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Learning Objectives Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies,

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Presentation on theme: "Learning Objectives Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies,"— Presentation transcript:

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2 Learning Objectives Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Evaluate patients for comorbid conditions to determine the relative risk for PAH. Use evidence-based guidelines to select the most appropriate treatment. Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The learning objectives for the program are as follows: * Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. * Evaluate patients for comorbid conditions to determine the relative risk for PAH. * Use evidence-based guidelines to select the most appropriate treatment. * Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. * Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring.

3 Overview of PAH US prevalence = estimates up to 50,000 to 100,000
15,000 to 25,000 diagnosed and treated Disease of small pulmonary arteries characterized by vascular narrowing and increased vascular resistance Vasoconstriction Cell proliferation and pulmonary vascular remodeling Thrombosis in situ Common cause of death: Right ventricular (RV) failure Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. The prevalence of PAH is estimated at nearly 50,000 to 100,000, with only 15,000 to 25,000 patients diagnosed and treated. PAH is a disease of small pulmonary arteries and is characterized by vascular narrowing and increased vascular resistance. The three key features of the disease are vasoconstriction, cell proliferation and pulmonary vascular remodeling, and thrombosis in situ. The most common cause of death in patients with PAH is right ventricular failure. The illustration shows pulmonary artery hypertrophy and near obliteration of the arterial lumen. Humbert, et al. J Am Coll Cardiol. 2004;43:13S-24S. 3

4 Mechanisms of Pathology for PAH
Endothelin pathway Prostacyclin pathway Nitric oxide pathway Endothelial cells L-arginine Preproendothelin Proendothelin Arachidonic acid Prostaglandin I2 NOS Nitric oxide Endothelin-1 Prostaglandin I2 Endothelin-receptor A Endothelin-receptor B Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. The graphic shows three pathways that are believed to play a key role in the pathology of PAH: the endothelin pathway, nitric oxide pathway, and the prostacyclin pathway. The illustration also shows the sites and targets for common treatment options. Endothelin receptor antagonists act on the endothelin receptors in that pathway. The target for the phosphodiesterase-5 inhibitors is the nitric oxide pathway. Meanwhile, the prostacyclin analogs target the prostacyclin pathway. Exogenous nitric oxide Prostacyclin derivates Endothelin-receptor antagonists cGMP cAMP Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Humbert, et al. N Engl J Med. 2004;351:

5 Pathophysiology of PAH
Genetic Predisposition } Vasoconstriction Cell Proliferation Thrombosis Vascular Remodeling Other Risk Factors (CTD, CHD, toxins, etc.) Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. The pathophysiology of PAH involves multiple processes. Often patient risk factors and/or a genetic predisposition combine with altered pathways and mediators to initiate the disease process. Vasoconstriction, cell proliferation, and thrombosis eventually lead to vascular remodeling. Altered Pathways And Mediators

6 Genetic Mutations in PAH
Mutations in the gene that codes for BMPR2 BMPR2 mutations are identified in ~ 70% of patients with heritable PAH BMPR2 mutations are also found in ~ 20% of patients with I-PAH » Clinical course – poor response to acute vasodilator testing and treatment with calcium channel blockers Mutations in the gene that codes for: Activin receptor-like kinase type 1 (ALK1) Endoglin (ENG) » Cause hereditary hemorrhagic telangiectasia (HHT) and may lead to the development of PAH Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Genetic mutations play a role in the pathogenesis of PAH. Predominant are mutations in the gene that codes for BMPR2. In fact, BMPR2 mutations are identified in ~ 70% of patients with heritable PAH and ~ 20% of patients with I-PAH. Patients with these mutations respond poorly to acute vasodilator testing and treatment with calcium channel blockers. Mutations can also be found in the gene that codes for activin receptor-like kinase type 1 (ALK1) and endoglin (ENG). These mutations can cause hereditary hemorrhagic telangiectasia (HHT) and may eventually lead to the development of PAH. Machado, et al. J Am Coll Cardiol. 2009;54:S32-42.

7 Vasoconstriction in PAH
Vasodilation Enhanced Vasoconstriction ↑ Endothelin ↑ Serotonin (5-HT) ↑ Thromboxane ↓ Potassium channel expression/activity Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Vasoconstriction is a key component in the pathophysiology of PAH. Vasoconstriction is enhanced, and patients have increased levels of endothelin, serotonin, and thromboxane. Potassium channel expression / activity is reduced. In addition, vasodilation is impaired in patients with PAH. Levels of prostacyclin, nitric oxide, and nitric oxide synthase are reduced. Impaired Vasodilation ↓ Prostacyclin ↓ Nitric oxide ↓ Nitric oxide synthase

8 Cell Proliferation in PAH
High PVR Proliferative / angiogenic / apoptosis resistant ↑ Endothelin, serotonin (5-HT), VEGF, BMPR2 and ALK1 mutations ↓ Potassium channel expression/activity Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. High PVR is present in patients PAH. Cells are considered proliferative, angiogenic, and apoptosis resistant. There are increased levels of endothelin, serotonin (5-HT), and VEGF. BMPR2 and ALK1 mutations are also present. Potassium channel expression/activity is decreased.

