Unraveling Pulmonary Artery Hypertension: Diagnosis, Management, and Prognosis

1. Grand Rounds March 2005 “I Forgot I was Breathless” Michael Hayes

2. Mrs HJ • 44 yo • Married • BMI 40 • Smoker 20 pack years • Presenting with progressive dyspnoea over 2 years

3. Background • Childhood • brain tumour • Hydrocephalus → shunt • Epilepsy • Controlled • Chronic short term memory difficulties

4. Background (cont.) • 1991 surgical revision of VP shunt • Post op DVT

5. Background (cont.) • 2002 unprovoked DVT left leg • Warfarin commenced • Thrombophilia screen • Uncertain hx of sister DVT • Post phlebitic syndrome

6. Background (cont.) • Dyspnoea mid 2003 (still on warfarin) • No chest pain, cough or haemoptysis • No orthopnoea or PND • Hx of snoring, witnessed apnoeas, fatigue

7. Ix • CXR and ECG • CT chest 2001 and 2004 • ↓ volume L lung. LLL changes • V/Q scans • CTPA • Sleep study – OSA but intolerant of CPAP • Spiro normal 2003

8. Further assessment 2004 • Profound hypoxia 91% on 2 litres at rest 76% after walking 20 metres • Examination – little to find • ECG

10. PFT’s

11. Diagnosis ?

12. Echocardiogram • RV dilation and hypertrophy • PAP 50-55 mmHg • PFO with R to L shunting on standing and exercise • “orthodeoxia”

13. Pulmonary Artery Hypertension • Cause in this woman ?

14. Treatment • Long term oxygen therapy • Continued warfarin

15. Progress • Worsening exercise tolerance • Retrosternal chest pains – nocturnal • odynophagia • Dry cough – post tussive vomiting • No benefit from PPI • Pertussis serology negative

16. Admission • Gastroscope • Mild oesophagitis. Monilial plaques • Small sliding HH • Reassess PAH • Echo PAP now 75-80mmHg • 6 min walk 187 metres

17. Admission • Telangiectases on hands • No other signs of connective tissue dx • ANA 1:640 • Anti-centromere antobodies • other ENA negative ? significance

18. Management • Right heart catheter • Bosentan (endothelin receptor antagonist)

19. Pulmonary Artery Hypertension Pulmonary artery hypertension is present when mean pulmonary artery pressure exceeds 25 mmHg at rest, or 30 mmHg with exercise.

20. Types • Primary • Secondary

21. Ohm’s law • Δ pressure = flow х resistance • Ppa – Ppv = Q х PVR • Ppa = (Q х PVR) + Ppv

22. Secondary Causes • Hypoxic vasoconstriction • COPD, Hypoventilation disorders • Decreased area of pulm vascular bed • large artery obstruction – PE • small artery obstruction – PE, CT disease, vasculitis • Volume & pressure overload • ASD, VSD • LA hypertension – MS or MR, LV dysfunction • Pulmonary venoocclusive dx

23. Other Causes • familial • Amphetamines • HIV • Anorectic drugs • HHV-8 • Portal hypertension

24. Primary • Diagnosis of exclusion • PAH with no other secondary cause

25. PAH begets PAH • Initial cellular/molecular mechanisms vary • Final common pathway • Endothelial dysfunction • Oxidative damage • Impaired vascular smooth muscle regulation • Muscularisation, intimal hypertrophy, intimal hyperplasia

26. Clinical Features • Dyspnoea on exertion • Progressive • Fatigue / lethargy • Exertional chest pain • Presyncope or syncope • Signs of RVF

27. Examination • Widening & fixed splitting of S2 • Increased intensity P2 • A right ventricular heave • Jugular venous distension • Prominent A and V wave venous pulsations • A right ventricular S3 • Murmurs of tricuspid regurgitation or pulmonic insufficiency • Peripheral edema • Hepatomegaly • Ascites

29. Role of Echo • Echocardiography commonly provides the initial objective evidence for pulmonary artery hypertension

30. Echo • Far more sensitive than the clinical examination • Himelman RB et al. Am J Med 1988 • 33 COPD • Cor pulmonale defined as PAH + RV hyper identified in 39% clinically (exam, ECG, CXR) • 75% by echo

