Pulmonary Hypertension, Current Guidelines and Future Directions of Therapy.


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Pulmonary Hypertension, Current Guidelines and Future Directions of Therapy.

  1. 1. Bassel Ericsoussi, MD Pulmonary and Critical Care Fellow University of Illinois at Chicago
  2. 3. Classification <ul><li>The World Health Organization (WHO) classified pulmonary hypertension into five groups on the basis of mechanisms: </li></ul><ul><ul><li>Group I. Pulmonary arterial hypertension </li></ul></ul><ul><ul><li>Group II. Pulmonary venous hypertension </li></ul></ul><ul><ul><li>Group III. Pulmonary hypertension associated with hypoxemia </li></ul></ul><ul><ul><li>Group IV. Pulmonary hypertension due to chronic thrombotic disease, embolic disease, or both </li></ul></ul><ul><ul><li>Group V. Miscellaneous </li></ul></ul>
  3. 4. N ENGL J MED 351;16 WWW.NEJM.ORG OCTOBER 14, 2004
  4. 5. Definition <ul><li>Disease of the small pulmonary arteries </li></ul><ul><li>Increased MPAP > 25 mm Hg at rest or > 30 mm Hg with exercise, with a PCWP and LVEDP of less than 15 mm Hg </li></ul>
  5. 6. The Pathophysiology of PAH <ul><li>Vasoconstriction </li></ul><ul><li>Remodeling: Smooth-muscle cell and endothelial-cell proliferation, vascular wall inflammation </li></ul><ul><li>Chronic vascular thrombosis : Thrombotic arteriopathy , thrombosis in situ. </li></ul>
  6. 7. <ul><li>Also there is an abnormal angiogenic response to hypoxia, increased vascular endothelial growth factor (VEGF), formation of plexiform lesions </li></ul>N ENGL J MED 351;16 WWW.NEJM.ORG OCTOBER 14, 2004
  7. 8. Natural History and Survival <ul><li>In the 1980s, the median survival of patients was 2.8 years after diagnosis </li></ul><ul><li>Death can result from a delay in the diagnosis and treatment of this disease </li></ul><ul><li>The development of new drugs increased the survival rate to: </li></ul><ul><ul><li>68-77% at 1 year </li></ul></ul><ul><ul><li>40-56% at 3 years </li></ul></ul><ul><ul><li>22-38%at at 5 years </li></ul></ul>
  8. 9. Poor Prognostic Factors <ul><li>Elevated pulmonary vascular resistance </li></ul><ul><li>History of right heart failure (NYHA) functional class III or IV </li></ul><ul><li>Elevated right atrial pressure </li></ul><ul><li>Decreased cardiac output </li></ul><ul><li>Low mixed venous oxygen saturation. </li></ul><ul><li>Six minutes walk test (the distance walked in six minutes) has a strong association with mortality </li></ul>
  9. 12. Hypoxia and PAH <ul><li>Hypoxia: </li></ul><ul><ul><li>Vasoconstriction in the pulmonary vasculature </li></ul></ul><ul><ul><li>Vasodilation in systemic vessels </li></ul></ul><ul><li>Chronic hypoxemia is due to: </li></ul><ul><ul><li>Impaired cardiac output </li></ul></ul><ul><ul><li>Right-to-left shunting through a PFO or a congenital heart defect. </li></ul></ul><ul><li>Acute: reversible changes in vascular tone </li></ul><ul><li>Chronic: induces structural remodeling </li></ul>
  10. 13. Appetite Suppressant and PAH <ul><li>Dexfenfluramine </li></ul><ul><li>Chronic use > 3 mon: PAH </li></ul><ul><li>Increases the release of serotonin from platelets and inhibits its reuptake </li></ul><ul><li>Serotonin: </li></ul><ul><ul><li>Vasoconstrictor </li></ul></ul><ul><ul><li>Smooth-muscle cell hypertrophy and hyperplasia </li></ul></ul>
  11. 14. CNS Stimulants and PAH <ul><li>Methamphetamine , cocaine: </li></ul><ul><ul><li>Medial hypertrophy of the pulmonary arteries </li></ul></ul>