9 Vascular Remodeling in PAH
Poorly understood PAH cells are pro-proliferative Many factors implicated in pro-proliferative phenotype Proliferative and obstructive remodeling of the pulmonary vessel wall Some new therapies aimed at controlling cell growth Several potential mediators Alterations in gene expression in growth-controlling pathways Growth factors Inflammatory mediators Covers learning objective 1) Utilize knowledge regarding the specific disease pathways for PAH in order to identify the sites and targets for common therapies, including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. The precise mechanism of vascular remodeling seen in patients with PAH is poorly understood. We do know that PAH cells are pro-proliferative and that there are many factors implicated in the pro-proliferative phenotype. With PAH, the pulmonary vessel wall undergoes proliferative and obstructive remodeling. Thankfully, research is looking at therapies which will control cell growth. The mediators believed to be responsible in the vascular remodeling in PAH include: alterations in gene expression in growth-controlling pathways, growth factors, and inflammatory mediators. Galie, et al. Eur Heart J. 2009;30:

10 Revised Classification of Pulmonary Hypertension Group 1: Pulmonary Arterial Hypertension (PAH)
Criteria mPAP ≥ 25 mm Hg PCWP  15 mm Hg No significant: Obstructive/Restrictive lung disease Left heart disease Thromboembolic disease Types Idiopathic PAH Heritable PAH BMPR2, ALK1, Endoglin Drug- and toxin-induced Associated with: Connective tissue disease HIV Portal pulmonary Congenital heart diseases Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of the newborn Covers learning objective 2) Evaluate patients for comorbid conditions to determine the relative risk for PAH. The 4th World Symposium on Pulmonary Hypertension (PH) was held in 2008 in Dana Point, California. Proceedings from this meeting were published in June of The classification of PH was updated to reflect new research and clinical findings. Group one under the category of PH is pulmonary arterial hypertension (PAH). The criteria for PAH are: PAP ≥ 25 mm Hg, PCWP  15 mm Hg, and no significant obstructive/restrictive lung disease, left heart disease, or thromboembolic disease. Types of PAH include: idiopathic PAH; heritable PAH (BMPR2, ALK1, endoglin); drug- and toxin-induced; associated with conditions (connective tissue disease, HIV, portal pulmonary, congenital heart diseases, schistosomiasis, chronic hemolytic anemia); and persistent pulmonary hypertension of the newborn. Under the category of drug- and toxin-induced PAH, the relative risks for individual substances are as follows: Definite: Aminorex, Fenfluramine, Dexfenfluramine, Toxic Rapeseed Oil Possible – Cocaine, Phenylpropanolamine, St. John’s Wort, Chemotherapeutic agents, SSRI Likely – Amphetamines, L-tryptophan, methamphetamines Unlikely – Oral contraceptives, estrogen, cigarette smoking Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54. 10

11 Differential Diagnosis of PAH
Clinical presentation Electrocardiogram (ECG) Chest radiograph Pulmonary function tests and arterial blood gases ECHO (right heart hemodynamics) Ventilation / perfusion lung scan High-resolution CT, contrast CT, pulmonary angiography Cardiac MRI Blood tests and immunology Abdominal ultrasound scan Right heart catheterization and vasoreactivity Covers learning objective 2) Evaluate patients for comorbid conditions to determine the relative risk for PAH. There are tests and procedures that can be used to assist in the diagnosis of PAH: Clinical presentation; electrocardiogram (ECG); chest radiograph; pulmonary function tests and arterial blood gases; ECHO (right heart hemodynamics); ventilation / perfusion lung scan; high-resolution CT, contrast CT, and pulmonary angiography; cardiac MRI; blood tests and immunology; abdominal ultrasound scan; and right heart catheterization and vasoreactivity. Galie, et al. Eur Heart J. 2009;30:

12 Invasive Diagnostic Testing for PAH
Right heart catheterization Mandatory for all patients being tested for PAH Pulmonary arterial pressure (PAP) Cardiac output (CO) Right atrial pressure (RAP) Pulmonary arterial wedge pressure (PAWP) Covers learning objective 2) Evaluate patients for comorbid conditions to determine the relative risk for PAH. Right heart catheterization is mandatory for all patients being tested for PAH. This diagnostic test measures PAP, CO, RAP, and PAWP. Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

13 Prevalence of PAH in Associated Conditions 4th World Symposium on PH (2008)
Systemic sclerosis 7-12 % HIV infection % Portal hypertension 2-6 % Congenital heart disease per million in those with congenital systemic-to-pulmonary shunts → % affected by Eisenmenger syndrome Schistosomiasis 4.6 % in those with hepatosplenic disease Chronic hemolytic anemia Highly variable; currently being studied Covers learning objective 2) Evaluate patients for comorbid conditions to determine the relative risk for PAH. The prevalence of PAH in associated conditions varies dramatically. Patients with systemic sclerosis have an estimated prevalence of 7-12%. Those with HIV infection have an estimated prevalence of less than 0.5%. The prevalence is 2-6% for patients with portal hypertension. PAH is prevalent in per million of patients with congenital systemic to pulmonary shunts. Furthermore, 25-50% go on to be affected by Eisenmenger syndrome. Just less than 5% of patients with hepatosplenic disease develop PAH. Patients with chronic hemolytic anemia are at an increased risk of developing PAH; however, the prevalence rates are highly variable and are being actively studied. Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.

