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  • 1. Targeting Pulmonary Hypertension in Thromboembolic disease, Left heart disease and Pulmonary disorders Ashok Kirumaki MD Director Pulmonary Hypertension Program Assistant Professor Pulmonary, Critical Care and Sleep Department of Internal Medicine Saint Louis University
  • 2. No Financial Disclosures
  • 3. Learning Objectives• Classification and Brief overview of PAH• Pulmonary hypertension in Left heart disease• Pulmonary hypertension in venous thromboembolism• Pulmonary hypertension in common lung disease – COPD
  • 4. Definition of Pulmonary Hypertension PH Mean PAP ≥ 25 mm Hg PAH Mean PAP ≥ 25 mm Hg plus PCWP/LVEDP ≤ 15 mm Hg (Absent) AHA -PVR > 3 Wood Units Badesch D et al. J Am Coll Cardiol. 2009; 54 S55- S66
  • 5. (Dana Point) CLINICAL CLASSIFICATION 2009 ARTERIAL HYPOXIA THROMBI VENOUS Simonneau G et al. J Am Coll Cardiol. 2009 ; 54 ; S 43- S54
  • 6. LOCATION OF OBSTRUCTION Pre Postcapillary capillary capillary TO SYSTEMIC CIRCULATION Pulmonary Chronic Arterial lung Pulmonaryhypertension disease venous CTEPH
  • 7. PATHOGENESIS OF PULMONARY ARTERIAL HYPERTENSION Smooth muscle hypertrophy Intimal proliferationGOOD FLOW ADVANCED VASULAR REVERSIBLE PLEXIFORM LESIONS VASOCONSTRICTION IRREVERSIBLE DISEASE NORMAL
  • 8. DIAGNOSTIC APPROACH TO PULMONARY HYPERTENSION
  • 9. PAH treatment GoalsFewer / Less severe symptomsImproved exercise capacityImproved hemodynamicsPrevention of clinical worseningImproved quality of lifeImproved survival
  • 10. ACCP Consensus : Definition of a responder PAP mean decreased by 10 mm Hg &Fall in PA Mean pressure < 40 mm Hg & No change or increase in cardiac output
  • 11. Survival in IPAH – (50% of acute responders or ≤ 6% of IPAH patients ) p = 0.0007 Sitbon O et al. Circulation 2005;111:3105-3111Copyright © American Heart Association
  • 12. Calcium Channel Blockers ONLY if “ Vasodilator Responsive”Pulmonary Vasodilation Systemic vasodilation Neg Inotropy↑cardiac output ↓cardiac outputHighly Varibale –Needing larger dosesInfluenced by the drug and the diseaseRisks of getting it wrong : tachycardia,dyspnea ,syncope and death Key PointCCBs should NOT be used empirically
  • 13. FDA approved Medications for PAH with their mechanisms of action Endothelin 1 Nitric OxideBosentan SildenafilAmbrisentan Tadalafil
  • 14. PROSTACYCLIN ANALOGUES Iloprost Treprostinil TreprostinilEpoprostenol Treprostinil
  • 15. What is the Optimal Treatment Strategy?
