1. Pulmonary Arterial Hypertension: Review and Updates Veronica Franco, MD, MSPH Section of Pulmonary Hypertension Section of Heart Failure and Transplantation Ohio State University

2. Today… Nomenclature review - classification Diagnosis Prognosis Treatment

3. Today… Nomenclature review - classification Diagnosis Prognosis Treatment

4. Is it Primary vs Secondary Pulmonary Hypertension? Is it Pulmonary Arterial Hypertension (PAH) or Non-PAH? No!!! Dated Nomenclature

5. Pulmonary Hypertension Is a Disease of Triggers

6. Pulmonary hypertension (PH) with left heart disease – WHO Class 2 –Trigger: High LA Pressure PH with lung disease/hypoxemia - WHO Class 3 –Trigger: Hypoxemia and Parenchyma Distortion PH due to chronic thrombotic and/or embolic disease – WHO Class 4 –Trigger: Obstruction The 2003 Venice Classification of Non-PAH Pulmonary Hypertension

7. The 2003 Venice Classification of PAH - WHO Class 1 Pulmonary Arterial Hypertension –Familial PAH (FPAH) –Idiopathic PAH (IPAH) –Associated PAH (APAH) Connective tissue disease (CTD) Human immunodeficiency virus (HIV) Portal hypertension Anorexigens Congenital heart disease (CHD) –Persistent pulmonary hypertension of the newborn (PPHN) –PAH with venule/capillary involvement Trigger: Mutation/Polymorphism Trigger: Permissive Phenotype

8. Importance of Classification: Why do it? Efficacy: What’s the trigger? Can you change it? Safety: Can it hurt the patient? Cost: How much are we spending for limited efficacy and small changes in QOL?

9. Efficacy: What’s the trigger? Can you change it?

10. Safety: Can it hurt the patient? LV dysfunction: Pulmonary edema ILD/COPD: Worsen V/Q mismatch CTEPH: Delay referral for thromboendarterectomy

11. Cost: How much are we spending for limited efficacy and small changes in QOL? Bosentan: ~35-40k per year Sildenafil: ~12-15k per year Inhaled Iloprost: ~60k per year IV Prostacyclins: ~60-120k per year

12. Pulmonary Arterial Hypertension Classification Diagnosis Prognosis Treatment

13. Schema for Patient Evaluation Echocardiogram Chest x-Ray PFTs +/- Chest CT ?RVSP,RVE, RAE Left heart disease (valvular, HF, CAD) Bubble echo - Congenital heart disease Emphysema Fibrosis Thoracic abnormality Sleep study Obstructive Sleep apnea VQ scan, angiogram Chronicthromboembolicdisease Serologies HIV CTD: scleroderma, SLE, RA, MCTD LFTs Evalcirrhosis and Portal HTN PortopulmonaryHypertension RHC Required for diagnosis of PAH Vasodilator study

14. RHC Diagnosis PAH =

15. Cardiac Catheterization to Assess Severity and Prognosis of PAH To measure wedge pressure or LVEDP Scrutinize wedge tracings!!!! Wedge sat; End expiration To exclude or evaluate CHD To establish severity and prognosis To test vasodilator therapy Catheterization is required for every patient with suspected pulmonary HTN. LVEDP = left ventricular end diastolic pressure.

16. Pulmonary Arterial Hypertension lumen media intima adventitia Normal pulmonary arteriole Plexiform lesion Pulmonary arteriole in PAH Barst et al. J Am Coll Cardiol. 2004;43:40S-47S. Mean Pulmonary artery ≥ 25 mmHg (rest) ≥ 30 mmHg (exercise). Wedge pressure ≤ 15 mmHg PVR > 3 Woods units

17. Pulmonary Venous Hypertension: Valvular heart disease (HD) Hypertensive HD Cardiomyopathies Transmitted pressure results in reactive vasoconstriction Treat primary problem

18. Pulmonary Arterial Hypertension Classification Diagnosis Prognosis Treatment

19. Natural History of PAH: NIH Registry 1,2 NIH = National Institutes of Health. Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension. 1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349. Predicted survival* 69% 56% 46% 38% Percent survival Years

20. Survival by PAH Etiology CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH = portopulmonary hypertension. McLaughlin et al. Chest. 2004;126:78S-92S. Years Percent survival Prognosis in Mixed Treated/Untreated Cohorts

21. PAH Determinants of Risk Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes GradualProgressionRapid II, IIINYHA classIV Longer (>400 m)6MW distanceShorter (<300 m) Minimally elevatedBNPVery elevated Minimal RV dysfunction Echocardiographic findings Pericardial effusion, significant RV dysfunction Normal/near normal RAP and CI HemodynamicsHigh RAP, low CI McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.