14 Patient Evaluation Confirm presence of PH
Determine type of PH present (PAH?) Gauge functional capacity Covers learning objective 2) Evaluate patients for comorbid conditions to determine the relative risk for PAH. The steps followed in the patient evaluation process are listed in this slide. After the diagnosis of PH is confirmed, the type of PH is determined. If PAH is the type present, the next step would be to gauge the functional capacity of the patient. Prognosis is then estimated based on determinants of patient risk. A treatment and monitoring plan is then developed for the individual patient. Estimate prognosis (survival) Determine treatment and monitoring plan

15 NYHA/WHO Functional Classification for PAH
No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope. Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and/or fatigue may be present at rest; discomfort is increased by any physical activity. Covers learning objective 2) Evaluate patients for comorbid conditions to determine the relative risk for PAH. The functional classification for PAH as developed and approved by the NYHA and WHO is listed in the table. A patient’s physical activity and abilities, comfort, and symptoms are used to determine the functional class. The class number increases as the patient’s health deteriorates. The classification is used to guide treatment selection. Taichman, et al. Clin Chest Med. 2007;28:1-22. 15 15

16 Predicting Survival in PAH
Hemodynamics Response to acute vasodilator therapy (calcium channel blockers, CCB) Exercise capacity NYHA/WHO functional class Biomarkers (i.e., BNP levels) Covers learning objective 4) Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. Determining a patient’s prognosis and recognizing a change in prognosis helps the clinician determine the most appropriate treatment choice. It also lets the clinician know when therapy needs to be augmented. The tests and clinical parameters that are used to help predict patient survival are as follows: hemodynamics, response to CCB therapy, exercise capacity, functional class, and biomarker levels. Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

17 Response to CCB Therapy and Survival in Patients with PAH
0.0 0.2 0.4 0.6 0.8 1.0 Long-term CCB responders (~50% of acute responders or ≤ 6% of IPAH patients) P = Cumulative Survival Long-term CCB non-responders Covers learning objective 4) Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. Sitbon and colleagues examined survival in patients with PAH. Survival in patients who responded to CCB therapy was significantly greater than survival in patients who did not respond to CCB therapy. 2 4 6 8 10 12 14 16 18 Years Long-term CCB responders Patients at risk (N) 38 33 30 22 13 8 3 3 2 1 19 12 7 4 Long-term CCB non-responders Sitbon, et al. Circulation. 2005;111:

18 Impact of Delay in Treatment on Patient Survival
96% 84% 86% ↑Transition placebo group to ambrisentan 76% Event-Free Survival (% Patients) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. This graph shows an interesting phenomenon. It comes from a study where two patient groups are followed over the course of 52 weeks. The first group received ambrisentan for the study duration. The second group transitioned from placebo to ambrisentan at week 12. With regard to improved survival, patients in the second group (placebo → ambrisentan) never quite catch up to patients in the first group. It reinforces the belief that early treatment is critical for improved patient survival. Weeks N = Ambrisentan N = Placebo → Ambrisentan ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.

19 Goals for Patients with PAH
Ultimate goals Feel better Do more Live longer Gap in understanding → ? Promote vasorelaxation ? Suppress cellular proliferation ? Induce apoptosis within pulmonary artery wall Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. The general goals for patients with PAH are quite simple. Ultimately, we want patients to feel better, do more, and live longer. Since we are still uncovering aspects of the pathology of PAH and mechanisms of disease, we are fine tuning the specific goals for patients. Researchers have studied methods to promote vasorelaxation, suppress cellular proliferation, and induce apoptosis within the pulmonary artery wall. Archer, et al. N Engl J Med. 2009;361:

20 PAH Evidence-Based Treatment Algorithm
Acute vasoreactivity test (A for IPAH) (E/C for APAH) Expert referral (E/A) Supportive therapy and general measures Avoid excessive physical exertion (E/A) Birth control (E/A) Psychosocial support (E/C) Infection prevention (E/A) Oral anticoagulants (E/B) – IPAH/HPAH Diuretics (E/A) Oxygen (E/A) Digoxin (E/C) Supervised rehabilitation (E/B) ACUTE RESPONDER NON-RESPONDER NO WHO Class I-IV Amlodipine, diltiazem, nifedipine (B) Strength of Recommendation WHO Class II WHO Class III WHO Class IV A Ambrisentan, Bosentan, Sildenafil Ambrisentan, Bosentan, Epoprostenol IV, Iloprost inh, Sildenafil Epoprostenol IV B Sitaxsentan, Tadalafil Sitaxsentan, Tadalafil, Treprostinil SC Iloprost inh C Beraprost Treprostinil SC E/B Iloprost IV, Treprostinil IV Initial combination therapy (see below) E/C Ambrisentan, Bosentan, Sildenafil, Sitaxsentan, Tadalafil Not approved Treprostinil inh Sustained response (WHO I-II) YES Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. This treatment algorithm comes from the Dana Point proceedings of the 4th World Symposium on PH. It is an evidence-based algorithm which follows a step-by-step approach to treatment. After the diagnosis of PAH, clinicians begin supportive therapy and general measures. Next, acute vasoreactivity testing is recommended. Patient response to the test will determine the next path. Patients who do not respond to the acute vasoreactivity test have several treatment options available to them. The table lists those choices. A patient’s functional class greatly influences the treatment selection. Sequential combination therapy is reserved for patients who have an inadequate response to monotherapy. Atrial septostomy and/or lung transplantation are used as a last resort. KEY: Strength of recommendation -- (A) Strong; (B) Moderate; (C) Weak; (D) Negative; (E/B) Moderate recommendation on the basis of expert opinion only; (E/C) Weak recommendation on the basis of expert opinion only Amlodipine, diltiazem, nifedipine (B) INADEQUATE CLINICAL RESPONSE Sequential combination therapy INADEQUATE CLINICAL RESPONSE PDE-5 I ERA + (B) Prostanoids 4th World Symposium on PH. Dana Point, CA Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. Atrial septostomy (E/B) and/or lung transplant (E/A) 20

