Treatment strategies for pulmonary hypertension

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  • PAH: how is it treated? There is currently no cure for PAH but advances in understanding how the disease develops means that there are now treatments available which have helped to improve prognosis for patients with this disease. Prognosis is influenced by the status of WHO FC when treatment is started – patients who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in more severe stages (WHO FC III or IV). 1 By recognising and treating patients as early as possible, disease progression may be delayed. Without treatment, patients in WHO FC II can rapidly deteriorate within 6 months to more advanced Pulmonary Arterial Hypertension (PAH) as evidenced by progression of symptoms. 2 References Sitbon O, Humbert M et al. J Am Coll Cardiol 2002; 40 :780-788. Galiè N, Rubin LJ et al. Lancet 2008; 371: 2093-2100.
  • PAH: Screening high risk populations The key to early diagnosis is introducing screening for high risk patient populations if they are asymptomatic. High risk patient populations include: Family members of a patient with familial Pulmonary Arterial Hypertension (FPAH) Patients with systemic sclerosis (SSc) Patients with HIV Patients with portopulmonary hypertension (PoPH) International guidelines now recommend annual screening high-risk groups with Doppler echocardiography. 1-3 Doppler echocardiography is currently the most effective method for screening, however, for a definitive diagnosis right heart catheterisation has to be performed. References Hachulla E and Coghlan JG. Ann Rheum Dis 2004; 63: 1009-1014. Galiè N, Torbicki A, Barst RJ, et al. European Heart Journal 2004; 25 :2243-2278. McGoon M, Gutterman D, Steen V, et al. Chest 2004; 126 :14S-34S.
  • Prostacyclin may soon be available in an inhaled formulation to eliminate the inconvenience and associated side effects of IV or SQ dosing. Inhaled iloprost is currently seeking approval at the FDA for the treatment of PAH in patients with NYHA class III or IV symptoms and is presently available in Europe. The dosing for inhaled iloprost (Trade name Ventavis) is via the breath-actuated nebulizer (ProDose®) in six to nine daily doses during the waking hours. The benefits seen with epoprostenol but limited by its dose route and regimen would be possibly extended to patients in this more convenient formulation. THIS MAY NEED TWEAKING!!!
  • Treatment strategies for pulmonary hypertension

    1. 1. Treatment Strategies for Pulmonary Hypertension Sarfraz Saleemi MRCP, FCCP, FACP Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia
    2. 2. Treatment of Pulmonary Hypertension <ul><li>Currently there is no cure for PAH </li></ul><ul><li>Those who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in the more severe stages </li></ul><ul><li>By recognising and treating patients as early as possible, disease progression may be delayed </li></ul>Sitbon O et al . J Am Coll Cardiol 2002
    3. 3. PAH: Screening high risk population <ul><li>Key to early diagnosis – screening high risk populations: </li></ul><ul><ul><li>Family members of a patient with familial Pulmonary Arterial Hypertension (FPAH) </li></ul></ul><ul><ul><li>Patients with systemic sclerosis (SSc) </li></ul></ul><ul><ul><li>Patients with HIV </li></ul></ul><ul><ul><li>Patients with chronic liver disease and portal hypertension </li></ul></ul><ul><li>International guidelines recommend annual screening with Doppler echocardiography. </li></ul><ul><li>Right heart catheterisation still the only method for definitive diagnosis </li></ul><ul><li>Hachulla E et al Ann Rheum Dis 2004 </li></ul><ul><li>Galie N et al . Eur Heart J 2004 </li></ul><ul><li>McGoon M et al . Chest 2004 </li></ul>