  12. 15. CTD and PAH <ul><li>Especially CREST syndrome: </li></ul><ul><ul><li>80 % histopathological changes consistent with PAH </li></ul></ul><ul><ul><li>10-15 % clinically significant PAH. </li></ul></ul><ul><li>SLE </li></ul><ul><li>mixed CTD </li></ul><ul><li>RA </li></ul>
  13. 16. HIV and PAH <ul><li>0.5 % of HIV patients have PAH (x 6-12 normal) </li></ul><ul><li>Related to the duration of HIV infection. </li></ul><ul><li>Independent of the CD4 cell count </li></ul><ul><li>The mechanism is unclear </li></ul>
  14. 17. HHV-8 and PAH <ul><li>HHV-8 causes Kaposi’s sarcoma </li></ul><ul><li>Endothelial changes in Kaposi’s sarcoma similar to the plexiform lesions in PAH </li></ul><ul><li>10/16 pts with PAH: HHV-8 infection in lung tissue specimens </li></ul>
  15. 18. Portal HTN and PAH <ul><li>Cirrhosis: </li></ul><ul><ul><li>0.73 % histologic changes c/w PAH (x 6 normal) </li></ul></ul><ul><ul><li>2-5 % hemodynamic studies showed PAH </li></ul></ul><ul><li>The risk increases with the duration of portal hypertension </li></ul><ul><li>The diagnosis of PAH is usually made within 4-7 years after the diagnosis of portal HTN </li></ul><ul><li>Cirrhosis without portal HTN appears to be insufficient for the development of PAH </li></ul><ul><li>The mechanism is unclear </li></ul>
  16. 19. Myelodysplastic and PAH <ul><li>Chronic myelodysplastic syndromes, thrombocytosis </li></ul><ul><li>Caused by: </li></ul><ul><ul><li>Splenectomy </li></ul></ul><ul><ul><li>Portal HTN </li></ul></ul><ul><ul><li>Pulmonary vascular obstructive disease as a result of chemotherapy </li></ul></ul><ul><ul><li>Infiltration of hematopoietic cells into the pulmonary parenchyma </li></ul></ul><ul><li>Platelet-derived serotonin, platelet-derived growth factor </li></ul><ul><ul><li>Vasoconstriction </li></ul></ul><ul><ul><li>smooth-muscle cell proliferation </li></ul></ul><ul><li>Correlation between with the platelet count and the level of PAH </li></ul>
  17. 20. Hemoglobinopathies and PAH <ul><li>b -thalassemia: 75 % echocardiograph showed PAH (overestimated) </li></ul><ul><li>Sickle cell disease: 8-30 % echocardiograph showed PAH </li></ul><ul><ul><li>The higher the MPAP the higher the mortality </li></ul></ul><ul><ul><li>PAH increases the risk of death in patients with sickle cell disease </li></ul></ul><ul><li>Mechanism: Hemolysis, oxyhemoglobin (cell-free hemoglobin) inactivates nitric oxide </li></ul><ul><ul><li>Vasoconstriction </li></ul></ul><ul><ul><li>Proliferation </li></ul></ul><ul><ul><li>Thrombosis </li></ul></ul>
  18. 21. Hereditary Hemorrhagic Telangiectasia and PAH <ul><li>Osler–Rendu–Weber syndrome: 15 % PAH </li></ul><ul><li>Genes mutations : </li></ul><ul><ul><li>Transforming growth factor b (TGF- b ) </li></ul></ul><ul><ul><li>Activin-receptor–like kinase 1 (ALK1) </li></ul></ul>
  19. 22. Genetic Abnormalities and PAH <ul><li>Familial PAH 6% </li></ul><ul><li>Autosomal dominant </li></ul><ul><li>In a successive generation, PAH occurs at a younger age and with greater severity than in the preceding generation. </li></ul>
  20. 26. Therapeutic Approaches to Pulmonary Hypertension <ul><li>No cure for PAH </li></ul><ul><li>Goal of treatment: </li></ul><ul><ul><li>Symptomatic relief </li></ul></ul><ul><ul><li>Survival prolongation </li></ul></ul><ul><ul><li>Quality of life improvement </li></ul></ul>