21 Acute Vasoreactivity Test for PAH
Calcium Channel Blockers (CCB) Acute vasoreactive response = Positive response in < 10% of patients with IPAH Responders are on higher than ordinary doses of CCB: amlodipine 10 mg twice daily; diltiazem 360 mg twice daily Moderate recommendation based on scientific evidence Reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO with acute pulmonary vasodilator challenge with either inhaled NO or IV epoprostenol Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Acute vasoreactivity testing is commonly used in patients with PAH. A positive response is defined as a reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO with acute pulmonary vasodilator challenge with either inhaled NO or IV epoprostenol. Less than 10% of patients with I-PAH demonstrate a positive response. Patients who do respond are placed on higher than usual doses of calcium channel blockers (CCB). Overall, the use of CCB is only moderately recommended based on scientific evidence. Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

22 FDA-Approved Agents for the Treatment of PAH
Prostacyclin analogs (PA) Epoprostenol Iloprost Treprostinil Endothelin-receptor antagonists (ERA) Ambrisentan Bosentan Phosphodiesterase-5 inhibitors (PDE-I) Sildenafil Tadalafil Medications approved for the treatment of PAH include the following categories and individual agents: Prostacyclin analogs – epoprostenol, iloprost, and treprostinil Endothelin-receptor antagonists – bosentan and ambrisentan Phosphodiesterase-5 inhibitors (PDE-I) – sildenafil and tadalafil

23 Route of Administration
Comparison of Agents Agent Route of Administration Adverse Events Epoprostenol Continuous IV infusion Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain Iloprost Inhalation Headache, cough, flushing, jaw pain Treprostinil » Subcutaneous » IV » Inhalation* » Pain and erythema at injection site, headache, nausea, diarrhea, rash » Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain » Cough, headache, flushing, throat irritation, nausea Ambrisentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edema Bosentan Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral edema, anemia Sildenafil Headache, flushing, dyspepsia, epistaxis Tadalafil Headache, dyspepsia, back pain, myalgia, flushing Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The table compares the individual agents in terms of route of administration used and adverse events reported. Epoprostenol is administered via continuous IV infusion. Iloprost is administered via inhalation (ultrasonic nebulizer). Treprostinil can be delivered subcutaneously, intravenously, or through inhalation. Adverse events common to these three agents include headache, jaw pain, and flushing. Injection site reactions are also possible for epoprostenol and treprostinil IV. Bosentan and ambrisentan are both administered orally. Bosentan has a greater incidence of LFT elevation compared to ambrisentan. Peripheral edema has been reported with both medications. Sildenafil and tadalafil are both administered orally. Headache, flushing, and dyspepsia have been reported with both agents. Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53: *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

24 Epoprostenol for PAH Prostacyclin analog
Indication – WHO group I - functional class III, IV Administration – continuous IV infusion via central venous catheter Dosage – ng/kg/min Storage – must keep medication cold with ice packs (stable for 8 hours at room temp) CADD pump Central line Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Epoprostenol is a prostacyclin analog indicated for patients with PAH, functional class III and IV. It is administered via continuous IV infusion. The typical dosage is ng/kg/min. It must be kept cold with ice packs because it is only stable for 8 hours at room temperature. 24

25 Epoprostenol for IPAH Patient Survival Epoprostenol (N=41) 100 80 60
40 20 P = 0.003 Conventional therapy (N = 40) Patient Survival (%) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. NOTE: Only PAH clinical study to demonstrate a patient survival benefit The graph illustrates findings from a study by Barst and colleagues. Following 12 weeks of treatment, patients receiving epoprostenol had significantly greater survival rates compared to patients receiving conventional therapy for I-PAH. 2 4 6 8 12 10 Weeks Barst, et al. N Engl J Med. 1996;334:

26 Iloprost for PAH Prostacyclin analog
Indication – WHO group I - functional class III, IV Administration Ultrasonic nebulizer Dosage = 2.5 to 5 mg, 6 to 9 times daily; maximum daily dosage evaluated in clinical studies = 45 mg Administration in well-ventilated areas Theoretical advantage of selectivity Pulmonary vs systemic administration Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Iloprost is a prostacyclin analog indicated for patients with PAH, functional class III and IV. It is administered via ultrasonic nebulizer. The typical dosage is 2.5 to 5 mg, 6 to 9 times daily. The maximum daily dosage evaluated in clinical studies was 45 mg. It needs to be administered in well-ventilated areas. The route of administration of iloprost takes advantage of the theoretical superiority of pulmonary administration. 26 26

