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Therapeutic Options for PAH ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas.

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Presentation on theme: "Therapeutic Options for PAH ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas."— Presentation transcript:

1 Therapeutic Options for PAH ADAANI FROST, MD Director, Pulmonary Hypertension Center Professor of Medicine Baylor College of Medicine Houston, Texas

2 2 Learning Objectives (CME, CE, CPE) ●At the completion of this educational activity, participants should be able to: - Discuss the improvements made in PAH-specific therapies over the past decade - Discuss data regarding the efficacy, safety, and tolerability of the major classes of PAH-specific therapies - Identify major class-related adverse effects associated with PAH-specific therapies - Identify issues related to drug-drug interactions and other aspects of clinical pharmacology that impact on patient care - List the major points of difference between the individual agents used to treat PAH

3 Introduction

4 4 PAH: Definition on Right Heart Catheterization Gaine SP, et al. Lancet. 1998;352: Increased mean pulmonary arterial pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise Normal pulmonary artery wedge pressure (PAWP) <15 mm Hg Increased pulmonary vascular resistance (PVR) >3 Wood units

5 5 Goals of Management of PAH ●Improve survival ●Prevent worsening ●Improve hemodynamics ●Maintain or improve functional class ●Improve exercise capacity ●Improve daily functioning and quality of life

6 6 General Measures ●Recommend regular cautious supervised exercise - Maintain skeletal muscle conditioning - Know the pre-determined stopping points (eg, significant dyspnea, chest pain, dizziness) ●Provide prophylaxis for pulmonary infections - Influenza and pneumococcal vaccines ●Maintain hemoglobin levels - Aggressive evaluation for anemia - Monitor for hyperviscosity syndromes in patients with congenital heart disease (eg, Eisenmenger syndrome) Phlebotomy may be indicated in patients with high hematocrit (>63) or with signs of neurologic symptoms Galie N, et al. Eur Heart J. 2004;25:

7 7 General Measures ●Counsel on avoiding pregnancy - High rate of mortality in patients with PAH - Caution with hormonal birth control methods when on bosentan It renders oral contraceptive less effective, so must add barrier method Ambrisentan does not interfere with oral contraceptives - Bosentan and ambrisentan are pregnancy category X Galie N, et al. Eur Heart J. 2004;25:

8 8 General Medical Care for PH ●Oxygen supplementation - Maintain O 2 saturation >90% at rest, with supervised exercise, and during sleep - Unless PAH is severe, most patients are only mildly hypoxemic in the absence of intracardiac shunt or concomitant lung disease O 2 supplementation may not alleviate PAH symptoms associated with shunts - Supplemental O 2 for air travel, if indicated - Avoid altitudes above 5000 feet Badesch DB, et al. Chest. 2004;126:35S-62S. Galie N, et al. Eur Heart J. 2004;25:

9 9 Considerations for Selecting Initial Therapy for PAH ●Severity of symptoms/functional class ●Physical examination (right-heart failure?) ●Rate of progression ●Echocardiogram (RV size and function) ●Cardiopulmonary hemodynamics ●6-minute walk distance/exercise capacity ●BNP/NT-pro-BNP ●Capability of patient to handle parenteral therapy - Parenteral therapy is first choice in very advanced patients ●Other issues - Drug-drug interactions, adverse events, comorbid conditions (eg, diabetes), route of administration, dosing intervals, cost

10 10 Mechanisms of Action of Therapies for PH Humbert M, et al. N Engl J Med. 2004;351: Nitric oxide cGMP Vasodilation and antiproliferation Endothelial cells Nitric oxide pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilation and antiproliferation Vasoconstriction and antiproliferation Endothelin- receptor A Endothelin- receptor B Endothelin pathwayProstacyclin pathway Endothelin-1 Endothelin- receptor antagonists Exogenous nitric oxide Prostacyclin derivates Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5

11 11 Commonly Reported Clinical Trial Outcomes in PAH ●6-minute walk distance - Primary endpoint in many clinical trials - Easy to administer - Correlates with other outcomes ●Change in NYHA/WHO functional class - Secondary endpoint in many trials ●Improvement in hemodynamics - Requires repeat catheterization