  • 16. Etiology of pulmonary hypertension on EchocardiogramKEY POINT --- PAH 2.3% majority in the patients are left heart disease and pulmonary disease
  • 17. PH due to left heart disease WHO group II • Due to systolic dysfunction--- heart failure with reduced ejection fraction HFREF • Due to diastolic dysfunction- Heart failure with Preserved Ejection fraction HFPEF • Due to valvular heart disease – Aortic or Mitral valve disease
  • 18. Pathogenesis of PH in Left heart disease • Passive process-- backward transmission of elevated Left atrial pressure (LAP) • Reactive (Out of Proportion)--Chronically elevated LAP with lead to pulmonary vascular remodeling causing functional and or structural abnormalities of distal pulmonary arteries • Fixed- medial hypertrophy and intimal fibrosis
  • 19. PH is present in 2/3rd of patients with heart failure with reduced ejection fraction Low pap/nl RV Low pap/low RVEF High PAP/nl RVEF High PAP /low RVEF (J Am Coll Cardiol 2001;37:183–8)
  • 20. Pre-transplant pulmonary hypertension, evenwhen reversible to a PVR of <2.5 WU, isassociated with a higher mortality J Heart Lung Transplant 2005;24:170 –7
  • 21. Fixed Pulmonary hypertension in acontraindication to heart transplantation alone This group of patients will need heart and lung transplantation
  • 22. FIRST TRIAL -EPOPROSTENOLA randomized controlled trial of epoprostenoltherapy for severe congestive heart failure: TheFlolan International Randomized Survival Trial(FIRST) 471 PATIENTS WITH ADVANCED HFREF CONTINUOUS EPOPROSTENOL STANDARD OF CARE INFUSION + STANDARD OF CARE American Heart Journal - Volume 134, Issue 1 (July 1997)
  • 23. Increased mortality rates and no evidence of improved quality of life American Heart Journal - Volume 134, Issue 1 (July 1997)
  • 24. CHRONIC USE OF EPOPROSTENOL IN PATINETS WITH HEART FAILURE IS CONTRAINDICATED American Heart Journal - Volume 134, Issue 1 (July 1997)
  • 25. Endothelin Receptor Antagonists• Endothelin plasma levels are elevated in heart failure and correlate with severity• In animal models of HF – ERAs prevented LV remodeling and improved exercise capacity• Short-term hemodynamic effects were encouraging with ERA bosentan and tezosentan which led to RCT
  • 26. Research on Endothelein Antagonists in Chronic Heart Failure (REACH -1) NYHA class III /IV 370 patinet Heart failure Randomized BOSENTAN PLACEBO 500MG BID 26 WEEKS STOPPED PREMATURELY – SAFETY ELEVATED LIVER FUNCTION TEST European Journal of Heart Failure 1999;1:197-200
  • 27. Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE) NYHA class III /IV 1613 Patients Heart failure EF< 35% BOSENTAN PLACEBO 125 MG BID 1.No improvements in Outcomes 2.Increased risk of early heart failure exacerbation due to fluid retention with Bosentan
  • 28. Sildenafil Improves Exercise Capacity and Quality of Life in Patients with Systolic heart failure with pulmonary Hypertension Randomized to 12 weeks of treatment with Sildenafil (50 mg orally 3 times daily) or placebo Improvement in 6-minute walk distance (29 m versus placebo; P 0.047) and Minnesota Living With Heart Failure score (14 versus placebo; P 0.01) Sildenafil group experienced fewer hospitalizations for HF Circulation. 2007;116:1555-1562
  • 29. PDE 5 inhibitor in heart failure• NO RCT has looked into long term use of this class of drugs in pulmonary Hypertension due to HFpEF
  • 30. Management of PulmonaryHypertension due to left heart disease• Optimizing traditional therapies for Heart failure• Out of proportion Pulmonary hypertension – look for other causes –V/Q scan, PFT and PSG• RHC can be done to clarify hemodynamic details• NO CLEAR INDICATIONS FOR ADDITIONAL PAH specific therapies
  • 31. NO evidence that Drugs approved forPAH are effective or safe in this settingMedications that lower PVR increase flow andthis increase in venous return to the leftventricle may increase left ventricular fillingpressure resulting in deterioration rather thanimprovement
  • 32. HF with Preserved EF -- HEFPFOccurs with the Left ventricle is unable toaccommodate an adequate volume of bloodduring diastole and maintain an appropriatestroke volumeCommonly due to Left ventricular diastolicdysfunction
  • 33. Risk factors• Post menopausal Women• Hypertension• Ischemic Heart Disease• Diabetes Mellitus• Obesity• Atrial fibrillation• Age --- 50% in HF patient greater than 70 years
  • 34. RHC – in HFPEFPCWP – may be borderline high at restSaline challenge or exercise challenge in thissetting may induce an increase of PCWPNo consensus on protocols for either saline orexercise testing
  • 35. Pulmonary hypertension with preserved ejection fraction work up Page 32
  • 36. Even after normalization of the left atrial pressureWhether modification of the metabolicsyndrome featuresdietary modification, weight reduction andaggressive blood pressure controlresults in improvements in patients symptomsand PAP with HFPEF with elevated pap is stillunknown?RELAX trial – ongoing – Sildenafil in HFPEF
  • 37. Summary - WHO class II• Optimizing traditional therapies for Heart failure• NO PAH medication is FDA approved and may be harmful• Remember a normal PCWP at rest does not rule out Diastolic heart failure as the cause of Pulmonary hypertension
  • 38. Definition of CTEPH WHO class IV• At least 3 months of effective anticoagulation• Mean pulmonary artery pressure ≥ 25 mmhg and PCWP ≤ 15 mmhg• One of more mismatched segmental or large perfusion defects detected by V/Q scanning, pulmonary angiography or multidetector CT angiography
  • 39. Natural history of Acute PE• Total or near total resolution and restoration of normal pulmonary hemodynamics within 30 days in more than 90 percent of patients.• Right heart pressures return to near normal values in most patients within 10 to 21 days.• A minority of patients who have survived an acute PE develop CTEPH
  • 40. Acute PE – clot removed from Trendlenberg embolectomy
  • 41. CTEPH – white fibrotic clot
  • 42. Incidence of Symptomatic CTEPH 1.0 % at 6 months 3.1 % at 1 year 3.8 % at 2 years No cases after 2 years -10 year follow up N Engl J Med 2004;350:2257-64.