    4. 4. Without treatment: survival correlates with functional class McLaughlin VV, et al. Chest 2004;126:78S-92S
    5. 5. Goals of Therapy <ul><li>Alleviate symptoms, improve exercise capacity and quality of life </li></ul><ul><li>Improve cardiopulmonary hemodynamics and prevent right heart failure </li></ul><ul><li>Delay time to clinical worsening </li></ul><ul><li>Reduce morbidity and mortality </li></ul>
    6. 6. PH treatment algorithm Badesch D. B. et.al. Chest 2007;131:1917-1928
    7. 7. Acute vasoreactivity test <ul><li>Reduction of at least 10 mmHg in mean PAP to reach an absolute value of 40 mmHg with an increased or unchanged CO </li></ul>
    8. 8. PAH Therapy: Life style considerations <ul><li>Sodium restriction </li></ul><ul><li>Abstinence from smoking </li></ul><ul><li>Avoid high altitude </li></ul><ul><ul><ul><li><4,000 feet above sea level </li></ul></ul></ul><ul><li>Avoid physical exertion in setting of pre- or frank syncopal symptoms </li></ul><ul><li>Avoid pregnancy </li></ul>
    9. 9. PAH Therapy: General measures <ul><li>Diuretic treatment is indicated in PAH patients with signs of RV failure and fluid retention </li></ul><ul><li>Continuous long-term O2 therapy is indicated in PAH patients when arterial blood O2 pressure is consistently less than 8 kPa (60 mmHg)c </li></ul><ul><li>Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH, and PAH due to use of anorexigens </li></ul><ul><li>Oral anticoagulant treatment may be considered in patients with APAH </li></ul><ul><li>Digoxin may be considered in patients with PAH who develop atrial tachyarrhythmias to slow ventricular rate </li></ul>
    10. 10. Targets for Current or Emerging Therapies Humbert M et al. N Engl J Med. 2004;351:1425-1436. Pathophysiology of PAH Big Endothelin Endothelin- converting Enzyme Endothelin Receptor A Endothelin Receptor B Vasoconstriction and Proliferation Endothelin Receptor Antagonists Endothelin-1 Endothelin Pathway Arginine Nitric Oxide Synthase Vasodilatation and Antiproliferation Nitric Oxide cGMP Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Prostacyclin Derivatives Prostacyclin Derivatives Prostacyclin Pathway
    11. 11. Choice of Initial PAH Therapy <ul><li>Dependent on many factors </li></ul><ul><li>– Disease severity </li></ul><ul><li>– Approval status </li></ul><ul><li>– Route of administration </li></ul><ul><li>– Side-effect profile </li></ul><ul><li>– Patient preference </li></ul><ul><li>– Physician experience, literature, clinical judgment </li></ul>Barst RJ, et al. J ACC 2009
    12. 12. PAH Determinants of Risk McLaughlin VV, McGoon MD. Circulation . 2006;114:1417-1431. Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes Gradual Progression Rapid II, III WHO class IV Longer (>400 m) 6MW distance Shorter (<300 m) Minimally elevated BNP Very elevated Minimal RV dysfunction Echocardiographic findings Pericardial effusion, significant RV dysfunction Normal/near normal RAP and CI Hemodynamics High RAP, low CI
    13. 13. Choice of Initial PAH Therapy
    14. 14. PAH: Randomized Control Trials of Approved Agents Headache, flushing, dyspepsia 6 MWD CPH Symptoms Double-blind, placebo 12 wks 278 IPAH,CT CHD II, III SUPER Sildenafil Citrate (20, 40 or 80 mg tid) PDE-5 Inhibitor Pain, erythema at infusion site Side effects 6 MWD Symptoms CPH Double-blind 12-wk 470 PAH II-IV SQ Treprostinil / SQ placebo Prostacyclin analogue Administration 6 to 9 times daily Composite Endpoint 6 MWD, sx Double-blind 12-week 203 PH III-IV Inhalational Iloprost / Placebo Prostacyclin analogue Hepatic toxicity (11%; transient, reversible) 6 MWD Symptoms Clinical Worsening CPH Double- Blind 16-wk 213 PAH III,IV BREATHE-1 Oral Bosentan / placebo ET-1 Antagonist Indwelling central line Pump (infection,malf) Side effects Disadvantages 6 MWD Symptoms CPH Survival Open- Label 12-wk 81 PPH III,IV IV Epoprostenol / Conventional Rx Prostacyclin Positive Results Design N Eunctional Class Study/ Drug Class of Drug
