Chronic thromboembolic pulmonary hypertension


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Chronic thromboembolic pulmonary hypertension

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Chronic thromboembolic pulmonary hypertension

  1. 1. An overview of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Sarfraz Saleemi MRCP FCCP Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia
  2. 2. WHO Classification- Dana Point 2008 Group 1: Pulmonary Arterial Hypertension Group 2: Pulmonary Hypertension Owing to Left Heart Disease Group 3: Pulmonary Hypertension Owing to Lung Diseases and/or Hypoxia Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Group 5: Pulmonary Hypertension With Unclear or Multifactorial Etiologies
  3. 3. The Association for Research in CTEPH is based in Basel, Switzerland and can be contacted as follows: Association for Research in CTEPH c/o artax Fide Consult AG Gartenstrasse 95 CH-4002 Basel, Switzerland e-Mail: Phone:+ 41 (0)61 225 66 66Fax:+ 41 (0)61 225 66 67
  4. 4. First international registry on chronic thromboembolic pulmonary hypertension (CTEPH) Prof. Dr Gerald Simonneau,, MD1, Prof. Dr Marion Delcroix,, MD2, Prof. Dr Eckhard Mayer,, MD3, Prof. Dr Irene Lang,, MD3 and Dr. Joanna Pepke-Zaba,, MD5. 1Service Pneumologie, Hopital Antoine Beclere, Paris, France; 2Pneumology, University Hospital Gasthuisberg, Leuven Belgium; 3Thoracic Surgery, Catholic Hospital Mainz SHK, Mainz, Germany; 4Cardiology, Medical University of Vienna, Vienna, Austria and Pulmonary Vascular Disease Unit, Papworth Hospital, Cambridge, United Kingdom. 42 registered sites in 20 European countries and Canada
  5. 5. Unique form of pulmonary hypertension amenable to curative intervention. Ann Thorac Surg 2007;83:1075– 81
  6. 6. Epidemiology of CTEPH: old studies Estimated incidence: 0.1-0.5% of patients with PE    Moser KM, et al Circulation. 1990;81:1735-43 Jamieson SW, Kapelanski DP. Curr Probl Surg. 2000; 37:165-252 Fedullo RF, et al. New Engl J Med. 2001;345:1465-72
  7. 7. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism Pengo V, et al. N Engl J Med. 2004; 350:2257-64  7/223 patients (5 patients in NYHA class II, 2 patients in NYHA class III) None of the remaining patients developed CTEPH after 2 years Cumulative incidence Of CTEPH 3 months 0% 6 months 1.0% 1 year 3.1% 2 years 3.8% Cumulative incidence of CTEPH (%)  *90% CI = 1.1 – 6.5 Pengo V, et al. N Engl J Med. 2004; 350:2257-64
  8. 8. Proposed annual incidence of CTEPH in USA DIAGNOSED PE 600,000 CTEPH 25,000
  9. 9. Survival without treatment- CTEPH mPAP 31-40 mmHg - 5-years survival 45% mPAP 41-50 mmHg - 5-years survival 33% mPAP >50 mmHg - 5-years survival 14% 26 patients Follow up 15 yrs
  10. 10. Survival   49 CTEPH patients treated only with anticoagulants 3-year mortality of 90% when the mean pulmonary artery pressure was ≥ 30 mm Hg. Lewczuk J et al. Chest. 2001;119:818–823
  11. 11. Pathophysiology of CTEPH VTE/DVT PE Obstructed pulmonary vessels Honeymoon period Thrombus organization in occluded vessels Shear forces in non-occluded vessels Small vessel arteriopathy in non-occluded circulation PVR Progressive pulmonary hypertension Curr opin cardiol 2008, Nov;23(6) Right heart failure
  12. 12. Pathophysiology Why thrombus does not resolve in CTEPH is not known    Misguided thrombus resolution triggered by infection (staphylococcus) , inflammation, autoimmunity and malignancy Abnormal fibrin resistant to fibrinolysis Fibrinogen Aa Thr 312 Ala allele and genotype J Suntharalingam et al Bonderman D et al. rterioscler Thromb Vasc Biol 2008; 28: 678–684.