12 12 Commonly Reported Clinical Trial Outcomes in PAH ●Time to clinical worsening - Combined endpoint being used more frequently - Variation in definition depending on study ●Mortality - Placebo-controlled survival studies not feasible/ethical with modern PAH therapies - Survival data available based on open-label long-term extension studies of placebo-controlled trials

13 13 Pharmacotherapy for PAH: Routes of Delivery ●Oral therapy - Endothelin receptor antagonists (ERAs) - PDE5 inhibitors - Calcium channel blockers (small minority of patients) ●Inhaled therapy - Prostanoids ●Intravenous/subcutaneous therapy - Prostanoids

14 14 Treatment Options for Patients Failing Acute Vasoreactivity Testing by NYHA Functional Class Functional Class II Functional Class III Functional Class IV Sildenafil Ambrisentan* Treprostinil sc Treprostinil iv Bosentan † Bosentan ‡ Ambrisentan* ‡ Sildenafil ‡ Epoprostenol iv Iloprost (inhaled) Treprostinil sc Treprostinil iv Epoprostenol iv Bosentan Iloprost (inhaled) Sildenafil Treprostinil sc Treprostinil iv Badesch DB, et al. Chest. 2007;131: Galie N, et al. Presented at ESC *Ambrisentan approved after development of updated guidelines. † Inclusion based on data presented at ESC ‡ Not necessarily in order of preference.

15 15 Options for Patients Failing to Improve or Deteriorating Under Initial Therapy Badesch DB, et al. Chest. 2007;131: Functional Class III or IV Atrial septostomy and/or Lung transplantation Combination Therapy(?) Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors

16 16 Management of PAH Therapy ●Up to 100% of PAH patients will report 1 or more adverse effects of PAH therapy ●Most adverse effects should be managed conservatively ●Since there are limited agents and alternatives, patient risk from adverse event needs to be judged against reduced efficacy of PAH therapy

17 PAH Therapies in Treatment-Naïve Patients

18 Calcium Channel Blockers

19 19 Oral Calcium Channel Blockers in IPAH ●Favorable acute response to vasodilator challenge - Decrease in mPAP of at least 10 mmHg to <40 mm Hg - Increased or unchanged cardiac output ●Patients who fail acute vasodilator challenge should not be treated with calcium channel blockers Badesch DB, et al. Chest. 2004;126:35S-62S.

20 20 French Registry: Response to Acute Vasodilator Challenge Response (%) Idiopathic n=649. Challenge with vasodilator at time of right heart catheterization. 10.3% Humbert M, et al. Am J Respir Crit Care Med. 2006;173: % 2.6% 0% 3.3% 1.6% 6.8% Familial Connective Tissue Congenital Heart Portal Hypertension Anorexigens HIV >2 Factors

21 21 Long-Term Response to Calcium Channel Blocker Therapy in IPAH ●Long-term responders to calcium channel blocker therapy (at least 1 year) - Less severe disease at baseline - More pronounced decrease in mPAP during acute challenge - Long-term responders 54% of acute responders 6.8% (95% CI, 4.7% to 8.9%) of patient sample - 5-year survival rate of calcium channel blocker therapy failures: 48% Responders Patients (%) Acute Vasodilator Challenge Long-Term Calcium Channel Blocker Therapy 12.6% 6.8% Sitbon O, et al. Circulation. 2005;111: n=557.

22 22 Survival on Oral Calcium Channel Blocker Therapy Sitbon O, et al. Circulation. 2005;111: Survival endpoint included those who received transplants or were lost to follow-up Years Failures Cumulative Survival Responders Subjects at Risk (n) Responders Failures Long-Term Calcium Channel Blocker Therapy

23 Prostanoids Intravenous/Subcutaneous Therapy

24 24 Prostanoid Intravenous/Subcutaneous Therapy for PAH ●Requires expertise as numerous complications and risks are associated with therapy - Adequate coordinator support for associated problems Adequate patient support for medication preparation Epoprostenol ●First PAH-specific therapy ●Requires continuous intravenous infusion Treprostinil ●Available both as continuous subcutaneous injection or continuous intravenous infusion ●Longer half-life and more chemically stable than epoprostenol Barst RJ, et al. N Engl J Med. 1996;334: Simonneau G, et al. Am J Respir Crit Care Med. 2002;165:

