Pulmonary Arterial Hypertension: A Few Steps on the Long March to Effective Treatment

1. Pulmonary Arterial Hypertension:A Few Steps on the Long March to Effective Treatment Edward Catherwood, MD, MS Cardiology Update, 2004

2. PAP CO= PVR Schematic Progression of PAH Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP Right Heart Dysfunction PVR Time

3. Humbert M, et al. NEJM. 2004.

4. Humbert M, et al. JACC. 2004

5. WHO World Symposium, Venice 2003PAH Classification • Pulmonary arterial hypertension • Familial • Idiopathic • Related to: • Collagen vascular disease • Congenital heart disease • Portal hypertension • HIV infection • Drugs / toxins/other • PAH with significant venous and/or capillary involvement • PAH related to disorders of respiratory system • PAH due to thromboembolic disease • PE • Sickle cell • Non-thrombotic pulmonary embolism: tumor, parasites • Miscellaneous: Sarcoid, extrinsic compression Humbert M, et al. NEJM. 2004.

6. PAH: A Progressive Disease of Poor Survival 68% 48% 34% Adapted from: D’Alonzo et al. Ann Internal Med. 1991

7. Survival Estimates in Scleroderma By Organ Involvement 100 90 80 None 70 60 Percent Survival 50 Lung Involvement (without PH) 40 30 PAH 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years from Diagnosis of Pulmonary Hypertension Koh et al. Brit J Rheumatol 1996

8. WHO Functional Assessmentof PAH Class ISymptoms do not limit physical activity: Ordinary physical activity does not cause undue discomfort. Class IISlight limitation of physical activity: Patient is comfortable at rest, yet experiences symptoms with ordinary physical activity. Class IIIMarked limitation of physical activity: Patient is comfortable at rest, yet experiences symptoms with minimal physical activity. Class IVInability to carry out any physical activity: Patient may experience symptoms even at rest. Discomfort is increased by any physical activity. These patients manifest signs of right heart failure. Humbert M. NEJM. 2004

9. Symptoms of PAH • Symptoms may include: • Dyspnea Fatigue • Syncope Edema • Dizziness Chest Pain • Non-specific nature of complaint: • Misdiagnosis • Delayed diagnosis Gaine et al. The Lancet, 1998.

10. Physical Examination • Loud pulmonic valve closure (P2) • TR murmur • Right-sided fourth heart sound • Right ventricular heave • Jugular venous distention • Peripheral edema, ascites

11. Findings on Chest Radiography • Cardiac enlargement • Prominent proximal PA • “Pruning” of distal PA • no evidence of pulmonary edema (sign of left-sided disease) • lungs look normal

12. IVS RV LV RA LA Signs indicative of PH on ECHO • Increased sPAP or TR jet • Right atrial & ventricular hypertrophy • Flattening of septum • Small LV dimension • Dilated PA

13. Normal Range in PASP • 3800 TTE database with PASP measured • 28% with PASP est. over 30 mmHg • 5% men over 50 had PASP >40 mmHg • Increasing values correlate with: Age, BMI, sex McQuillan BM, et al. Circulation. 2001

14. Auxillary Studies • Baseline labs: CBC, LFTs, ANA, coagulation battery, HIV serology • PFTs: screen for restrictive or obstructive disease, diffusing capacity • Pulmonary thromboemboli: Perfusion lung scan, CT scan, angio • OSA: sleep study

15. Right Heart CatheterizationDiagnostic Gold Standard • CO/CI • RAP • mPAP, SVO2 • PAOP • PVR • Prognostic (RAP, CI, mPAP)

16. 6 MWT Methods • The 6 MWT is a non-encouraged test performed on room air • The corridor should be a minimum of 30 meters in length • Required equipment • Stop watch • 2 cones • Portable pulse oximeter • Patient instructions: • “The object of this test is to walk as far as possible for 6 minutes. You are permitted to slow down, to stop, and to rest as necessary. You may lean against the wall while resting, but resume walking as soon as you are able to.” • “You will be walking back and forth around the cones (or chairs). You should pivot briskly around the cones and continue back the other way without hesitation..”

17. 100 Long distance group 80 p < 0.001(Logrank test) 60 Survival (%) 40 Short distance group 20 0 0 10 20 30 40 50 60 Months 6MW Predicts Survival at Initial Screening Miyamoto et al Am J Respir Crit Care Med 2000.