  13. 13. Risk factors for CTEPH 687 patients assessed at the time of diagnosis between 1996 and 2007 VA-shunts and infected pacemakers Splenectomy Previous venous thromboembolism (VTE) Recurrent VTE Blood groups non-0 Lupus anticoagulant/anti-phosph antibodies History of malignancy Thyroid replacement therapy p<0.001 p=0.017 p<0.001 p<0.001 p=0.019 p=0.004 p=0.005 p<0.001 ERJ Express Published on September 17, 2008
  14. 14. Other Potential predictors of CTPH        Age Persistent residual embolism Idiopathic PE Severity of perfusion defect Right ventricular dysfunction Myeloproliferative syndromes Chronic Inflammatory disease (IBD, Osteomyelits) Thromb Haemost. 2005;93:512-516. Pengo V, et al, N Engl J Med 2004;350:2257-64
  15. 15. CTEPH and history of VTE  142 consecutive patients with CTEP 63% did not have a history of symptomatic VTE at presentation. N Engl J Med 2004;350:2236–2238  500 consecutive PEA cases at UCSD Only 45% of CTEPH patients had a history of VTE Ann Thorac Surg. 2003;76:1457-1464  Perfusion lung scans in 622 outpatients with proximal DVT confirmed by venography and no clinical indication of PE. 40–50% had silent PE.
  16. 16. CTEPH and Thrombophilia No clear link between CTEPH and antithrombin, protein S, protein C, factor II or factor V Leiden . Antiphospholipid antibodies have been reported in approximately 20% of CTEPH cohort. Proc Am Thorac Soc 2006 Prothrombotic factor VIII was also found to be elevated in 41% of a CTEPH cohort. Eur Respir J. 2000;15:395-399 Thromb Haemost. 2003;90:372.
  17. 17. Diagnosis of CTEPH    Symptoms A transthoracic echocardiogram Ventilation-perfusion (V˙/Q˙) lung scan -Screening test of choice to differentiate CTEPH from PAH ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S
  18. 18. Ventilation–Perfusion Scintigraphy Is More Sensitive than Multidetector CTPA in Detecting Chronic Thromboembolic Pulmonary Disease as a Treatable Cause of Pulmonary Hypertension Nina Tunariu1, Simon J.R. et al J Nucl Med 2007; 48:680–684 CTPEA Non--CTEPA Intermediate-High High
  19. 19.  A normal V˙/Q˙ scan virtually rules out CTEPH  A normal contrast-enhanced CT scan or MRI scan does not rule out a diagnosis of CTEPH  Right heart catheterization  Pulmonary angiogram N Engl J Med 2001;345:1465–1472. Chest 1983;84:679–683. Eur Radiol 2003;13:2365–2371
  20. 20. Contrast enhanced MRA (CEMRA) Pulmonary angiography MRA
  21. 21. Management of CTEPH Diagnosis of CTEPH with functional impairment and/or right heart failure Anticoagulation Advanced pulmonary vascular disease PVR disproportionately elevated Estimated reduction in PVR <50% Surgically accessible obliteration of pulmonary vessels Estimated reduction in PVR>50% Severe comorbidities Precluding surgery No PEA Severe comorbidities Precluding surgery Yes Yes Medical Therapy Persistent symptomatic PHT No Lung transplant Persistent symptomatic PHT Circulation 2006;113;2011-2020