25 25 Improved Survival With Epoprostenol for IPAH P=0.003 versus conventional therapy (anticoagulants, oral vasodilators, diuretic agents, cardiac glycosides, and supplemental oxygen). Barst RJ, et al. N Engl J Med. 1996;334: Epoprostenol (n=41) Conventional therapy (n=40) Weeks Survival (%)

26 26 Intravenous Epoprostenol for Severe PAH: 3-Year Survival n=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from historical controls. *P<0.001 at all time points. McLaughlin VV, et al. Circulation. 2002;106: Months Survival (%) * * * Observed Expected

27 27 Hemodynamic Variables Improved With Epoprostenol Therapy McLaughlin VV, et al. Circulation. 2002;106: mPAP mRAP Cl PVR Change (mm Hg) Change (L/min/m 2 ) Change (Wood units ) Change (mm Hg) Epoprostenol Epoprostenol Epoprostenol

28 28 Subcutaneous Treprostinil: Week-12 Change From Baseline in 6-Minute Walk Distance by Dose Quartile Simonneau G, et al. Am J Respir Crit Care Med. 2002;165: Mean Change in 6-Minute Walk Distance (meters) < <8.2 n=470. Chronic study drug infusion initiated at 1.25 ng/ kg/min. At Week 12, the maximum allowable dose was 22.5 ng/kg/min. *P=0.006 for all doses of treprostinil versus placebo <13.8 >13.8 Dose Quartile (ng/kg/min)

29 29 Long-Term Outcomes With Subcutaneous Treprostinil Barst RJ, et al. Eur Respir J. 2006;28: Patients (%) Discontinue for Deterioration Death n=860. Patients followed for up to 4 years. Switch Therapy Add Therapy Discontinue for Adverse Events 14% 16% 11% 15% 23%

30 30 SC Treprostinil as Naïve, Add-On, and Transition Therapy Soto FJ, et al. Am J Respir Crit Care Med. 2008;177:A966. Changes in 6-Minute Walk Distance: >1 Year Follow-Up n=52. *P=0.0009; † P=0.01; ‡ P=0.02 versus baseline for each group. Change from baseline 6-MWD (m) Naïve (n=25) Add-On (n=15) Transition (n=13) 120* 128 † 76 ‡

31 31 Intravenous Treprostinil: Impact on 6-Minute Walk Distance Baseline n=16. *P=0.008 and † P=0.001 versus baseline. Week 6Week 12 Tapson VF, et al. Chest. 2006;129: * 400 † Total 6-Minute Walk Distance (meters)

32 32 Intravenous Treprostinil: Hemodynamic Changes at 12 Weeks mPAP mRAP Cl PVR Change (mm Hg) Change (L/min/m 2 ) Change (Wood units ) Change (mm Hg) -4.2 Treprostinil -0.8 Treprostinil Treprostinil Tapson VF, et al. Chest. 2006;129: Treprostinil

33 33 Epoprostenol Pharmacokinetics Half life2.7 minutes Bioavailability100% MetabolismSpontaneous and enzymatic degradation ExcretionUrinary CYP interactionsNone StabilityUnstable at room temperature; requires refrigeration Epoprostenol full prescribing information

34 34 Treprostinil Pharmacokinetics Half life4 hours Bioavailability~100% MetabolismHepatic ExcretionUrinary CYP interactionsNone known Treprostinil full prescribing information

35 35 Adverse Events Associated With Prostanoid Injection Therapy ●Common adverse events - Adverse events associated with therapy should be expected (incidence rates >80%) Most adverse events associated with vasodilation - Headache, jaw pain, flushing/skin rash, diarrhea, nausea and vomiting - Catheter infections and injection site reactions (treprostinil) Epoprostenol full prescribing information Treprostinil full prescribing information

36 36 Epoprostenol and Treprostinil: Common Adverse Effects ●Flushing ●Headache ●Diarrhea, nausea, vomiting ●Jaw pain ●Myalgia ●Hypotension ●Anxiety, nervousness, agitation ●Chest pain ●Dizziness ●Bradycardia ●Abdominal pain ●Dyspnea ●Back pain ●Sweating ●Dyspepsia ●Paresthesia ●Tachycardia ●Delivery site complications Epoprostenol full prescribing information Treprostinil full prescribing information

37 37 Thrombocytopenia Correlated With Epoprostenol Dose and With RAP Chin KM, et al. Am J Respir Crit Care Med. 2008;177:A260. n=54 current and former epoprostenol-treated patients RAP <10 mmHg RAP mmHg RAP >15 mmHg Platelet Count (1000s) Epoprostenol Dose (ng.kg/min)

38 38 Epoprostenol-Related Thrombocytopenia Platelet Count Drop >50,000 Noted in Red Platelet Count at Baseline Platelet Count 2-4 Months Platelet Count at 8-12 Months Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206.