    15. 15. PAH-specific drug therapy European Heart Journal (2009) 30, 2493–2537
    16. 16. IV epoprostenol (flolan)
    17. 17. Ventavis ® (iloprost) Inhalation <ul><li>Indicated for inhalation via the Prodose ® AAD ® system only </li></ul><ul><li>2.5 mcg initial dose </li></ul><ul><ul><li>increase to 5 mcg if 2.5 mcg dose is tolerated </li></ul></ul><ul><ul><li>maintain at maximum tolerable dose (2.5 mcg or 5 mcg) </li></ul></ul><ul><li>6-9 inhalations daily during waking hours; 8-10 minutes each </li></ul>
    18. 18. Subcutaneous Treprostinil (Remodulin  ) <ul><li>SQ administration </li></ul><ul><li>Longer half-life than epoprostenol </li></ul><ul><li>Pre-mixed </li></ul><ul><li>Stable at room temperature </li></ul>
    19. 19. Evaluation of Response to therapy <ul><li>Physical exam – JVP, murmurs, edema, </li></ul><ul><li>ascites, liver enlargement, hypotension </li></ul><ul><li>Functional – history (WHO or NYHA </li></ul><ul><li>functional classification, 6 minute walk, </li></ul><ul><li>exercise test </li></ul><ul><li>Labs - BNP, renal and hepatic function </li></ul><ul><li>Echocardiography – RV function, pericardial effusion </li></ul><ul><li>Right heart catheterization – RAP, CI </li></ul>
    20. 20. Relationship Between The Mean 6 MWD at Baseline and Rate of Fatal Events During 3-Month Follow Up (Adjusted R² = 0.5519, P = .0109) Macchia, et al. Am Heart J 2007; 153:1037-1047
    21. 21. Suggested assessments and timing for the follow-up of patients with PAH European Heart Journal (2009) 30, 2493–2537
    22. 22. PAH: Composite Score Predicts Disease Progression Anderson D, et al. AJRCCM 2008
    23. 23. <ul><li>Combination Therapy </li></ul>
    24. 24. Combination Therapy <ul><li>Concurrent </li></ul>+ + Drug 1 Drug 2 Drug 2 Drug 1 Sequential High risk group Low risk group
    25. 25. Combination Therapy: Ongoing or Recently Completed Clinical Trials
    26. 26. Overview of Combination Therapy Trials for PAH + 20 m 235 RCT Bosentan + Inhaled Treprostinil TRIUMPH-1 + 26 m 267 RCT Sildenafil and IV Epoprostenol PACES NS 33 RCT Bosentan and IV Epoprostenol BREATHE-2 NS 40 RCT Iloprost/Beraprost and Bosentan COMBI + 26 m 67 RCT Iloprost inhalation and Bosentan STEP + 19 m 29 RCT Bosental and Sildenafil EARLY
    27. 27. <ul><li>- Thrombendartrectomy CTEPH- Chronic thromboembolic pulmonary Hypertension </li></ul><ul><li>-Atrial Septostomy </li></ul><ul><li>-Lung Transplant </li></ul><ul><li>-Heart and Lung Transplant </li></ul>Non-Pharmacological Treatment
    28. 28. New Treatments on the Horizon
    29. 29. Pulmonary Arterial Hypertension Cellular Processes Newman JH. Circulation 2004;109:2947-2952
    30. 30. <ul><li>• Tyrosine kinase/growth factor receptor inhibitors </li></ul><ul><li>– Imatinib, sorafenib sorafenib </li></ul><ul><li>• Guanylate cyclase (sGC) stimulators </li></ul><ul><li>- Riociguat </li></ul><ul><li>• Vasoactive intestinal peptide (VIP) </li></ul><ul><li>• Serotonin transporter agonists </li></ul><ul><li>• Adrenomedullin </li></ul><ul><li>• Rho-kinase inhibitors </li></ul><ul><li>• Cicletanine </li></ul><ul><li>• Endothelial progenitor cells </li></ul><ul><li>• Gene therapy </li></ul><ul><li>– Vectors expressing </li></ul>Investigational/New Therapies
    31. 32. THANKS

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