22. McLaughlin VV, et al. Circulation. 2002;106:1477-1482. 0 20 40 60 80 100 Survival (%) 0122436486072 84 No. at risk 16233957048302010 Months FC=3 FC=4 p=0.0001 by log-rank test 847260483624120 100 80 60 40 20 0 FC=1 No. at risk: FC=2 FC=3 FC=4 Survival (%) Months Impact of Functional Class on Survival Functional Class at Baseline Functional Class at 17±15 mos 102030466386112115

23. Correlation of Six-minute-walk Test and WHO Functional Class *p<0.05 vs control subjects † p<0.05 vs WHO functional class II ‡ p<0.05 vs WHO functional class III Miyamoto S et al. Am J Respir Crit Care Med. 2000;161:487-492. 0 100 200 300 400 500 600 700 800 ControlWHO IIWHO IIIWHO IV Distance walked in 6 minutes (m) * *† *†‡

24. Correlation of Six-minute-walk Test With Survival in PPH 0 20 40 60 80 100 0102030405060 Survival rate (%) Long distance group (≥332 m) Short distance group (<332 m) Time (mo) 6-minute-walk distance strongly predictive of survival –<332 m: 20% 3-year survival –>332 m: 92% 3-year survival Miyamoto S et al. Am J Respir Crit Care Med. 2000;161:487-492.

25. Nagaya N et al. Circulation. 2000;102:865-870. p<0.05 p<0.0001 By multivariate analysis, higher BNP at baseline (RR=11.971, p=0.0348) and at follow-up (RR=25.880, p=0.0243) were independent predictors of mortality 0 20 40 60 80 100 012243648 BNP <150 pg/mL BNP ≥150 pg/mL Survival rate (%) Time (mo) 0 20 40 60 80 100 012243648 Survival rate (%) Time (mo) BNP ≥180 pg/mL BNP <180 pg/mL Baseline BNPFollow-up BNP Plasma BNP as a Prognostic Indicator of Mortality in Patients With PPH

26. Predicting Survival and Following Therapy Clinical parameters –functional class –exercise capacity –neurohormones Hemodynamics Imaging –right ventricle: function and size –pulmonary artery remodeling (future)

27. Schematic Progression of PAH Time PAP PVR CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold CO= TPG PVR PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD.

28. Schematic Progression of PAH Time PAP PVR CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold Right Heart Dysfunction Declining/ Decompensated CO= TPG PVR PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD.

29. Goals of Therapy Improve symptoms –6-minute walk (>380 m) –functional class (I or II) –CPET (VO 2 max >10.4) –quality of life Improve hemodynamics Improve survival

30. What Drug and When

31. PAH Treatments― a Historical Overview CCB, anticoagulation, digitalis, diuretics Epoprostenol Bosentan Iloprost Ambrisentan Sildenafil SC treprostinil IV treprostinil CCB = calcium channel blocker. <1995199519961997199819992000 2001 200220032004200520062007

32. When to use a Calcium Antagonist ?

33. (Years) Long-term CCB responders Long-term CCB failure 383330221383321 1912740 Subjects at risk, n Cumulative Survival Long-term CCB responders Long-term CCB failure 0.2.4.6.8 1 024681012141618 O. Sitbon et al. Circulation 2005;111:3105-3111 Survival in IPAH Long-term CCB responders p=0.0007

34. PAH Basic therapy Oral anticoagulants, Diuretics, O 2, Digoxin... Oral CCB Continue CCB Sustained Response Yes Positive Negative Vasodilator study No CCB +++ Fall in mPAP > 10 mmHg + mPAP < 40 mmHg + Normal CO Sitbon O, et al. Circulation. 2005;111:3105-3111. 3 rd World PAH Symposium. J Am Coll Cardiol 2004;43:1S-90S. ACCP Guidelines. Chest 2004;126:1S-92S. Galiè N, et al. ESC Guidelines. Eur Heart J 2004;25:2243-78. Close monitoring of long-term clinical and hemodynamic effects

35. Vasodilator Study Anticoagulate ± Diuretics ± Oxygen ± Digoxin Sustained Response Positive Oral CCB Continue CCB Yes Negative Lower RiskDeterminants of RiskHigher Risk No Clinical Evidence of RV Failure Yes GradualProgressionRapid II, IIINYHA ClassIV Longer (>400 m)6 Minute Walk DistanceShorter (<300 m) Minimally elevatedBNPVery elevated Minimal RV Dysfunction Echocardiographic Findings Pericardial Effusion Significant RV Dysfunction Normal/Near normal RAP and CI HemodynamicsHigh RAP, Low CI What is the Optimal Treatment Strategy? McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.

