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Primary Pulmonary Hypertension and Sildenafil

Primary Pulmonary Hypertension and Sildenafil

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Primary Pulmonary Hypertension and Sildenafil

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  1. Primary Pulmonary Hypertension andSildenafil Azim E. Surka WFUMC Resident Grand Rounds November 11, 2003

  2. Overview: • Background • WHO Classification • Epidemiology • Pathophysiology • Current Therapies • Sildenafil

  3. Primary Pulmonary Hypertension • Rare disorder characterized by elevated pulmonary arterial pressures • First described in 1951 by Dresdale • Presenting symptom is most commonly dyspnea • Can also present with syncope, chest pain and peripheral edema

  4. Primary Pulmonary Hypertension • Incidence is 1-2 cases per million in general population • Mean survival was 2.8 years after diagnosis • Although survival probably longer since the advent of IV epoprostenol

  5. Primary Pulmonary HypertensionNIH • Defines PPH as mean pulmonary arterial pressure (PAP) > 25 mmHg at rest, or >30 mmHg with exertion • Absence of heart disease, chronic thromboembolic disease, underlying pulmonary disorder, or other secondary cause

  6. WHO Classification • In 1998 World Health Organization reclassified pulmonary hypertension • Subdivided all Pulmonary Hypertension into 5 groups • Primary Pulmonary Hypertension is characterized as a subclass of Pulmonary Arterial Hypertension

  7. WHO Classification • Pulmonary Arterial Hypertension • Primary Pulmonary Hypertension (PPH) • Familial • Sporadic • Related to: • Collagen Vascular Disease • Congenital systemic to pulmonary shunts • Portal Hypertension • HIV • Drugs/Toxins, i.e. appetite suppressants • Persistent pulmonary hypertension of the neonate

  8. WHO Classification • Pulmonary venous hypertension • Left sided valvular or ventricular disease • Pulmonary Hypertension associated with disorders of the respiratory system/ hypoxemia • COPD, interstitial lung disease, sleep disorders

  9. WHO Classification • Pulmonary hypertension due to chronic thrombotic and/or embolic disease • Pulmonary emboli, and sickle cell disease • Pulmonary Hypertension due to disorders directly affecting pulmonary vasculature • Sarcoid, schistosomiasis

  10. Epidemiology of PPH • Female predominance of 2 to 1 • No ethnic or geographical predisposition • Approximately 6% of cases are familial

  11. Pathophysiology • Associated with obstruction of small pulmonary arteries • Microscopic characteristics • Medial hypertrophy • Plexiform lesions • Thrombotic lesions • Concentric laminar fibrosis • Bone Morphogenetic Protein Receptor gene found in 2000 in patients with Familial PPH • May play role in pathophysiology

  12. Pathophysiology

  13. Current Therapies • Calcium Channel Blockers • Anticoagulation • Prostacyclin • Bosentan (endothelin antagonist) • Lung transplantation

  14. Calcium Channel Blockers • Has shown to benefit small number of people • Nifedipine and diltiazem are the CCB of choice • Side effects include hypotension, edema, and hypoxemia

  15. Anticoagulation • PPH patients more likely to have thrombosis secondary to sluggish blood flow and sedentary lifestyle • Increased levels of thromboxane have also been found in PPH patients • Goal INR 2.0

  16. Lung Transplantation • Only curative therapy for PPH • Indications • NYHA Class III or IV despite optimum medical therapy • Cardiac Index less than 2L/min/m2 • Right Atrial Pressure > 15 mmHg • Pulmonary Arterial Pressure > 55mmHg • Limited by availability

  17. Epoprostenol (Flolan) • Prostacyclin • Increases exercise capacity and decrease PAP after 12 week period • Improves survival at 1, 3, and 5 years • Side Effects include hypotension, jaw pain, diarrhea, flushing, and nausea and vomiting • Tachyphalaxis is common and dosages have to be increased

  18. Epoprostenol (Flolan) • Delivered through continuous IV pump • Infection and thrombosis can occur • Dose Limited by hypotension • Cost of epoprostenol and pump delivery is $5000/month • Iloprost • Aerosolized prostacyclin • Available in Europe • Easier delivery through nebulizer • Must be dosed 6-12 times a day

  19. Bosentan (Tracleer) • Endothelin 1 and 2 antagonist • Given Orally • Endothelin is a potent vasoconstrictor and smooth muscle mitogen • PPH patients have been shown to have greater endothelin 1 concentration in plasma and lungs

  20. Bosentan (Tracleer) • Two Randomized controlled trials showed improvement in six minute walk time, cardiopulmonary hemodynamics, and WHO functional Class • No mortality data on Bosentan

  21. Sildenafil (Viagra) • A Phosphodiesterase 5 Inhibitor (PDE5) • Currently approved for treatment of Erectile Dysfunction in U.S. • Thought to work by increasing levels of cGMP, a vasodilator • PDE5 is found in greater amounts the lung and breaks down cGMP