  • 43. CTEPH is a dual vascular disorder• Obstruction of the vascular bed by non resolving or recurrent thromboembolism or in situ pulmonary-artery thrombosis• In the non occluded areas pulmonary vascular remodeling and the development of a hypertensive pulmonary arteriopathy are seen• The extent of vascular obstruction is a major determinant of pulmonary hypertension• In majority of patients, more than 40 percent of the pulmonary vascular bed is obstructed.
  • 44. Natural History of CTEPH• “Honey-moon” period of months to years, during which the patient has no clinical symptoms• For this reason, the early natural history of the condition is not completely known• 25-30 % deny previous symptoms or diagnosis of VTE• Estimated from PE registries 0.1- 9.1%
  • 45. Presentation• Nonspecific symptoms including exercise intolerance and dyspnea, chest pain, fatigue and syncope• Most patients with chronic thromboembolic pulmonary hypertension present late in the course of the disease with Progressive dyspnea, hypoxemia and Right ventricular failure
  • 46. RISK factors for CTEPH• Traditional plasmatic prothrombotic risk factors are not risk factors for CTEPH• A negative CT PE protocol does not rule out CTEPH however a negative V/Q scan rules out this disorder
  • 47. Risk factors -Observational case –control analysis • History of splenectomy • VA shunts and pacemakers with history of device infection • IBD • Thyroid hormone replacement • Circulating antiphospholipid antibody • Survived cancer • Non-O blood groups • Elevated plasma coagulation factor VIII • Carriers of Fibrinogen A alpha THr312a1a polymorphism
  • 48. CTEPH patients with history of splenectomy, infected VA shunt,inflammatory bowel disease or osteomyelitis have worse outcomecompared to one without a clinical risk factor Circulation. 2007;115:2153-2158
  • 49. Predictors of Outcome in Chronic Thromboembolic Pulmonary HypertensionDiana Bonderman, MD; Nika Skoro-Sajer, MD; Johannes Jakowitsch, PhD;Christopher Adlbrecht, MD; Daniela Dunkler, MSc;Sharokh Taghavi, MD; Walter Klepetko, MD;Meinhard Kneussl, MD; Irene M. Lang, MDThe presence of associated medical conditionspredicts increased operative risk and worse long-term outcome in CTEPH. Circulation. 2007;115:2153-2158
  • 50. Pulmonary Thromboendarterectomy Pulmonary Endarterectomy is the treatment of choice Curative in patients with CTEPH Operable mortality rates in specialized centers is < 5% but 36 % are non operableN Engl J Med, Vol. 345, No. 20 November 15, 2001
  • 51. Long-term Outcome after Pulmonary Endarterectomy1994 and 2006,157 patients Long-term survival after PEA is excellent Am J Respir Crit Care Med Vol 178. pp 419–424, 2008
  • 52. Long-term Outcome after Pulmonary Endarterectomy 75% of patients, the long-term functional outcome was good and almost a half of the patients recovered good exercise tolerance. Am J Respir Crit Care Med Vol 178. pp 419–424, 2008
  • 53. Candidates for Endarterectomy• Confirmed CTEPH in NYHA class II, Class III and class IV• A preoperative PVR > 300 dynes.s.cm-5• Proximal disease – Thrombi in the main lobar or segmental pulmonary arteries• Absence of severe comorbidities• 40% of all newly diagnosed patients are currently on PAH vasodilator treatment in clinical trials in Europe
  • 54. BENEFiT STUDYBosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a Randomized, Placebo- Controlled Trial 16 week study Symptomatic Inoperable CTEPH with 6MWD<450m J Am Coll Cardiol. 2008;52(25):2127-2134
  • 55. Bosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary Hypertension TREATMENT effect 1.Statistically significant decrease in PVR and hemodynamic improvement BNP NO CHANGE IN 6MWD J Am Coll Cardiol. 2008;52(25):2127-2134
  • 56. Ongoing multicenter trials in CTEPH• CTREPH--- subcutaneous Treprostinil• CHEST– Riociguat• Ongoing Vasodilator trials in patients with nonoperable CTEPH will clarify whether medical therapy for CTEPH is effective
  • 57. Pulmonary hypertension associated withlung disease or Hypoxemia WHO Group III • COPD • ILD • Alveolar hypoventilation disorder • Sleep apnea
  • 58. Pathogenesis of Pulmonary hypertension in COPD
  • 59. Pulmonary Hypertension and COPD• PH when present in patients with severe COPD is mild to moderate - extremely prevalentMild (PAP 26–35 mmHg)Moderate (36–45 mmHg)Severe (45 mmHg)• In patients listed for LVRS or lung transplantation the prevalence of PH would lie between 70–90%.