36. Vascular Pathology: Balance of Powers Courtesy of: Ronald J. Oudiz, MD. Vasodilators Antiproliferatives Anticoagulants Vasoconstrictors Growth Factors Procoagulants ET-1 Serotonin Thromboxane A2 PAI-1 TGF-B Angiotensin II Angiopoietin 1/TIE2 NO Synthase Prostacyclin t-pa activity ADVERSE REMODELING of Vascular Tree IncreasedDecreased

37. ↓ vasoconstriction ↓ proliferation

38. Prostacyclins Intravenous (epoprostenol, treprostinil)* Subcutaneous (treprostinil*) Inhaled (iloprost*, treprostinil † ) Oral (beraprost ‡ ) * FDA approved † Investigational/in development ‡ Non-FDA approved

39. Epoprostenol: Indications NYHA Class III or IV PAH Contraindicated in severe LV systolic dysfunction (LVEF <30%) Cost ~ $60,000 to $120,000/year depending on dose

40. Important Points: Epoprostenol Functional capacity, hemodynamics, and survival are improved Baseline NYHA functional class is predictor of survival Response after 12 to 18 months can predict subsequent outcomes Most benefit apparent in first 12 to 18 months Dosing: Outcomes with moderate dosing are the same as with aggressive dosing McLaughlin VV et al. Circulation. 2002;106:1477-1482.

41. IV Treprostinil Approved by FDA in January 2005 Has safety (longer half-life) and convenience advantages (no mixing or cold packs, smaller pump) over IV epoprostenol Can be used for de novo patients and transitions from epoprostenol Improvements in hemodynamics and functional status similar to epoprostenol Requires at least double the epoprostenol dose (may be more expensive)

42. SC Treprostinil Requires capable patient Site pain is major impediment –Affects 85% –Local measures: ice, heat, lidocaine, capsaicin, collagenase ± effective –NSAIDs, narcotics, gabapentin ± effective –PLOgel new topical; promising, but unconfirmed reports of benefit; not useful at active site Expensive (~$60,000 to $120,000/year) pain erythema induration pain erythema induration

43. Inhaled Iloprost Approved for class III - IV PAH Duration of hemodynamic effect only 90 minutes Requires frequent administration; at least 6x/day at 10 to 15 minutes Has favorable effects on gas exchange in pulmonary fibrosis Cost of ~ $60,000-$70,000/year Olschewski H, et al. N Engl J Med. 2002;347:322-329.

44. Endothelin Antagonists (ERAs) Oral –“Nonselective” ERA/ERB Bosentan* –“Selective” ERA Ambrisentan * Sitaxsentan † * FDA approved † Investigational/in development

45. Bosentan (Tracleer) Indication PAH with WHO Class III (or II - IV) symptoms “to improve exercise capacity and decrease the rate of clinical worsening” Dose 62.5 mg BID oral for 4 weeks 125 mg BID oral thereafter if liver functions OK Costs ~$36,000/year Contraindicated with glyburide and cyclosporine

46. EARLY trial: Bosentan in NYHA class II Galie N et al. Lancet 2008; 371: 2093-2100

47. Bosentan Monitoring Liver enzymes: initial and monthly (stop if >5x elevation) reversible with cessation; can try rechallenge with lower dose Watch for leg edema/pulmonary edema/nasal congestion Hemoglobin: initial, 1 and 3 months May interfere with hormonal birth control; barrier method advised Caveat: Response takes time (up to 2 to 3 months), should be used with caution in Class IV patients and not without right heart catheterization to document presence of PAH

48. Ambrisentan (Letairis) Indication PAH with WHO Class II - III symptoms “to improve exercise capacity and decrease the rate of clinical worsening” Dose 5 mg qD Consider increasing to 10 mg qD if tolerated Costs ~$36,000/year Contraindicated with cyclosporine