18. History • 35yo woman, single mother, notes increasing DOE over two years duration. • Ultimately develops SOB at rest and marked swelling in her legs • Diuresis of 15 lbs at OSH with improvement. • ECHO demonstrates RA/RV dilatation, PASP 60 mmHg, normal LV

19. PMH: • Toxemia of pregnancy • Mild diastolic hypertension • No history of PE, COPD, OSA, diet drug use, coll-vasc disease, liver disease, toxic exposures • Single, 8yo child, works as a waitress. 15 ppd smoker. No alcohol excess • FH negative • ROS: Nonproductive cough, hoarse voice

20. Physical Exam • WD, WN 35 yo woman, BP 100/70 P 90 R 12, Wt. 70kg • HEENT: No JVD • Lungs: Clear • Cardiac exam: Loud P2, RV lift. • ABD: unremarkable • Ext: Trace edema • Neuro: Normal

21. ECG

22. CXR

23. Lab Studies • CBC: Hgb 17.8, Hct 52 WBC 7800 with unremarkable differential Plts 27K • Na+ 131 K+ 3.8 Cl 94 CO2 28 Creat 0.7 • LFTs normal • ANA neg • CT chest negative for PE or interstitial lung abn. • Abdominal CT: spleen mildly enlarged • PFTs: Mild obstructive pattern, DLCO 77%

24. Right Heart Cath

25. What Do You Think?? • What is the etiology of her PHTN? • What additional testing or examination would you order? • Would you treat her PHTN now? With what?

26. Treatments for PAH • Treat modifiable contributors • Left heart disease, shunts • Pulmonary parenchymal or thrombotic processes, OSA • Pharmacotherapies • General measures: diuretics, warfarin, O2, ?Dig • Ca++ channel blockers • Prostanoids • Endothelin antagonists • Phosphodiesterase inhibitors

27. Prostanoid Therapy • Physiologic impact • Induces vasodilatation of vascular smooth muscle cells (cAMP) • Inhibits growth of vascular SMCs • Potent inhibitor of platelet aggregation • Available agents • Epoprostenol (Flolan): central access, constant infusion • Treprostinil (Remodulin): sq constant infusion • Iloprost: inhaled • Beraprost: oral

28. Longer Term Impact of Epoprostenol on iPAH • 162 patients with iPAH • Eposprostenol compared to expected survival • 62% vs 35% at 3 yrs. • Keys to survival: • Functional class • CI, mean PA pressure Epo Rx Historical Controls Historical Controls McLaughlin VV, et al. Circulation. 2002.

29. McLaughlin VV, et al. Circulation. 2002.

30. Endothelin-1 • Family of 21 amino acid peptides • Identified in 1988 • Highest expression in lung, vascular endothelium, smooth muscle and airway epithelium • One of the most potent endogenous vasoconstrictors • 100 x more potent v/s NE • 10 x more potent v/s A-II Adapted from Yanagisawa M, et al. Nature. 1988.

31. Endothelin Receptor Antagonists • Bosentan (Tracleer): • Blocks ETA and ETB Agents in Phase III Trials • Sitaxentan: • ETA selective blockade • Ambrisentan: • ETA selective blockade

32. Channick, et al. Lancet 2001 PAH due to iPAH scleroderma other connective tissue diseases WHO functional class III Baseline 6-min walk test  150 m and  500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec•cm-5 PCWP < 15 mmHg Rubin, et al. NEJM 2002 PAH due to iPAH scleroderma other connective tissue diseases WHO functional class III or IV Baseline 6-min walk test  150 m and  450 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec•cm-5 PCWP < 15 mmHg Main Inclusion Criteria Channick R et al. Lancet 2001. Rubin L, et al. NEJM 2002.

33. Baseline Hemodynamics Rubin, et al. NEJM 2002 Channick, et al. Lancet 2001 Bos (n = 144) Pbo (n = 69) Bos (n = 21) Pbo (n = 11) Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 Mean  SD Channick R et al. Lancet 2001. Rubin L, et al. NEJM 2002.

34. Bosentan Prevented Significant Hemodynamic Decline • Bosentan therapy significantly improved hemodynamics over 12 weeks • Conventional therapy led to worsening hemodynamics over 12 weeks +191 dyn-sec-cm-5 +0.5L/min/m2 ‡ ‡ +5.1mm Hg -1.6mm Hg ‡ ‡ -223dyn-sec-cm-5 • 0.52L/min/m2 Treatment Effect: 6.7 mm Hg - 415 dyn-sec cm-5 1.02 L/min/m2 Adapted from Channick, et al. Lancet 2001. ‡ significant change vs baseline

35. Known Drug Interactions TRACLEER [package insert], 2003

36. Bosentan Safety • Mild anemia may be induced • LFT surveillance • Teratogencity: may be an ERA class effect • Ensure negative Pregnancy test before Rx • Monthly thereafter • Headaches, peripheral edema TRACLEER [package insert], 2003

37. Phosphodiesterase Inhibitors • Block cGMP breakdown by PDE type 5 • Enhance NO-dependent vasodilatation • Sildenafil studied in limited series Mikhail GW, et al. Eur Heart J. 2004.

38. Pulmonary Hypertension, Class III-IV Begin Conventional Rx Right Heart Cath Vasodilator Challenge - + Ca++ Channel Rx Class III Class IV Sustained Response Endothelin Antagonist Prostacyclins Prostacyclin Endothelin Antagonist Yes No Maintain Ca++ Channel Rx. Sildenafil, Atrial septostomy, lung transplantation

39. Future Directions • Combination therapy • BREATHE-2: Prostacyclin with bosentan • Other novel treatments: • Vasoactive intestinal peptide • Serotonin blockers • NO supplementation • Studies on earlier intervention