The document discusses chronic thromboembolic pulmonary hypertension (CTEPH) and its pathophysiology. It describes the core pathologic process as an imbalance between prothrombotic factors and disturbed thrombus resolution, leading to in situ thrombosis over thromboembolic lesions. It also discusses the BENEFIT trial which found that treatment with bosentan improved exercise capacity and hemodynamics in inoperable CTEPH patients. The CHEST trial then evaluated riociguat, a soluble guanylate cyclase stimulator, in inoperable or recurrent CTEPH patients and found improvements in pulmonary vascular resistance and other outcomes.

1. DRUGS FOR CTEPH Dr. Marco Morsolini, MD Research Doctorate in Experimental Surgery and Microsurgery University of Pavia School of Medicine Division of Cardiac Surgery Foundation I.R.C.C.S. “San Matteo” Hospital – Pavia – Italy

2. PATHOPHYSIOLOGY

3. PATHOPHYSIOLOGY

4. Hypertensive remodeling of the patent arteries Chronic arteriopathy of the obstructed branches Plexiform lesions Development of pathological arterial shunts In situ thrombosis ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

5. Hypertensive remodeling of the patent pulmonary vascular bed (Eisenmenger-like) due to volume and pressure overload ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

6. “… the development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time…” ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

7. Hypertensive remodeling of the patent arteries Chronic arteriopathy of the obstructed branches Plexiform lesions Development of pathological arterial shunts In situ thrombosis ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

8. Chronic arteriopathy of the obstructed branches with calcifications and possible retraction of the distal vessels ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

9. “… thrombotic material can provide the basis elements for the pultaceous core of atherosclerotic plaques, whereas it has not been observed in the hypertensive non-thromboembolic arteries…” ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

10. Hypertensive remodeling of the patent arteries Chronic arteriopathy of the obstructed branches Plexiform lesions Development of pathological arterial shunts In situ thrombosis ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

11. Plexiform lesions stemming from the capillary bed ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

12. “… patients with plexiform lesions failed to show dramatic hemodynamic improvement despite successful PEA, suggesting that plexiform lesions were probably responsible for persistent pulmonary hypertension…” ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

13. Hypertensive remodeling of the patent arteries Chronic arteriopathy of the obstructed branches Plexiform lesions Development of pathological arterial shunts In situ thrombosis ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

14. Development of pathological systemic-to-pulmonary arterial shunts to overcome the chronic segmental lung hypoperfusion, often causing hemoptysis bronchial arteries (orthotopic / heterotopic) intercostal arteries internal mammary arteries frenic arteries coronary arteries PERCUTANEOUS EMBOLIZATION ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

15. Right bronchial artery Right mammary artery Before After Right thoracic artery ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

16. Right intercostal artery Right frenic artery Before After ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

17. Hypertensive remodeling of the patent arteries Chronic arteriopathy of the obstructed branches Plexiform lesions Development of pathological arterial shunts In situ thrombosis ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

18. The core of the pathologic process in CTEPH is the imbalance between prothrombotic factors and disturbed thrombus resolution Moreover, pulmonary hypertension itself is associated with endothelial and platelet dysfunction CTEPH patients are more likely to develop in situ thrombosis over their thromboembolic lesions ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

19. Such pathophysiological modification of the pulmonary circulation are absolutely not predictable , since CTEPH may develop during indefinite months or years: following a single episode of acute PE with incomplete resolution despite medical treatment due to chronic relapses of asymptomatic PE due to an acute symptomatic PE over chronic relapsing PE ACCORDING TO THE LENGTH OF THE DISEASE PATHOPHYSIOLOGY

20. EARLY DIAGNOSIS EARLY TREATMENT

21. Growing single surgeon’s experience due to learning curve OPERABILITY ASSESSMENT Which lesions have to be considered as inoperable ? Different operability assessments from different Centers

22. JAMIESON CLASSIFICATION L.M.E.L. - 65 yrs M - Oct 2004 - PEA #119 mPAP 39  19 (-51%) CO 4.4  5.4 (+23%) PVR 665  222 (-66%) G.A.C. - 52 yrs F - Jul 2003 - PEA #96 mPAP 48  27 (-44%) CO 2.1  4.2 (+100%) PVR 1638  381 (-77%) B.A. - 43 yrs F - May 2009 - PEA #233 mPAP 49  19 (-61%) CO 3.3  5.0 (+52%) PVR 1067  224 (-79%)

23. Exclusively distal lesions MEDICAL THERAPY ! OPERABILITY ASSESSMENT

24. SURVIVAL OF UNTREATED PATIENTS

25. Higher operability rate PH RECURRENCY AFTER PEA More Jamieson type III PEAs MEDICAL THERAPY ! Higher PH recurrence after PEA

26. FOLLOW-UP TIMING AFTER PEA discharge 3 th month yearly for 5 years 7 th , 10 th and 15 th year

27. Pre-operative V/Q scan Pre-operative right pulmonary angiogram Pre-operative RHC mPAP 50 CI 1.4 PVR 1241 RVEF 9 PRE-OPERATIVE LONG LASTING DISEASE