49. Which ERA? FDA approved: both Cost: similar Dosing: BID (bosentan) vs QD (ambrisentan) Sildenafil interaction (bosentan) LFT issue: 11% bosentan vs 2-3% ambrisentan 1. Galie N, et al. Presented at: the Annual Meeting of the American Thoracic Society; May 20, 2005; San Diego, CA

50. PDE 5 Inhibitors Oral – Sildenafil* – Tadalafil † * FDA approved † Investigational/in development

51. Sildenafil FDA approved in June 2005 for PAH (WHO Group 1) “to improve exercise ability” regardless of functional class Must not be used with nitrates, but compatible with other drugs Metabolized by liver (CYP3A4 isoenzyme), slowed in cirrhotics, no effect of renal failure Oral and relatively inexpensive (~ $12,000/year) Side effects: headache, Blue haze periphery of vision in up to 11%

52. *p<0.0001 * * * Sildenafil in PAH: SUPER-1, 6-Minute Walk Test Change from Baseline to Week 12 45 m 46 m50 m n=278 Change from Baseline (m) Ghofrani HA, et al. Presented at: the 20th Annual Meeting of the American College of Chest Physicians; October 23, 2004; Seattle, Washington.

53. Exercise Capacity at Week 12 and 1 Year Mean = 50 m Mean = 54 m Rubin L, et al. Presented at: the Annual Meeting of the American Thoracic Society; May 20, 2005; San Diego, CA.

54. Investigational Protocols Vasodilator Study Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Continue CCB Higher Risk Sustained Response Positive Lower Risk Yes Negative What is the Optimal Treatment Strategy? Atrial septostomy Lung Transplant Reassess – consider combo-therapy ERAs or PDE-5 Is (oral) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) Treprostinil (SC) No Epoprostenol or Treprostinil (IV) Iloprost (inhaled) ERAs or PDE-5 Is (oral) Treprostinil (SC) McLaughlin VV and McGoon M. Circulation. 2006;114:1417-1431.

55. Rx of Heart Failure Jessup M, Brozena S. N Engl J Med. 2003;348:2007-2018. Stage A High risk with no symptoms Stage B Structural heart disease, no symptoms Stage C Structural disease, previous or current symptoms Stage D Refractory symptoms requiring special intervention Risk factor reduction, patient and family education Treat hypertension, diabetes, dyslipidemia; ACE inhibitors or ARBs in some patients ACE inhibitors or ARBs in all patients; beta-blockers in selected patients ACE inhibitors and beta-blockers in all patients Dietary sodium restriction, diuretics, and digoxin Cardiac resynchronization if bundle-branch block present Revascularization, mitral-valve surgery Consider multidisciplinary team Aldosterone antagonist, nesinitide Inotropes VAD, transplantation Hospice

56. Early, Risk-based and Combination Therapy: Changing Paradigms for PAH?

57. Rx of Pulmonary Hypertension Stage A High risk with no symptoms Stage B PAH with + VDC Stage C PAH with - VDC Low Risk Stage D Refractory symptoms requiring special intervention Risk factor reduction, patient and family education Calcium Channel Blockers Bosentan +/- Sildenafil +/- Ventavis Dietary sodium restriction, diuretics Aldactone and digoxin IV meds (Flolan or Trepostonil) Consider multidisciplinary team Inotropes, atrial septostomy Transplantation Hospice Stage C PAH with - VDC High Risk Combination therapy Sleep apnea, Obesity, Uncontrolled hypertension and/or depress LVEF, drug abuse

58. Hoeper et al. Eur Respir J. 2005;26:858-863. Goal-Oriented Therapy Diagnosis of PAH Vasoreactivity test negative NYHA II or IV Baseline examination and 3-to-6-month reevaluation to assess treatment goals (6MWD >380 m, peak VO 2 >10.4 mL/min/kg, peak systolic BP >120 mm Hg during exercise) Treatment goals not met First-line treatment bosentan Treatment continued Addition of sildenafil Treatment continued Addition of inhaled iloprost Treatment continued Transition from inhaled to intravenous iloprost Treatment continued Highly urgent lung transplantation

