39:589-96

20. Baseline variables associated with outcome (Exercise capacity and hemodynamics) Hazard ratioP value WHO functional class 2.3 (1.0 – 5.1)0.04 6MWD1.2 (1.0 – 1.1)0.002 Hemodynamic variables RA pressure [mmHg] 1.2 (1.0 – 1.3)0.001 PAPm [mmHg]1.0 (0.9 – 1.1)0.18 Cardiac index [l/min/m 2 ]1.7 (1.4 – 2.6)0.01 PVR [dyn·sec·cm ‑ 5 ]1.0 (0.8 – 1.1)0.42 SvO 2 [%]1.2 (1.1 – 1.4)0.02 Nickel N et al., Eur Resp J 2012;39:589-96

21. Baseline variables associated with outcome (Biomarkers) Biochemical variables Hazard ratio P-Value NT-proBNP [ng/l]1.3 (1.1 – 1.6)0.04 Bilirubin [µmol/l]1.1 (1.0 – 1.3)0.023 γGT [U/l]1.0 (0.9 – 1.2)0.07 Creatinine [µmol/l]1.4 (1.2 – 1.9)0.04 BUN [mmol/l]1.1 (0.9 – 1.2)0.06 Uric acid [µmol/l]1.1 (1.0- 1.6)0.01 CRP [mg/l]1.3 (1.1 – 1.6)0.04 RDW [%]1.1 (0.6 – 1.2)0.16 Nickel N et al., Eur Resp J 2012;39:589-96

22. Follow-up variables associated with outcome (Exercise capacity and hemodynamics) Biochemical variables Hazard ratio P-Value Δ WHO functional class 2.0 (1.1 – 3.6)0.02 Δ 6MWD0.91 (0.94 – 1.1)0.08 Hemodynamic variables Δ RA pressure [mmHg] 0.98 (0.94 – 1.0)0.37 Δ PAPm [mmHg]0.81 (0.69 – 1.1)0.29 Δ Cardiac index [l/min/m 2 ]2.1 (1.2 – 3.9)0.01 Δ PVR [dyn·sec·cm ‑ 5 ]0.94 (0.8 – 1.2)0.28 Δ SvO 2 [%]2.1 (1.2 – 3.6)0.008 Nickel N et al., Eur Resp J, epub 01.09.2011

23. Follow-up variables associated with outcome (Biomarkers) Biochemical variables Hazard ratio P-Value Δ NT-proBNP [ng/l]2.4 (1.3 – 4.5)0.003 Δ Bilirubin [µmol/l]1.2 (0.9 – 1.3)0.08 Δ µGT [U/l]1.4 (0.8 – 2.5)0.32 Δ Creatinine [µmol/l]1.2 (0.6 – 2.0)0.55 Δ Uric acid [µmol/l]1.3 (0.8 – 2.3)0.25 Δ CRP [mg/l]1.4 (0.7 – 2.7)0.24 Δ RDW [%]0.9 (0.4 – 1.8)0.79 Nickel N et al., Eur Resp J, epub 01.09.2011

24. Follow-up variables associated with outcome (multivariate analysis) Biochemical variables Hazard ratio P-Value NYHA FC 1.4 (1.2 – 2.4)0.04 NT-proBNP (ng/l) 1.3 (1.2 – 1.8)0.007 Cardiac index (l/min/m 2 ) 1.8 (1.1 – 2.9)0.02 SvO 2 (%) 2.2 (1.2 – 4.2)0.01 Nickel N et al., Eur Resp J 2012;39:589-96

25. Variables associated with outcome at baseline and follow-up Group 1FC I/II BL and F/U Group 2FC III/IV BL FC I/II F/U Group 3FC I/II BL FC III/IV F/U Group 4FC III/IV BL and F/U WHO Functional Class I/II versus III/IV Nickel N et al., Eur Resp J 2012;39:589-96

26. Variables associated with outcome at baseline and follow-up Group 1FC I/II BL and F/U Group 2FC III/IV BL FC I/II F/U Group 3FC I/II BL FC III/IV F/U Group 4FC III/IV BL and F/U Nickel N et al., Eur Resp J 2012;39:589-96 WHO Functional Class I/II versus III/IV

27. Variables associated with outcome at baseline and follow-up Group 1CI ≥2.5 BL and F/U Group 2CI <2.5 BL, ≥2.5 at F/U Group 3CI ≥2.5 BL, <2.5 at F/U Group 4CI <2.5 at BL and F/U Cardiac Index, cut-off 2.5 L/min/m 2 Nickel N et al., Eur Resp J 2012;39:589-96

28. Variables associated with outcome at baseline and follow-up Group 1NT-proBNP <1,800 ng/l BL and F/U Group 2NT-proBNP ≥1,800 BL, <1,800 at F/U Group 3NT-proBNP < 1,800 BL, ≥ 1,800 at F/U Group 4NT-proBNP ≥1,800 at BL and at F/U NT-pro brain natriuretic peptide (NT-ProBNP), cut-off 1,800 ng/L Nickel N et al., Eur Resp J 2012;39:589-96

29. Variables associated with outcome at baseline and follow-up Group 1SvO2 ≥65% BL and F/U Group 2SvO2 <65% at BL, ≥65% F/U Group 3SvO2 <65% BL, ≥65% at F/U Group 4SvO2 <65% at BL, F/U Mixed-venous oxygen saturation (SvO 2 ), cut-off 65% Nickel N et al., Eur Resp J 2012;39:589-96

30. Evidence-based treatment goals Non-invasive variables associated with survival: WHO functional class (I/II) NT-proBNP (<1.800 ng/ml) Hemodynamic variables associated with survival were Cardiac index (≥ 2.5 l/min/m 2 ) SvO 2 (≥65%) Follow-up assessments at least as important as baseline assessments for prognostification Nickel N et al., Eur Resp J 2012;39:589-96

32. McLaughlin VV et al. J Am Coll Cardiol 2013;62:D73-81

33. Summary A goal-oriented treatment strategy is recommended for patients with PAH Treatment goals are based on variables with prognostic importance Several treatment goals (FC I/II, NT-proBNP <1.800 ng/L, CI ≥2.5 L/min/m 2, SvO 2 ≥65%) have been validated