39 39 Catheter Infections Associated With Intravenous Prostacyclins ●Infection rates range from 0.43 to 1.13 infections per 1000 treatment days ●IV treprostinil associated with slightly higher infection rates compared with epoprostenol - Treprostinil also associated with higher incidence of Gram-negative bacteria ●Exposure to Gram-negative pathogens may occur during bathing or showering ●A closed-hub system may decrease bacterial contamination of the hub Doran AK, et al. Int J Clin Pract. 2008;62(suppl 160):5-9.

40 40 Preventing and Managing Catheter Infections ●Complete guidelines available at ●Use a cuffed and tunneled CVC ●No submersion of catheter in water ●Remove catheter if bacterial infection is documented - Do not use “clear the line” approach ●Use of gloves does not eliminate hand hygiene need ●Do not use topical antibiotics or creams on insertion sites Doran AK, et al. Int J Clin Pract. 2008;62(suppl 160):5-9.

41 41 Treprostinil SC Infusion Site Pain and Reaction ●Infusion site pain and infusion site reaction (redness and swelling) occur in the majority of patients ●These symptoms were often severe and could lead to treatment with narcotics or discontinuation of treprostinil ●Infusion site pain is not related to dose ●Site pain varies by patient as well as by infusion site ●There are sometimes simply “good” sites and “bad” sites ●Site pain is often the worst 2 to 5 days into a new injection site Treprostinil full prescribing information

42 42 Treprostinil Site Pain Care: Nonpharmacologic Approaches ●Encourage patients to change a “bad” site right away ●Allow patients to maintain a “good” site for several days ●Try alternative sites such as upper buttocks or backs of upper arms ●Remove any medication droplets on the end of the needle after priming ●For frequent topical medication application, apply thin DuoDERM ® prior to catheter insertion ●Try dry catheter preplacement method before initiating medication ●Change to a more concentrated solution to allow for less volume infusion per hour

43 Prostanoids Inhalation Therapy

44 44 Prostanoid Mechanisms of Action Humbert M, et al. N Engl J Med. 2004;351: Newman JH, et al. Circulation. 2004;109: cAMP Vasodilation and antiproliferation Arachidonic acid Prostaglandin I 2

45 45 Inhaled Prostanoid Therapy for PAH: Iloprost ●Stable prostacyclin analogue ●Effect on PVR approximately equivalent to inhaled NO or oral sildenafil during acute testing ●6 to 9 inhalations daily required - Half-life of 20 to 30 minutes Olschewski H, et al. N Engl J Med. 2002;347: Ghofrani HA, et al. J Am Coll Cardiol. 2004;43:68S-72S. Rubin LJ, et al. Proc Am Thorac Soc. 2006;3:

46 46 Inhaled Iloprost for Severe PAH: Combined Endpoint Analysis Patients (%) All 16.8%* Non-IPAH 4.9% 20.8% 12.5% n=203. *P=0.07 versus placebo. Non-IPAH group included patients with chronic thromboembolic pulmonary hypertension (n=57). Iloprost Placebo Olschewski H, et al. N Engl J Med. 2002;347: % 4.3% IPAH Improvement of 1 NYHA Class and >10% Increase in 6-Minute Walk Distance

47 47 Inhaled Iloprost Pharmacokinetics Half life20 to 30 minutes BioavailabilityUndetermined MetabolismHepatic ExcretionUrinary CYP interactionsNone known Iloprost full prescribing information

48 48 Safety and Tolerability Considerations With Inhaled Iloprost ●Adverse events - Flushing, headache, jaw pain typical of prostanoid therapy - Cough associated with route of delivery ●Warnings and precautions - Risk of hypotension in patients with low systemic blood pressure Iloprost full prescribing information


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