  22. Sildenafil (Viagra)

  23. Long Term Treatment With Oral Sildenafil in Addition to Continuous IV Epoprostenol in Patients with Pulmonary Arterial HypertensionStiebellehner, et al. Chest 123, 1293-1295, 2003

  24. Stiebellehner, et al. • Case Study • Three female patients • Ages 61, 33, 51 • Patients 1 and 2 had PPH, Patient 3 had PAH secondary to closure of atrial septal defect

  25. Stiebellehner, et al. • All had baseline six minute walk time (6MWT) and cardiopulmonary hemodynamic measurements • Primary endpoint was PAP and 6MWT after 5 months of therapy

  26. Stiebellehner, et al.Baseline Characteristics

  27. Stiebellehner, et al.Intervention • Patient 1 received 50 mg of Sildenafil four times a day • Patient 2 and 3 received 12.5 mg of Sildenafil six times a day secondary to nausea and vomiting • All patients continued with current dose of epoprostenol

  28. Stiebellehner, et alResults:

  29. Stiebellehner, et al. • Conclusions: • All patients had decrease in PAP and increase in 6MWT after 5 months of therapy • Effects of sildenafil were additive to epoprostenol

  30. Stiebellehner, et al. • Limitations: • Case Series • Small sample group • Lack of control • No randomization

  31. Effect of Inhaled Iloprost Plus Oral Sildenafil in Patients with PPH Wilkens H, et al Circulation 104: 1218-1222, 2001

  32. Wilkens, et al • Crossover study with iloprost and sildenafil • 5 patients with PPH with NYHA class III or IV • Exclusion Criteria: pregnancy, hypotension, and secondary pulmonary hypertension • Patients admitted to ICU and Swan-Ganz catheters were placed • PAP, CO, and PVR were measured

  33. Wilkens, et alPatient Characteristics

  34. Wilkens, et alInterventions • Patients were given iloprost, and measurements were taken every 15 minutes for 2 hours • Patients were then given two 25 mg doses of Sildenafil 30 minutes apart, and Swan-Ganz measurements were taken • Patients were given additional 50 mg of sildenafil if there was no response after 60 min • Patients were then given inhaled iloprost 90 minutes after first sildenafil

  35. Wilkens, et alResults • PAP • Iloprost • -16.3% +/-2.2% p<0.01 • Sildenafil • -12.6% +/-0.9% p<0.01 • Sildenafil +Iloprost • -24.7%+/-3.0% p<0.002

  36. Wilkens, et al

  37. Wilkens, et alResults • Similar Decreases in Pulmonary Vascular Resistance • Iloprost • -43.8%+/- 3.9% (p<0.05) • Sildenafil • -21.8% +/- 3.0% (p<0.05) • Sildenafil and Iloprost • -43.0% +/- -2.7% (p<0.02)

  38. Wilkens, et al

  39. Wilkens, et al • Conclusions: • Effects of iloprost began to wear off after 1 hour • Sildenafil’s effect on PAP and PVR was still evident after 90 min • Additive effect of two agents together • Most of effect of sildenafil was after the first 25 mg dose

  40. Wilkens, et al • Limitations: • Small sample group • No randomization • Open crossover study

  41. Combination Therapy with Oral Sildenafil and Inhaled Iloprost Severe Pulmonary Hypertension Ghofrani, et al Annals Internal Medicine, 136: 515-522, 2002

  42. Ghofrani, et al • Randomized open label trial in the ICU • 30 Patients: • 16 patients with Pulmonary Arterial Hypertension • 10 with PPH and 6 with CREST • 13 with chronic thromboembolic disease • 1 with PH secondary to aplasia of left pulmonary artery • 23 women and 7 men

  43. Ghofrani, et al • Inclusion Criteria: • Severe PAH i.e. PAP >40mm Hg • NYHA class III or IV • Exclusion Criteria: • Pulmonary Hypertension secondary to COPD • Pulmonary Venous Congestion • Congenital Heart Disease • Pregnancy • Inflammatory Lung Disease

  44. Ghofrani, et al • After Swan-Ganz catheter placement, each patient had a trial of inhaled nitric oxide • PAP, PVR, CI, and SVR were measured • Iloprost was delivered after all measurements had returned to baseline • Iloprost decreased PAP, PVR, and Increased CI

  45. Ghofrani, et alPatient Characteristics

  46. Ghofrani, et al

  47. Ghofrani, et al

  48. Ghofrani, et al

  49. Ghofrani, et al

  50. Ghofrani, et al • Conclusions: • Sildenafil lowered PAP and PVR and increased CI without many systemic symptoms or side effects • Combination of drugs had more dramatic but transient benefit • Improved hemodynamics of those with PPH and chronic thromboembolic disease