27 Iloprost for PAH Composite Primary Endpoint at Week 12
Responders (% Patients) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. A study by Olschewski and colleagues measured the response to iloprost in 203 patients with PAH. After 12 weeks, the composite primary endpoint was significantly poorer in placebo-treated patients compared to iloprost-treated patients. The composite primary endpoint combined change in exercise capacity, functional class, and clinical deterioration. N = 203 Olschewski, et al. N Engl J Med. 2002;347:322-9.

28 Treprostinil for PAH Prostacyclin analog
Indication – WHO group I -functional class II, III, IV Dosage – 1.25 – 40 ng/kg/min Administration Subcutaneous IV Inhalation Infusion site reaction Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Treprostinil is a prostacyclin analog indicated for patients with PAH, functional class II, III, and IV. The typical dosage for treprostinil is 1.25 – 40 ng/kg/min. The routes of administration for treprostinil are: subcutaneous, IV, and inhalation. 28

29 Treprostinil SC for PAH Change in 6-MWD (from Baseline to Week 12)
5 10 15 20 25 30 35 40 36.1 P = 0.03 20 Change from Baseline (meters) N = 470 Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Simonneau and colleagues evaluated treprostinil subcutaneous in patients with PAH. Change in 6-MWD from baseline to week 12 was greatest for the highest dose of treprostinil. 3.3 1.4 < 5.0 ng/kg/min ng/kg/min 8.2 – 13.8 ng/kg/min > ng/kg/min Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.

30 Treprostinil IV for PAH Change from Baseline to Week 12
Change in 6-MWD Change in Functional Class N = 14 Change from Baseline (meters) Number of Patients Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Tapson and colleagues measured the change in 6-MWD and the change in functional class for patients with PAH treated with treprostinil IV for 12 weeks. The results for change in 6-MWD can be found in the bar chart on the left. The results for change in functional class can be found in the bar chart on the right. Weeks Baseline 12 Weeks Tapson, et al. Chest. 2006;129:683-8.

31 Treprostinil Inhalation for PAH: TRIUMPH-1 Clinical Trial
FDA approval – July, 2009 Administered four times daily Study design – phase lll, randomized, double-blind, placebo-controlled, 12-week study Combination with bosentan or sildenafil Open-label extension for 24 months N= 206 Adverse events – cough, headache, nausea, diarrhea, flushing, throat irritation Change in 6-MWD from Baseline (meters) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Preliminary results from the TRIUMPH-1 clinical trial were presented at the 2009 ATS meeting. This trial was a phase III, randomized, double-blind, placebo-controlled study of treprostinil inhalation administered four times daily. Background therapy with bosentan or sildenafil was permitted. Following 12 weeks of treatment, 206 patients entered a 24-month, open-label extension. Exercise capacity, as measured by 6-MWD, improved dramatically over the course of the study. Adverse events were mild to moderate in severity, and included cough, headache, nausea, diarrhea, flushing, and throat irritation. Months ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

32 Endothelin Receptor Antagonists Comparison of Agents
Bosentan Ambrisentan Use in pregnancy Pregnancy category X (non-hormonal birth control method required) LFT elevation Monthly LFT monitoring required; ≥ 3x ULN in ~ 11% patients (pooled data from 16-week studies) Monthly LFT monitoring required; ≥ 3x ULN in 0.8% patients in 12-week studies, 2.8% patients in 1-year studies Peripheral edema 1.7% patients (placebo-adjusted; fluid retention/edema) 6% patients (placebo-adjusted) Additional adverse events Respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, irregular heartbeat Nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, constipation Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. This table compares the endothelin receptor antagonists, bosentan and ambrisentan. Both agents are pregnancy category X. Monthly LFT monitoring is required for both agents. However, the incidence of LFT elevation differs between the two medications. A greater than three times the upper level of normal increase in LFT has been reported in nearly 11% of bosentan-treated patients and 0.8% or 2.8% of ambrisentan-treated patients. The incidence of peripheral edema is approximately 1.7% for bosentan and 6% for ambrisentan. Adverse events reported during bosentan therapy include respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, and irregular heartbeat. Adverse events reported during ambrisentan therapy include nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, and constipation. Source: FDA-approved product labeling for individual agents.

33 Endothelin Receptor Antagonists Comparison of Drug-Drug Interactions
Bosentan Ambrisentan Ritonavir Rifampin Cyclosporine A Hormonal contraceptives Sildenafil Tadalafil1 Glyburide Simvastatin (+ other CYP3A-metabolized statins) CYP2C9 inhibitors (fluconazole, amiodarone) CYP3A inhibitors (ketoconazole, itraconazole, amprenavir, erythromycin, fluconazole, diltiazem) Tacrolimus Phenytoin2 Warfarin2 Hormonal contraceptives3 Omeprazole4 Ketoconazole2,4 Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. This table compares the drug-drug interactions for bosentan and ambrisentan. Common to both medications are drug interactions with: ritonavir, rifampin, cyclosporine A, hormonal contraceptives, and ketoconazole. Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S ) Galie, et al. Eur Heart J. 2009;30: ) Spence, et al. ATS. San Diego, CA. May 15-20, ) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.