28. A right monolateral PEA was performed Impossible to wean off the patient from cardio-pulmonary by-pass due to right ventricle failure On ECMO for two days; the sternum was left open for two more days Mechanical ventilation 9 days ICU stay 14 days Hospital stay 21 days First PO RHC control mPAP 26 (-48%) CI 2.0 (+43%) PVR 410 (-67%) RVEF 25 (+178%) PRE-OPERATIVE LONG LASTING DISEASE

29. No CT-scan evidence of new thromboembolic material Very long pre-operative NYHA III-IV class period (65 months): probably severe and non-reversible small vessels disease 2 years follow-up RHC PRE-OPERATIVE LONG LASTING DISEASE TYPICAL PATIENT WITH RECURRENT PH AFTER PEA mean Pulmonary Artery Pressure 0 10 20 30 40 50 60 Before PEA Discharge 3 months 1 year 2 years Cardiac Index 0.0 0.5 1.0 1.5 2.0 2.5 Before PEA Discharge 3 months 1 year 2 years Pulmonary Vascular Resistances 0 200 400 600 800 1000 1200 1400 Before PEA Discharge 3 months 1 year 2 years Right Ventricle Ejection Fraction 0 5 10 15 20 25 30 35 Before PEA Discharge 3 months 1 year 2 years

30. PH MEDICAL THERAPY Pulmonary hypertension is a rare disease… … but not an orphan disease at all!

31. PH MEDICAL THERAPY BOSENTAN AMBRISENTAN SILDENAFIL TADALAFIL EPOPROSTENOL ILOPROST TREPROSTINIL

32. CTEPH MEDICAL THERAPY No drugs are currently approved for CTEPH Further clinical trials are needed

33. CTEPH MEDICAL THERAPY PHASE II STUDIES Author Drug Study Design Patients WHO Treatment Results McLaughlin (1999) Epoprostenol Observational 3 III-IV 8-16 months Hemodynamic and exercise tolerance improvement Higenbottam (1998) Epoprostenol Iloprost (i.v.) Observational 39 II-IV 1-4 years Survival improvement (if SV O 2 < 60%) Olschewski (2002) Iloprost (inhaled) Controlled 33 III-IV 12 weeks No improvement Nagaya (2002) Beraprost (oral) Open 16 II-III 8-12 weeks Exercise tolerance improvement Vizza (2001) Beraprost (oral) Open 3 II-IV 12 months Exercise tolerance improvement

34. BENEFiT TRIAL – PHASE III –

35. STUDY DESIGN Phase III, randomized vs. placebo (1:1) International multicentre (26 sites in 13 Countries) 157 pts (18 – 80 yrs) CTEPH - inoperable (exclusively distal lesions) persistent or recurrent PH after PEA WHO functional class II – IV 6mWT distance < 450 m Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

36. BENEFiT TRIAL Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34

37. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

38. *Analysis excluded patients judged operable by the Operability Evaluation Committee (n=11) † Analysis excluded patients with missing baseline or post-baseline assessment(s) (n=9 for pulmonary vascular resistance [PVR] analysis; n=6 for 6-min walk distance [6MWD] analysis) mPAP = mean pulmonary artery pressure mRAP = mean right atrial pressure NT-proBNP = N-terminal pro-brain natriuretic peptide; PEA = pulmonary endarterectomy; TPR = total pulmonary resistance; WHO = World Health Organization. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

39. BENEFiT TRIAL Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34

40. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

41. Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34 BENEFiT TRIAL

42. RESULTS AFTER PEA p < 0.01 Pre-op 3m 1y 3y 5y 7y 10y

43. SOME COMMENTS: CTEPH patients are generally older than other-PH patients We are still far from early diagnosis of CTEPH (75% at diagnosis are in WHO functional class III or IV) Significant muscolar and psychological deconditioning (19 months of WHO III or IV symptoms before diagnosis) Short observation time (main phase study only 16 weeks) Hemodynamic endpoint satisfied Functional endpoint not satistied BENEFiT TRIAL

44. NEW PERSPECTIVES

45. RATIONALE RIOCIGUAT Soluble guanylate-cyclase stimulator CHEST STUDY Ch ronic Thrombo e mbolic Pulmonary Hypertension sGC- S timulator T rial riociguat

46. Phase III, double-blind, randomized vs. Placebo (2:1) International, multicenter (28 Countries) N = 270 pts (18 – 75 yrs) Inoperable CTEPH (peripheral localization) or recurrent PH after PEA PH pts WHO II-IV 6 MWD > 150 m and < 450 m PVR > 300 dyne*sec*cm -5 mPAP > 25 mmHg CHEST STUDY Ch ronic Thrombo e mbolic Pulmonary Hypertension sGC- S timulator T rial riociguat

47. STUDY DESIGN CHEST STUDY Ch ronic Thrombo e mbolic Pulmonary Hypertension sGC- S timulator T rial 2 weeks 2 weeks 2 weeks 2 weeks 2.0 mg tid 1.5 mg tid 1 mg tid ∑ : 16 weeks V2 V1 V3 V4 V5 V7 V7 V7 V7 V7 0.5 mg tid 1.5 mg tid 1.0 mg tid 2.0 mg tid 2.5 mg tid 2.5 mg tid