  21. 28. Basic (Conventional) Therapy <ul><li>Activities as tolerated </li></ul><ul><li>Advanced PAH: limited activity is advised (life-threatening syncope) </li></ul><ul><li>Oxygen: maintain O2 Sat > 90% </li></ul><ul><li>Diuretic: right heart failure </li></ul><ul><li>Digoxin: concomitant intermittent or chronic atrial fibrillation. </li></ul><ul><li>Pregnancy and labor are contraindicated (OCP if no h/o thromboembolic disease or thrombophilia) </li></ul>
  22. 29. Anticoagulion in PAH <ul><li>PAH: Thrombotic arteriopathy, thrombosis in situ </li></ul><ul><li>Recommended in: </li></ul><ul><ul><li>IPAH </li></ul></ul><ul><ul><li>Pulm HTN due to chronic thrombotic/embolic disease (group IV) </li></ul></ul><ul><ul><li>Pulm HTN a/w a-fib </li></ul></ul><ul><ul><li>RFs for VTE: </li></ul></ul><ul><ul><ul><li>Heart failure </li></ul></ul></ul><ul><ul><ul><li>Sedentary lifestyle </li></ul></ul></ul><ul><ul><ul><li>Thrombophilic predisposition </li></ul></ul></ul><ul><li>Controversial in PAH associated with an underlying condition </li></ul><ul><ul><li>Scleroderma –CREST syndrome: increased risk of GI bleeding from luminal telangectasia during anticoagulation </li></ul></ul><ul><li>Improve prognosis an survival (especially if no response to vasodilators) </li></ul><ul><li>Warfarin with a target INR between 1.5-2.5 is recommended </li></ul>
  23. 30. Simvastatin in PAH <ul><li>Statins: </li></ul><ul><ul><li>Antiproliferative and anti-inflammatory effects </li></ul></ul><ul><ul><li>Induce endothelial NO </li></ul></ul><ul><li>Simvastatin 20-80 mg/day: </li></ul><ul><ul><li>Improves in 6MW performance </li></ul></ul><ul><ul><li>Improves in CO </li></ul></ul><ul><ul><li>Decreases in RVSP </li></ul></ul><ul><ul><li>Improves survival (Class IV patients ) </li></ul></ul>
  24. 31. Aspirin and Plavix in PAH <ul><li>IPAH: </li></ul><ul><ul><li>Thrombosis in situ </li></ul></ul><ul><ul><li>Increased Tx A2 (Platelets aggregation) </li></ul></ul><ul><li>A randomized, double-blinded, placebo-controlled study: </li></ul><ul><ul><li>ASA and Plavix inhibit platelet aggregation </li></ul></ul><ul><ul><li>ASA reduces Tx A2 metabolite production without affecting PGI2 metabolite synthesis </li></ul></ul><ul><li>More studies should be done </li></ul>
  25. 32. ASA and Simvastatin in PAH <ul><li>Still under investigation </li></ul><ul><li>Study completion date: March 2010 </li></ul><ul><li>Randomized, double blinded study: </li></ul><ul><ul><li>Group I: Aspirin 81 mg + Simvastatin 40 mg (6 mon) </li></ul></ul><ul><ul><li>Group II: Aspirin 81 mg + Placebo (6 mon) </li></ul></ul><ul><ul><li>Group III: Placebo + Simvastatin 40 mg (6 mon) </li></ul></ul><ul><ul><li>Group IV: Placebo + Placebo (6 mon) </li></ul></ul>
  26. 33. CCB in PAH <ul><li>Identify pts that may benefit from CCB </li></ul><ul><li>Acute vasodilator challenge during right heart catheterization (short-acting agents): </li></ul><ul><ul><li>IV prostacyclin </li></ul></ul><ul><ul><li>IV adenosine </li></ul></ul><ul><ul><li>NO inhaler </li></ul></ul><ul><li>Don’t use CCB during the acute vasodilator challenge: severe, life-threatening hemodynamic compromise </li></ul><ul><li>Response to vasodilation: </li></ul><ul><ul><li>Decrease in the MPAP and of PVR by at least 20% </li></ul></ul><ul><ul><li>OR, decrease in the MPAP more than 10 mm Hg, to a value lower than 40 mm Hg, with a normal or high CO </li></ul></ul><ul><li>Response to CCB (10% of all pts): </li></ul><ul><ul><li>NYHA functional class I or II </li></ul></ul><ul><ul><li>Normal MPAP, PVR after at least one year of follow-up </li></ul></ul><ul><li>CCB prolongs survival among these pts </li></ul>
