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Treatment of submassive pulmonary embolism Is thrombolysis the best treatment??

Egyptian Society of Chest Diseases & Tuberculosis The 55 th International Conference 25-28 March 2014 Cairo, Egypt. Treatment of submassive pulmonary embolism Is thrombolysis the best treatment??. Majdy M Idrees Saudi Arabia. Gulf Thoracic Meeting Abu Dhabi, UAE MArch 18-20, 2010 .

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Treatment of submassive pulmonary embolism Is thrombolysis the best treatment??

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  1. Egyptian Society of Chest Diseases & Tuberculosis The 55th International Conference 25-28 March 2014 Cairo, Egypt Treatment of submassive pulmonary embolismIs thrombolysis the best treatment?? Majdy M Idrees Saudi Arabia Gulf Thoracic Meeting Abu Dhabi, UAE MArch 18-20, 2010

  2. The 55th ESCT conference • Financial disclosure • Honoraria for lecturing for Actelion, BSP, pfizer, AstraZeneca, MSD & GSK • Research grant from pfizer & Actelion • Multi-national RCT sponsored by Actelion, BSP, and pfizer

  3. The 55th ESCT conference “Venous thrombosis is always a severe disease and is often fatal, because fragments of the thrombi may detach and occlude branches of the pulmonary artery... the occlusion of the main branches of the pulmonary artery causes a striking rise of the blood pressure in these vessels. This rise, which the right heart might fight in order to ensure circulation, may sometimes lead to cardiac arrest.” Picot 1884 Leconsde Clinique Médicale

  4. The 55th ESCT conference The aphorisms of Hippocrates “In acute diseases, coldness of the extremities,, “is a very bad sign”

  5. The 55th ESCT conference • 74-year-old lady presented with progressive shortness of breath (WHO functional class IV) over 10-day period • She had one attack of syncope 2 days before her presentation • Recent surgery (appendectomy 3 weeks earlier)

  6. The 55th ESCT conference • BP 155/88, PR 92/min, O2 sat 84% on r/a and 92% on 4 L/min • Physical examination revealed Rt. heart strain • Doppler USnegative • EKG revealed sinus tachycardia with T wave inversion in the anterior precordial leads • NT-pro BNP 4200

  7. The 55th ESCT conference • Echocardiography: • Dilated RV • Severe TR • sPAP 84 mmHg • Small posterior PE

  8. The 55th ESCT conference • CT angiogram.. • PE occluding the main right PA • RV:LV > 1

  9. The 55th ESCT conference Management issues: How severe is this patient’s PE? What is the risk of mortality? Risk-stratifying Is the pathobiology different from massive PE? What is the “best” management approach?

  10. Outcome in pulmonary embolism Sudden Death 100 70 30 10 0 Cardiac Arrest Our patient Infliction Point Mortality Shock RV Dysfunction Severity Embolism size Cardiopulmonary Status

  11. Outcomes in hemodynamically-stable, RV-strained PE treated with Heparin Study Year Number PE Death % Mortality

  12. The 55th ESCT conference Different pathophysiology Massive Pulmonary Embolism Well-understood Obstructive shock Sub-massive Pulmonary Embolism Poorly understood

  13. Hemodynamic – PE 120 Systemic Arterial Pressure 100 80 60 Pressure (mmHg) 40 m PAP RV Pressure 20 COP 10 0 RAP -10 Total Occlusion Zero Occlusion Progressive PR occlusion Guyton Cir Res 1954; 2:326-332

  14. 30 20 10 0 10 20 30 PE: Vascular resistance vs. obstruction • • • • • • PVR • • • • • • • ° ° • • • • • • ° ° • • • ° • ° ° ° Miller index Petitpretz Circ 1984; 70:861-866.

  15. Thrombolytic therapy in massive PE • Randomized trial • Aimed for 40 patients • Patients with massive PE (SBP<90) • IV bolus of SK Vs Heparin The study was prematurely Terminated. ThromThrombolysis 1995

  16. Thrombolytic therapy in massive PE 100 Heparin 80 Streptokinase 60 Survival 40 20 0 4 4 Conclusion: Although a small study, it strongly support the current indication for thrombolytic therapy in massive PE. J Throm Thrombolysis 1995