34 Bosentan for PAH Endothelin receptor antagonist (ETA/ETB non selective) Indication – WHO group I - functional class II, III, IV Dosage – 62.5 mg oral twice daily for 4 weeks then 125 mg oral twice daily Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Bosentan is an endothelin receptor antagonist indicated for the treatment of PAH, functional class II, III, and IV. The initial dosage of bosentan is 62.5 mg oral twice daily for 4 weeks. Patients are then titrated to 125 mg oral twice daily.

35 Change from Baseline (meters)
Bosentan for PAH: BREATHE Clinical Trial Change in 6-MWD (from Baseline to Week 16) -40 -20 20 40 60 80 Bosentan (N= 144) Change from Baseline (meters) P = Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The BREATHE clinical trial was conducted by Rubin and colleagues. The trial was a double-blind, placebo-controlled, 16-week study in patients with PAH. Patients who received bosentan were titrated from 62.5 mg twice daily to 125 mg or 250 mg twice daily at week 4. A significant improvement in exercise capacity (6-MWD) was noted in patients treated with bosentan (N = 144) compared to patients treated with placebo (N = 69). The investigators also reported that bosentan was well tolerated in patients. Placebo (N= 69) Baseline Week 4 Week 8 Week 16 62.5 mg bid 125 or 250 mg bid Bosentan Rubin, et al. N Engl J Med. 2002;346:

36 Bosentan for PAH Comparison of 6-MWD in 6-Month, Open-Label Study
Change from Baseline (meters) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Here is another study that shows placebo-treated patients not quite catching up to the active treatment group during an open-label extension phase. These patients all started out in a double-blind, placebo-controlled, four-month study (baseline controlled study). Following this study, 29 patients continued with the open-label extension for 6 months. Placebo-treated patients were transitioned to bosentan for the open-label part. As you can see, the improvement in 6-MWD was less robust for the former placebo-treated patients compared to the patients treated with bosentan from the start. This study underscores the importance of early treatment for patients with PAH. Six-month, open-label study of bosentan (125 mg bid) after a double-blind, placebo-controlled, four-month study Delay in treatment in former placebo patients → less robust improvement in 6-MWD during open-label extension Sitbon, et al. Chest. 2003;124:

37 Bosentan for PAH: EARLY Clinical Trial
Change in PVR (from Baseline to Week 24) Decrease in PVR: Surrogate marker for delaying disease progression P < % of Baseline PVR at Week 24 (geometric means) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Results from the EARLY clinical trial are graphically represented in these next slides. The change in PVR from baseline to week 24 was significantly less for bosentan-treated patients compared to placebo-treated patients. A decrease in PVR is considered a surrogate marker for delaying disease progression. Treatment effect = - 22.6% Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5:

38 Bosentan for PAH: EARLY Clinical Trial
Change in 6-MWD (from Baseline to Week 24) 25 20 15 11.2 Placebo (N= 91) 10 P = 0.076 Bosentan (N= 86) 5 Change in 6-MWD (meters) 5 12 weeks 24 weeks Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. In this slide, change in 6-MWD from baseline to week 24 is plotted. Patients treated with bosentan had a significant improvement in exercise capacity compared to patients taking placebo. The 6-MWD increased by 11.2 meters (on average) in the bosentan group and decreased by 7.9 meters (on average) in the placebo group. The average treatment effect was an improvement of 19.1 meters. 10 - 7.9 15 Treatment effect = meters 20 Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5: 38

39 Bosentan for PAH: EARLY Clinical Trial
Time to Clinical Worsening (from Baseline to Week 32) 100 P < 0.02 80 Placebo 60 Bosentan Event-Free Patients (%) 40 20 Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The EARLY trial also examined time to clinical worsening in patients. A significant delay in the time to clinical worsening was seen in bosentan-treated patients compared to placebo-treated patients. 4 8 12 16 20 24 28 32 weeks 92 90 89 86 84 83 18 77 9 Patients at risk (N) 93 92 87 85 84 83 27 80 15 Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5: 39

40 Ambrisentan for PAH Endothelin receptor antagonist (ETA selective)
Indication – WHO group I - functional class II, III Dosage – 5 mg and 10 mg oral daily Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Ambrisentan is an endothelin receptor antagonist indicated for the treatment of PAH, functional class II and III. The dosage of ambrisentan is 5 mg and 10 mg oral once daily.