  27. 34. Prostacyclin Therapy in PAH <ul><li>Intravenous Prostacyclin ( IV Epoprostenol) </li></ul><ul><li>Subcutaneous Prostacyclin (SQ Treprostinil) </li></ul><ul><li>Oral Beraprost </li></ul><ul><ul><li>Approved therapy for pulmonary arterial hypertension in Japan </li></ul></ul><ul><li>Inhaled Iloprost </li></ul><ul><ul><li>Not an approved therapy in the USA </li></ul></ul>
  28. 35. IV Prostacyclin ( IV Epoprostenol) <ul><li>Stimulates the production of cAMP </li></ul><ul><ul><li>Vasodilation </li></ul></ul><ul><ul><li>Inhibits proliferation </li></ul></ul><ul><ul><li>Inhibits platelet aggregation </li></ul></ul><ul><li>After 3 mon therapy </li></ul><ul><ul><li>Clinical functional improvement </li></ul></ul><ul><ul><li>Improve mortality (but not in pts with scleroderma), long-term survival </li></ul></ul><ul><ul><li>Decreases MPAP, PVR </li></ul></ul><ul><li>May prevent the need for lung transplantation, but if no functional improvement after 3 months consider lung transplant </li></ul>
  29. 36. Intravenous Prostacyclin (cont.) <ul><li>Short half-life (3 min), continuous intravenous infusion </li></ul><ul><li>Expensive </li></ul><ul><li>Side effects : jaw pain, headache, diarrhea, flushing, leg pain, and nausea </li></ul><ul><li>Catheter related complications: </li></ul><ul><ul><li>catheter-related sepsis </li></ul></ul><ul><ul><li>Pump failure or dislocation of the central venous catheter </li></ul></ul>
  30. 37. Subcutaneous Prostacyclin (SQ Treprostinil) <ul><li>Continuous subcutaneous infusion </li></ul><ul><li>After 3 mon therapy </li></ul><ul><ul><li>Symptomatic improvement </li></ul></ul><ul><ul><li>Exercise capacity (6 min walk test) improvement </li></ul></ul><ul><ul><li>Hemodynamics (MPAP, PVR) improvement </li></ul></ul><ul><li>Side effect: Local pain at the infusion site (85%) </li></ul><ul><li>No catheter related complications: Preferred over IV prostacyclin </li></ul>
  31. 38. Endothelin-receptor Blockers in PAH <ul><li>Endothelin-1 receptors: </li></ul><ul><ul><li>A receptors: </li></ul></ul><ul><ul><ul><li>Vasoconstriction </li></ul></ul></ul><ul><ul><ul><li>Vascular smooth-muscle cells proliferation </li></ul></ul></ul><ul><ul><li>B receptors: </li></ul></ul><ul><ul><ul><li>Endothelin clearance </li></ul></ul></ul><ul><ul><ul><li>NO and prostacyclin production (vasodilation) </li></ul></ul></ul><ul><ul><li>Fibrosis </li></ul></ul><ul><ul><li>Pro-inflammatory mediator (enhance the expression of adhesion molecules) </li></ul></ul>
  32. 39. Bosentan <ul><li>Non-selective endothelin (A and B) blocker </li></ul><ul><ul><li>Block receptors A: Vasodilation, inhibit proliferation </li></ul></ul><ul><ul><li>Block receptors B: inhibit clearance, vasodilation (NO, Prostacyclin) </li></ul></ul><ul><li>Studies showed: </li></ul><ul><ul><li>Exercise capacity improvement </li></ul></ul><ul><ul><li>Hemodynamics (MPAP, PVR, CO, CI) improvement </li></ul></ul><ul><ul><li>Improvement in the time to clinical worsening </li></ul></ul><ul><li>Side effect: </li></ul><ul><ul><li>Acute hepatitis: dose-dependent (Monthly monitoring of liver function tests is mandatory) </li></ul></ul><ul><ul><li>Teratogenic: contraindicated during pregnancy </li></ul></ul>
  33. 40. Sitaxsentan and Ambrisentan <ul><li>Selective endothelin A blocker </li></ul><ul><ul><li>Block receptors A: Vasodilation, inhibit proliferation </li></ul></ul><ul><ul><li>No effect on receptors B: clearance, vasodilation (NO, Prostacyclin) </li></ul></ul><ul><li>Side effect: </li></ul><ul><ul><li>Acute hepatitis, continuous monitoring of liver function </li></ul></ul>