  22. 22. Pulmonary Endartrectomy (PEA) Calif Med. 1957 February; 86(2): 108–114. THE SURGICAL TREATMENT OF ARTERIOSCLEROTIC OCCLUSIVE DISEASE— Thromboendarterectomy in Selected Cases Charles A. Kruse and Frederick G. Kirby
  23. 23. Pulmonary Endartrectomy (PEA) Pioneered at the University of California, San Diego (UCSD). 1,500 cases of PEA Excellent long-term outcome Surgical mortality rate of 4.4% in the last 500 cases Ann Thorac Surg 2003; 76:1457–1462 J Thorac Cardiovasc Surg 2006;131:307-313
  24. 24. PEA mortality and PVR
  25. 25. Surgery for Chronic Thromboembolic Pulmonary Hypertension—Inclusive Experience From a National Referral Center Munir Boodhwani, Marc Ruel, Carole J. Dennie and Thierry Mesana Fraser D. Rubens, Michael Bourke, Mark Hynes, Donna Nicholson, Marian Kotrec, Ann Thorac Surg 2007;83:1075-1081    106 PATIENTS 30 DAY PERIOPERATIVE MORTALITY 9.4% Most common cause of mortality-persistent pulmonary hypertension
  26. 26. Advanced secondary arteriopathy ? Proximal, accessible lesions Patient consent mPAP ≥ 40 mm Hg PEA Absence of severe comorbidity PVR > 300 -5 NYHA functional class III/IV Surgical expertise ACCP guidelines
  27. 27.  Concomitant coronary artery disease or cardiac valvular defect is not a contraindication and can be corrected at the time of PEA. Ann Thorac Surg. 2001;72:13-19  Severe right heart failure does not exclude a patient from being a PEA candidate; indeed, such patients often have the most dramatic improvements following surgery J Thorac Cardiovasc Surg. 2006;131:307-313.
  28. 28. Reverse right ventricular remodeling after pulmonary endarterectomy RV before PEA RV after PEA J Thorac Cardiovasc Surg 2007;133:58-64
  29. 29. The two major postoperative complications Persistent PH  Reperfusion pulmonary edema (RPE). 
  30. 30. Predictors of Surgical Success Prior history of pulmonary embolism and/or deep vein thrombosis “honeymoon period” (period of months to years between acute embolic event and clinical symptoms of chronic thromboembolic pulmonary hypertension) Angiographic lesions located proximally in pulmonary arteries or lobar branches Correlation between pulmonary vascular resistance and anatomic obstruction
  31. 31. Medical therapy    CTEPH is inoperable in as many as 50% of cases Around 10-15% patients do not respond to PEA Patients left untreated have a poor prognosis.
  32. 32. Mid-1990s, Late Ken Moser, world authority on the subject “Why would we use vasodilator therapy for CTEPH?—it’s a mechanical problem.”
  33. 33. Targets for Current or Emerging Therapies Prostacyclin Pathway Endothelin Pathway Nitric Oxide Pathway Arachidonic Acid Big Endothelin Arginine Prostacyclin Synthase Endothelinconverting Enzyme Nitric Oxide Synthase Prostacyclin Endothelin-1 Nitric Oxide cAMP cGMP Prostacyclin Prostacyclin Derivatives Derivatives Endothelin Receptor Antagonists Endothelin Receptor A Vasodilatation and Antiproliferation Endothelin Receptor B Vasoconstriction and Proliferation Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Vasodilatation and Antiproliferation Humbert M et al. N Engl J Med. 2004;351:1425-1436.