59. Traditional therapies; diuretics, oxygen, phlebotomy still used as indicated; anticoagulants recommended Calcium Channel Blockers should be used in Class II or III acute responders but followed closely for safety & efficacy Newer agents are tailored to WHO class – ACCP Guidelines –Class IV – Infused prostacyclins –Class III – Oral endothelin receptor antagonists (ERAs), phosphodiesterase (PDE) 5 inhibitors, infused or inhaled prostacyclins –Class II – PDE 5 inhibitors, or ERAs Consider therapy if evidence of Right Ventricular Dysfunction Combination therapies and an array of investigational therapies hold hope for the future Role of transplantation/septostomy now diminished because of new effective pharmacologic therapies Summary: T reatment

60. Rubin, L. J. et. al. Ann Intern Med 2005;143:282 - 292 Indications for Referral to a Specialized Center forRxof PAH Unexplained dyspnea on exertion with evidence of PH on Echo Evidence of moderate to severe PH Estimated PAS pressure > 45 mm Hg on Echo Symptoms consistent with NYHA functional class II or worse Near-syncope or syncope Absence of substantial left-sided cardiac disease or parenchymal lung disease Clinical or echocardiographic evidence of RV dysfunction Lower-extremity edema Ascites Right ventricular enlargement or systolic dysfunction on echocardiography

61. veronica.franco@osumc.edu veronica.franco@osumc.edu 614-293-4967

64. Rubin, L. J. et. al. Ann Intern Med 2005;143:282 - 292 The Role of PCP inDxand Coordinated Care of PAH RECOGNIZE possible PAH in the pt w unexplained DOE INITIATE appropriate SCREENING CXR, PFT, Echo, VQ, Oximetry FACILITATE appropriate referral to specialty center Contact the specialist in PAH Obtain referrals and approvals from pt’s insurer Provide pt’s records to the specialty center PROVIDE regular FOLLOW UP in the pt’s local community Assess volume status, vital signs and oxygenation Monitor lab tests : E-lytes,LFTs, BUN/Cr Manage anticoagulation for INR 2-3 PROVIDE EMERGENCY CARE in the pt’s local community

65. Adapted from Gaine S. J Am Med Assoc 2000;284:3160-68 Normal Artery Reversible Disease Irreversible Disease PAH: A Progressive Vasculopathy Stop progression and Reverse Disease

66. IPAH: Contrast enhanced CT shows dilated pulmonary artery with mosaic attenuation in the lung parenchyma. Non-PAH: Severe ILD: Coarse reticular changes with honeycombing suggesting pulmonary fibrosis in the lower lobes in this patient with IPF Using Appropriate Diagnostic Strategies for Appropriate Patient Types: HRCT

67. Other Investigational Therapies Statins (HMG coreductase inhibitors) K+ channel openers NO donors Rho kinase inhibitors Tyrosine kinase inhibitors Angiogenesis factors Gene therapy –NOS, K+ channel openers Serotonin receptor antagonists Inhaled vasoactive intestinal peptide

68. Subcutaneous Patient No Low No Hours MinutesHalf-life Yes (no ice)YesBulky pump High Risk of serious infections, including sepsis LowHigh Risk of cardiovascular collapse NoYes Sterile conditions for frequent drug constitution required Yes Thrombus Surgical Implant of catheter Intravenous Delivery of drug TrepostinilEpoprostenolCharacteristic Subcutaneous Treprostinil: Potential Advantages Over IV

69. Indications for SC Treprostinil PAH with WHO Class II to IV symptoms Cost ~$60,000 to $120,000/year (exclusive of costs for administration/monitoring; IV more expensive)

70. Treprostinil Sodium Injection Administered via continuous infusion using an ambulatory pump designed for subcutaneous infusions Administered via a self- inserted subcutaneous catheter Patients must have immediate access to backup infusion pump to prevent the risk of worsening of PAH symptoms due to interruption of therapy

71. Smooth muscle cell vasoconstriction Smooth muscle cell proliferation ? Apoptosis The Endothelin System SMC ET B EC ET B Receptor ET A Trp Ile AspLeuHisCys Tyr ValPheCys Ser Glu Ser Leu Met Asp Lys N C ET converting enzyme ET-1 Big ET-1 sitaxsentan ambrisentan bosentan  Circulating ET-1 levels in PAH  PA endothelial cell expression in PPH

72. Summary: Use of Clinical Parameters, Hemodynamics, and Imaging Techniques to Predict Survival and Therapeutic Options High index of suspicion Thorough diagnostic evaluation, need RHC Exclude thromboembolic disease Vasodilator testing to eliminate inappropriate CCB use

73. Placebo 44 meters