  34. 41. Nitric Oxide in PAH <ul><li>Endothelium derived </li></ul><ul><li>Increases intracellular (cGMP): </li></ul><ul><ul><li>Vasodilatation </li></ul></ul><ul><ul><li>Antiproliferation </li></ul></ul><ul><ul><li>Antithrombosis </li></ul></ul><ul><li>Pts with PAH have decreased NO </li></ul><ul><li>Short-term inhalation (part of the acute vasodilation challenge) </li></ul><ul><li>Long-term Tx is not preferred: an interruption in its administration can cause hemodynamic deterioration </li></ul><ul><li>L-arginine: product of nitric oxide synthase </li></ul><ul><ul><li>reduces pulmonary-artery pressure </li></ul></ul><ul><ul><li>increases exercise tolerance </li></ul></ul>
  35. 42. Sildenafil in PAH <ul><li>PDE-5 inhibitors </li></ul><ul><li>Inhibits the breakdown of cGMP: </li></ul><ul><ul><li>Vasodilatation </li></ul></ul><ul><ul><li>Antiproliferation </li></ul></ul><ul><ul><li>Antithrombosis </li></ul></ul><ul><li>IV sildenafil: short term Tx, acute pulmonary vasodilator </li></ul><ul><li>Oral sildenafil: long-term Tx: </li></ul><ul><ul><li>Exercise capacity improvement </li></ul></ul><ul><ul><li>Hemodynamics improvement </li></ul></ul>
  36. 44. VIP in PAH <ul><li>Vasoactive intestinal peptide </li></ul><ul><ul><li>Pulmonary vasodilation </li></ul></ul><ul><ul><li>Inhibits proliferation of vascular smooth-muscle cells </li></ul></ul><ul><ul><li>Inhibits platelet activation </li></ul></ul><ul><li>Inhalation </li></ul><ul><ul><li>Functional improvement </li></ul></ul><ul><ul><li>Hemodynamics improvement </li></ul></ul>
  37. 45. SSRIs in PAH <ul><li>IPAH </li></ul><ul><ul><li>Elevated levels of plasma serotonin </li></ul></ul><ul><ul><li>Reduced content of serotonin in platelets </li></ul></ul><ul><li>Serotonin: </li></ul><ul><ul><li>Vasoconstrictor </li></ul></ul><ul><ul><li>Promotes smooth-muscle cell hypertrophy and hyperplasia </li></ul></ul><ul><li>The level of serotonin itself is probably not a determinant of pulmonary hypertension </li></ul><ul><li>SSRIs are not associated with an increased incidence of pulmonary hypertension </li></ul><ul><li>Fluoxetine may provide protection against pulmonary hypertension!!!! </li></ul>
  38. 46. Combination Therapy in PAH <ul><li>To maximize the clinical benefit: </li></ul><ul><ul><li>Prostacyclin + sildenafil </li></ul></ul><ul><ul><li>Prostacyclin + bosentan (ETRB) </li></ul></ul><ul><li>Other study: </li></ul><ul><ul><li>Addition of long-term treatment with sildenafil had minimal effects on functional status and right-heart function </li></ul></ul>
  39. 47. 10 % Defined as NYHA functional class I or II who have normal hemodynamic values after at least one year of follow-up
  40. 48. References <ul><li>Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004 Oct 14;351(16):1655-65. </li></ul><ul><li>Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007 Jun;131(6):1917-28. </li></ul><ul><li>Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004 Sep 30;351(14):1425-36. Review. </li></ul><ul><li>Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006 Aug;130(2):545-52. Review. </li></ul><ul><li>Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest. 2005 Apr;127(4):1446-52. </li></ul><ul><li>Robbins IM, Kawut SM, Yung D, Reilly MP, Lloyd W, Cunningham G, Loscalzo J, Kimmel SE, Christman BW, Barst RJ. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J. 2006 Mar;27(3):578-84. </li></ul><ul><li>A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension. ClinicalTrials.gov Identifier: NCT00384865 </li></ul>