31. Echocardiography • Berger M et al. J Am Coll Cardiol 1985 • PAP > 35mmHg • 80% sensitivity • PAP > 50mmHg • 95% sensitivity • 97% correlate of measured pressure with R heart catheter Exercise echo increase sensitivity

32. R Heart Catheter • Gold standard • Diagnosis and quantification • Indications • Echo doesn’t permit measurement of TR jet • Verify presence and severity of L to R shunts • ? When therapy is determined by precise measurement of PVR and response to vasodilators • Highly suspected and noninvasive is not definitive

33. PFT’s • Most have ↓ DLCO • Normal does not exclude PAH • Often a mild restrictive deficit

34. Often delayed diagnosis • Subtle clinical signs initially • PPAH - average 2.5 yrs from symptoms till diagnosis • SPAH - manifestations often masked by underlying aetiology

35. Important ! • The status of the pulmonary vascular bed should be considered in any patient with dyspnoea in whom no compelling cause can be established.

36. PPAH - terrible disease • Mean survival from diagnosis is 3 years for PPAH • Severe PAH or RVF tend to die in 1 year • Development of SPAH worsens prognosis in many of the causative conditions

37. Treatment • SPAH • Treat underlying disease • Prior to irreversible damage • Specific interventional and medical therapies can correct PAH

38. Treatment • O2 therapy • Anticoagulation • Ca2+ blockers • Prostacyclin • Endothelin receptor antagonists (Bosentan) • Phosphodiesterase inhibitors • Transplant

39. Oxygen • Used in COPD • Good evidence for improved survival • Use extrapolated to other groups of patients with SPAH

40. Anticoagulation • Some evidence of improved survival in PPAH if non-uniform blood flow on perfusion scan • Clearly indicated with chronic PE • Some investigators recommend in all cases of SPAH

41. Ca2+ antagonists • Use in PPAH only • Need haemodynamic study to identify response to vasodilators • 25 – 30% of patients • Evidence for survival benefit in “reponders”

42. Prostacyclin • Good evidence for improved survival in PPAH • Evidence for improved functional capacity in SPAH – limited use • Continuous infusion • Inhaled prostacyclin analogue • Oral analogue

43. Bosentan • Endothelin receptor antagonist • Endothelin is potent vasoconstrictor and proliferative agent • Is over-expressed in lungs in PPAH • Increased plasma levels in PPAH, IPF, CT disease

44. Proven efficacy of bosentan in PPAH • Clinical studies in PPAH show: • Improved hemodynamics, exercise capacityand WHO functional class 1,2 • Delay in time to clinical worsening 2 • Improvements in RV and LV function andpositive effects on cardiac remodeling 3 • Efficacy maintained over time with stableWHO functional class (1 yr) 2,4 • Improved Survival and QoL5,6 • 1 Channick et al. 2001 2 Rubin et al. 2002 3 Galié et al. 2003 4 Sitbon et al. 2003 5 Mc Laughlin et al. 2003 6 Keogh et al. 2004

45. Improves survival • McLaughlin et al. Eur. Resp. Journal Feb 2005 • 3 year follow-up of 169 pts with PPAH • Pts enrolled in 2 studies of bosentan as first line therapy

46. 100 90 Observed1 80 70 60 % of event-free patients 50 Predicted(NIH2) 40 30 20 Event Rate / year (exponential): 5.5% 10 0 0 6 12 18 24 30 36 months 169 167 163 153 113 23 16 Patients at risk 1Mc Laughlin et al. Am J Respir Crit Care Med 2003;167:441 2 D’Alonzo et al, Ann Intern Med 1991;115:343 Bosentan long-term outcome Kaplan-Meier survival estimates with 99% CIfor observed vs predicted survival

47. Of initial cohort 78% and 55% were alive and on bosentan monotherapy at 1 and 2 years • Major adverse effect was transaminitis in up to 14%

48. Summary • PAH is a difficult diagnosis to make. Suspect it! • Echocardiography is good investigation along with CXR, ECG, PFT’s • Now therapies with reasonable evidence of efficacy