  34. 34. Indication for medical therapy    Where there is inoperable distal disease or comorbidities that make PEA a high-risk option; As a therapeutic bridge to PEA or lung transplant for high-risk patients; or Patients with persistent or residual PH after PEA
  35. 35. Prostanoids Therapeutic agent No. of pts. with CTEPH Hemody- Clinical namics Dyspnea/ 6 min walk Epoprostenol 9 Epoprostenol 11 + Trepostinil 23 NA Iloprost 10 Beraprost 8 Beraprost 43 + _ _ + References NA Eur Respir J 2004; 23: 595–600 + + Ital Heart J 2004;5:618–623 NA Ann Thorac Surg 2003;76:711–718. + + Cardiology 2006;106:168-173 Chest 2006;129;1636-1643 Chest 2003;123:1583–1588
  36. 36. Inhaled Iloprost AIR study randomized controlled clinical trial 203 patients 57 patients with CTEPH. Overall positive study No significant beneficial effects of inhaled Iloprost in the subgroup of CTEPH patients Volume 347:322-329
  37. 37. Sildenafil No. of Hemodynamics Clinical pts. with Dyspnea/ CTEPH 6 min walk References 12 + Am J Respir Crit Care Med 2003;167:1139–1141 + Eur Respir J 2007; 30:922-927 104 + +
  38. 38. Long-term Use of Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension (CHEST 2008; 134:229–236) Double-blind, placebo-controlled pilot study 19 subjects with inoperable CTEPH Randomly assigned to sildenafil (10) or placebo(9) for 12 weeks. All subjects were transferred to open-label sildenafil at the end of the study and offered repeat assessment at 12 months.
  39. 39. Primary end point- change - 6-min walking distance (6MWD). p=NS Sidenafil Placebo Baseline 6 weeks 12 weeks
  40. 40. Secondary endpoints statistically significant improvements in Pulmonary vascular resistance, Change in WHO functional class, Quality of life Score (CAMPHOR)
  41. 41. Outcome Measures at Baseline and at 12 Months (n 17)*
  42. 42. Endothelin Receptor Antagonists No. of pts. with CTEPH Hemodynamics Clinical Dyspnea/ 6 min walk 16 + + + + + + 19 47 16 8 43 + _ + + + + References Chest 2005;128;2363-2367 Hoeper MM et al. Eur Respir J 2006; 28: 138–143 SWISS MED WKLY 20 07;137:573–580 Cardiology 2006;106:168-173 Chest 2003;123:1583–1588
  43. 43. BENEFiT Trial design: Patients with inoperable CTEPH or persistent pulmonary hypertension after pulmonary endarterectomy were randomized to bosentan (n = 77) or placebo (n = 80). Follow-up was 16 weeks. PVR: -146 dyn⋅sec⋅cm-5 with bosentan vs. +30 dyn⋅sec⋅cm-5 with placebo (P<0001) WHO functional Class and NT-BNP Change (300 dyn⋅sec⋅cm-5) 6-minute walk improved significantly distance: +2.9 m vs. +0.8 m respectively, (p = 0.54) Conclusion: 30 (p < 0.0001) The improvement in pulmonary vascular resistance did not translate into a beneficial effect on 6-minute walk distance. -146 Bosentan Placebo Jais X, et al. J Am Coll Cardiol 2008;52:212734
  44. 44. Survival in CTEPH Without treatment With medical treatment Longterm survival of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) N. Saouti, F. de Man, A. Boonstra, A. Vonk-Noordegraaf (Amsterdam, Netherlands)
  45. 45. Survival after treatment-Swiss registry No significant difference in survival of the main 3 WHO groups Total patients 222 SWISS MED WKLY 20 08;138(25–26):371–378
  46. 46. Investigational/New Therapies        Ambrisentan Sitaxsentan Tadalafil Inhaled treprostinil Oral treprostinil Inhaled vasoactive intestinal peptide (VIP) Imatinib (PDGF-inhibitor)
  47. 47. Investigational/New Therapies • Tyrosine kinase/growth factor receptor inhibitors – Imatinib Imatinib, sorafenib sorafenib • Guanylate cyclase (sGC) stimulators - Riociguat • Vasoactive intestinal peptide (VIP) • Serotonin transporter agonists • Adrenomedullin • Rho-kinase inhibitors • Cicletanine • Endothelial progenitor cells • Gene therapy – Vectors expressing
  48. 48. SUMMARY      PEA should be considered as the first line treatment option in patients with CTEPH Pulmonary hypertension is likely to persist in 10-15% after PEA Medical intervention in inoperable patients and those post-PEA persistent PH should be given Anticoagulation therapy should be continued for life Lung transplantation may be undertaken where PEA has failed and in non-responders to medical therapy
  49. 49. Thanks