  17. Non-shock mortality thrombolytic therapy Patients Mortality Study Lytic Heparin Lytic % (N) Heparin % (N)

  18. Thrombolytic therapy in patients with non-shock pulmonary embolism? • Randomized, DB, multicenter trial • 256 pt • PE confirmed by HP V/Q scan, spiral CT or angiogram • Normal BP • RV dysfunction (echo, ECG or RHC) • Primary endpoint: • In-hospital mortality • Worsening circulation • Need for additional therapy • Secondary endpoint: • 30-days mortality • Recurrent PE American Journal of Cardiovascular Drugs 2004, 4(2):69-74

  19. Thrombolytic Therapy in patients with non-shock pulmonary embolism? 25 5 4 3 2 1 0 24.6 % 20 P = 0.0058 P = NS 15 Composite PEP In-hospital Mortality 11 % 10 2.4 % 2.1 % 5 0 Heparin TPA Heparin Alteplase Am J of Cardiovascular Drugs, 4 (2) 2004 , 69-74

  20. Non-shock PE: Pathobiology • Observations: • Clinical observation • Lack of response to anti-obstructive lytic treatment • Science: • Inflammatory neurohormonal mediators’ release  bilateral pulmonary vasoconstriction, bilateral V/Q mismatch  PVR RV dysfunction Stein M, ProgCardiovascDis 1974; 17:167-174 Malik AB, Physiol Rev 1983; 63: 1114-1207 Alpert JS, Chest 1978; 73: 795-797

  21. Novel approach for the management of sub-massive pulmonary embolism • Methods: • Inhaled Iloprost used in 11 patients with Submassive PE, • who refused to receive thrombolytic therapy • NYHA III to IV for duration between 1-14 day • Helical CT angiogram was confirmatory • Echocardiography was used to evaluate the RV • All patients were stable hemodynamically • Beside anticoagulation, all patients received inhaled Iloprost, 2.5-5 µg every 4 hours for 3 weeks. • Idrees et al. Ann Thorac Med 2012; 7(3):157-161.

  22. Prostanoids Platelets Vessels Leukocytes SMC fibroblasts platelets monoc PMN T-cells vasodilation anti- proliferation matrix secretion anti- coagulation MAPK iNOS burst elastase leuko- trienes TNF IFN IL-2 NFkB TNF IL-1 IL-10 Olschewski et al. PharmacolTher, 2004

  23. Novel approach for the management of sub-massive pulmonary embolism • End points: • Improvement in echocardiographic parameters for right ventricular strain/PH • Functional class improvement • Improvement in dyspnea score • Exercise improvement • Biomarker (Pro BNP) • Improvement in oxygenation • Mortality Idrees et al, ATM, Submitted

  24. Results P = 0.01 P < 0.001 P = 0.03 P = 0.01 P < 0.003 1800 1500 1200 900 600 300 0 lll + 600 - - 450 - - 300 - - 150 - - 0 IV III II I 0 100 80 60 40 20 520 m 1620 89 X VIII VI IV II 0 Vlll 155 m l + 420 38 ll sPAP NT - Pro 6MWT Dyspnea NYHA BNP Score Pre Iloprost Post Iloprost Idrees et al, ATM, Submitted

  25. Novel approach for the management of sub-massive pulmonary embolism • Conclusion: • In sub-massive pulmonary embolism, directing therapy towards decreasing PVR is effective in improving the hemodynamics derangement associated with this condition. • This strategy might turn to be the most effective • approach for treating this condition and probably safer than thrombolytic therapy. • However, these conclusion should be confirmed in a large, randomized, placebo-controlled study Idrees et al, ATM, Submitted

  26. Take Home Messages The 55th ESCT conference

  27. Summary • Pulmonary embolism could be a fatal disease • Diagnostic-Therapeutic approach based on risk stratification is probably the most important step in the management • RV Dysfunction • Shock • Cardiac arrest • Sudden arrest

  28. Summary • Thrombolytic therapy in M-PE: • Accelerated clot lysis • Hemodynamic improvement • May improve Recurrent embolism • CTEPH • Quality of life •  Symptoms •  Mortality • Thrombolytic therapy in SM-PE: • Controversial issue • Administrating early in the course of sub-massive pulmonary embolism prevents worsening of the disease • In SM-PE • Directing therapy towards  PVR rather than clotting lysis might be the ideal approach in this patients’ population • Need to be tested in randomized clinical studies

  29. Egyptian Society of Chest Diseases & Tuberculosis The 55th International Conference 25-28 March 2014 Cairo, Egypt Thank you

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