  • 60. Natural History of PH in COPD• PH may first appear during exercise and during sleep• PH occurs in COPD - cardiac output is usually normal and PVR increases mildly• The main feature of PH in COPD is it mild to moderate degree 20-35 mmHg
  • 61. Suspect PH In COPD if• Distinctive PFT pattern with less severe airflow obstruction but more severe hypoxemia, hypocapnia and markedly reduced DLCO• PH even if mild at baseline may worsen in sleep , during exercise and during acute exacerbation of the disease
  • 62. The progression of pH in COPD is generally slow and PAP usually remains stable over 2-5 years The level of PAP is a good indicator of prognosis Thorax 1981 ;36:752-758 Weitzenblum, Hirth, Ducolone, Mirhom, Rasaholinjanahary, Ehrhart
  • 63. Survival of patinets with pulmonary hypertension withno other cause and COPD in 3 groups PAP > 40 mmHg , Between 40 and 20 ,and < 20 mmHg Ari Chaouat, et al Am J Respir Crit Care Med Vol 172. pp 189–194, 2005
  • 64. Sleep and COPD• Some patients experience transient arterial hypoxemia during REM sleep• Not related to apneas but alveolar hypoventilation or V/Q mismatch• The more profound the dips of hypoxemia the more severe the peaks of PH• Home oxygen protocol reduced mean PAP in 8 weeks of therapy
  • 65. Treatment of PH in COPD is based on oxygen therapyLTOT –Long term Oxygen therapy for greater than 18 hours per day significantly decreased resting and exercise PAP after 6 months of use NOTT –Nocturnal Oxygen therapy trial MRC – Medical research council study
  • 66. The oral administration of the endothelinreceptor antagonist bosentan not only failed toimprove exercise capacity but also deterioratedhypoxemia and functional status in severechronic obstructive pulmonary disease patients Eur Respir J 2008; 32: 619–628
  • 67. Key points of PH in COPD• A pap pressure of >40 mmhg is unusual in a stable state of COPD with PH• PH even if mild at baseline may worsen in sleep , during exercise and during acute exacerbation of the disease
  • 68. Summary• PAH – pulmonary arterial hypertension is present in 2.3 % and is relatively uncommon and most patinet (90%) with PH are not appropriate for therapies with PAH specific medication .• No PAH medication is approved in patients with left heart disease, COPD or CTEPH and in fact is likely to cause harm in these settings.
  • 69. Summary• A normal PCWP on RHC at rest does not rule out Diastolic dysfunction as the cause of PH• CTEPH is a dual vascular disease with risk factors very different from acute PE• A negative V/Q scan (and not CT PE protocol) is needed to rule out CTEPH• Pulmonary endarterectomy is the treatment of choice in CTEPH and is curative
  • 70. Summary• In COPD patinets PH is usually seen in advanced disease and is usually mild with PAP less than 40 mmHg but worsens in REM sleep, periods of acute exacerbation and with exertion and has poor prognosis• No Role for PAH specific therapies in patinets with PH due to left heart disease,COPD or CTEPH except in an approved clinical trial
  • 71. Thank you Thank You