41 Ambrisentan for PAH Change in 6-MWD (from Baseline to Week 12)
ARIES 1 ARIES 2 50 60 N= 202 N=192 10 mg: +43.6 m 5 mg: +49.4 m 40 25 5 mg: +22.8 m 2.5 mg +22.2 m 20 Change from Baseline (meters) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The ARIES-1 and ARIES-2 clinical trials were concurrent, double-blind, placebo-controlled studies of ambrisentan for patients with PAH. The primary endpoint for the studies was the change in 6-MWD from baseline to week 12. All ambrisentan groups showed significant improvement in 6-MWD. For ARIES-1, the placebo-adjusted improvement in 6-MWD was 31 meters for ambrisentan 5 mg and 51 meters for ambrisentan 10 mg. For ARIES-2, the placebo-adjusted improvement in 6-MWD was 32 meters for ambrisentan 2.5 mg and 59 meters for ambrisentan 5 mg. Placebo: -7.8 m Placebo: -10.1 m -20 -25 4 8 12 weeks 4 8 12 weeks Placebo-adjusted change at week 12: Ambrisentan 5 mg = 31 m; 10 mg = 51 m Placebo-adjusted change at week 12: Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m Galie, et al. Circulation. 2008;117: 41

42 Ambrisentan for PAH: ARIES 1 and 2 Clinical Trials Time to Clinical Worsening
100 --- Placebo mg (P = 0.03) --- 5 mg (P = 0.005) mg (P = 0.03) 90 Event-Free Patients (%) 80 Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Another study endpoint for the ARIES clinical trials was time to clinical worsening. The definition of clinical worsening included death, lung transplantation, hospitalization, atrial septostomy, and/or study withdrawal. Ambrisentan was better than placebo at increasing time to clinical worsening. The relative risk reduction attributed to ambrisentan was 71%. 70 4 8 12 Weeks Ambrisentan → 71% relative risk reduction Galie, et al. Circulation. 2008;117: 42

43 Ambrisentan for PAH: ARIES-E Change in 6-MWD (from Baseline to 24 Months)
2.5 mg (N = 93) 5 mg (N = 186) 10 mg (N = 96) 70 60 50 40 30 28 m Change from Baseline (meters) 23 m 20 10 7 m Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Oudiz and colleagues examined the long-term efficacy of ambrisentan in patients with PAH. Long-term ambrisentan treatment was associated with sustained improvements in 6-MWD for the 5 mg and 10 mg groups. -10 -20 0.0 0.25 0.5 1.0 1.5 2.0 Years Mean ± 95% CI; LOCF for missing data Oudiz, et al. J Am Coll Cardiol. 2009;54(21):

44 Ambrisentan for PAH: ARIES-E Change in WHO Functional Class
100 90% 86% 80 79% Maintained or Improved 60 2.5 mg (N= 94) 5 mg (N = 187) 10 mg (N = 96) 40 Patients (%) 20 10% Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The ARIES-E clinical trail also examined change in WHO functional class in patients treated with long-term ambrisentan therapy. Functional class was maintained or improved for the majority of patients on long-term ambrisentan. At two years, 79% of patients in the 2.5 mg group, 90% of patients in the 5 mg group, and 86% of patients in the 10 mg maintained or improved their functional class. 14% 20 Worsened 21% 40 0.0 0.25 0.5 1.0 1.5 2.0 Years LOCF for missing data Oudiz, et al. J Am Coll Cardiol. 2009;54(21):

45 Phosphodiesterase-5 Inhibitors Comparison of Drug-Drug Interactions
Sildenafil Tadalafil Nitrates Alpha blockers Amlodipine Ritonavir Bosentan1 HMG CoA reductase inhibitors1 Phenytoin1 Erythromycin1 Ketoconazole1 Cimetidine1 Rifampin1 Phenobarbital1 Carbamazepine1 Antihypertensive agents Ketoconazole Rifampin Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. This table compares the drug-drug interactions associated with sildenafil and tadalafil. Common to both medications are interactions with nitrates, alpha blockers, ketoconazole, ritonavir, rifampin, and bosentan. Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:

46 Sildenafil for PAH PDE-5 inhibitor
Indication – to increase exercise capacity, decrease clinical worsening in patients with WHO group I – functional class II, III, IV Dosage – 20 mg oral three times daily IV formulation Approved December, 2009 Dosage – 10 mg three times daily Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Sildenafil is a phosphodiesterase-5 inhibitor which is used to increase exercise capacity and decrease clinical worsening in patients with PAH, functional class II, III, and IV. The dosage of sildenafil is 20 mg oral three times daily. An IV formulation for sildenafil was recently approved. The dosage for the IV formulation is 10 mg three times daily. 46

47 Sildenafil for PAH: SUPER Clinical Trial Change in WHO Functional Class (from Baseline to Week 12)
Placebo (N= 70) Sildenafil (N= 203) 100% 80% 60% Patients (%) 40% Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The SUPER clinical trial also examined change in functional class in patients over the 12-week study period. Compared to placebo, all sildenafil doses significantly improved functional class in patients. The percent of patients with an improvement of at least one functional class were as follows: 7% of placebo group, 28% of sildenafil 20 mg group, 36% of sildenafil 40 mg group, and 42% of sildenafil 80 mg group. 20% 0% Baseline Week 12 Baseline Week 12 Class I Class II Class III Class IV Galie, et al. N Engl J Med. 2005;353: 47

48 Change from Baseline (meters)
Sildenafil for PAH: Long-Term Extension of SUPER Clinical Trial Change in 6-MWD (from Baseline) Change from Baseline (meters) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Results from the long-term extension of the SUPER clinical trial were reported by Galie and colleagues. The improvement in 6-MWD seen at 12 weeks in the sildenafil-treated patients was maintained for the long-term extension. The mean change in 6-MWD from baseline was 48 meters in 273 patients at 12 weeks, and 51 meters in 222 patients at 12 months. (N= 273) (N= 222) Galie, et al. N Engl J Med. 2005;353:

49 Sildenafil for PAH: SUPER 2 Clinical Trial
Study design Open-label, long-term extension of SUPER clinical trial Patients N= 259 enrolled; 180 completed 3 years of follow-up Dosage = mg three times daily Study results at 3 years Functional class – improved in 30%; unchanged in 31% Kaplan-Meier estimated survival = 79% Patient disposition – 53 patients died (29%); 44 discontinued therapy (24%) Combination therapy – 20% Adverse effects – mild/moderate in severity Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Preliminary results from the SUPER 2 clinical trial were presented at a recent CHEST meeting. SUPER 2 is an open-label, long-term extension of the SUPER clinical trial. A total of 259 have been enrolled. Investigators shared the results for 180 patients who completed 3 years of follow-up. Sildenafil improved functional class in 30% of patients. The Kaplan-Meier estimated survival was 79%. By the three-year mark, 53 patients had died and 44 patients had discontinued treatment. A total of 20% of patients received sildenafil in combination with another agent. Reported adverse effects were deemed mild to moderate in severity. ABSTRACT: Rubin, et al. CHEST. Philadelphia, PA. Oct , 2008.

50 Tadalafil for PAH FDA approval – May, 2009 PDE-5 inhibitor
Indication – to increase exercise capacity, decrease clinical worsening in patients with WHO group I – functional class II, III, IV Dosage – 40 mg oral daily Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Tadalafil is a phosphodiesterase-5 inhibitor which is used to increase exercise capacity and decrease clinical worsening in patients with PAH, functional class II, III, and IV. The dosage of tadalafil is 40 mg oral once daily.

51 Tadalafil for PAH: PHIRST Clinical Trial
Subgroup analysis: Study design – phase lll, double-blind, placebo-controlled, multicenter, 16-week study Comparison of tadalafil monotherapy (N= 189) to combination therapy with bosentan 125 mg twice daily (N= 216) Dosage of tadalafil = 20 mg and 40 mg Study results No greater improvement in 6-MWD with combination therapy compared to monotherapy Change in 6-MWD from Baseline (meters) Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The PHIRST clinical trial was a phase III, double-blind, placebo-controlled, multicenter study. Tadalafil monotherapy (20 mg and 40 mg daily) was compared to combination therapy with bosentan (125 mg twice daily). At 16 weeks, no greater improvement in 6-MWD was noted with combination therapy compared to monotherapy. ABSTRACT: Barst, et al. ATS. San Diego, CA. May 15-20, 2009. Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):

52 Tadalafil for PAH: PHIRST Clinical Trial
Study Results Efficacy Greater improvement in 6-MWD in treatment-naïve patients compared to patients with background bosentan Significant improvements in quality of life and time to and incidence of clinical worsening (68% relative risk reduction) Safety Most common adverse events were headache, myalgia, and flushing which were mild to moderate in severity Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. The findings from the PHIRST clinical trial included greater improvement in 6-MWD in treatment-naïve patients compared to patients with background bosentan therapy. In addition, patients demonstrated significant improvements in quality of life and time to and incidence of clinical worsening. The most common adverse events reported were headache, myalgia, and flushing. All adverse events were considered mild to moderate in severity. Galie, et al. Circulation. 2009;Epub May 26. Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):

53 Tadalafil for PAH: PHIRST Clinical Trial
Short Form 36 (SF-36) Domains Mean Change from Baseline to Week 16 Quality of life measure: Higher scores reflect better functioning and health status Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Quality of life was an important study endpoint for the PHIRST clinical trial. The SF-36 was used to measure changes in a patient’s quality of life with regard to physical functioning, physical role, bodily pain, general health, vitality, and social functioning. Higher scores on the SF-36 reflect better functioning and health status. After 16 weeks of treatment, significant quality of life improvements were seen in patients taking tadalafil 40 mg compared to placebo. P< 0.01 vs Placebo Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):

54 Tadalafil for PAH: Long-Term Extension of PHIRST
Change in 6-MWD from Baseline (meters) Study design – phase lll, double-blind, placebo-controlled study (16 weeks) → long-term extension study (44 weeks) Dosage = 20 mg and 40 mg N = 241 Study results Efficacy 6-MWD: sustained improvement over 44 weeks Safety 62 patients withdrew from study including: 17 due to PAH progression; 12 due to adverse events; 11 due to death Covers learning objective 3) Use evidence-based guidelines to select the most appropriate treatment. Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. Preliminary results have been presented for the long-term extension of the PHIRST clinical trial. Patients who completed the phase III, double-blind, placebo-controlled PHIRST clinical trial were able to enroll in the long-term extension. Tadalafil (20 mg and 40 mg) was administered to 241 patients for 44 weeks. The initial improvement in 6-MWD was maintained over the 44 weeks. A total of 62 patients withdrew from the study, including 17 due to PAH progression, 12 due to adverse events, and 11 due to death. Weeks ABSTRACT: Oudiz, et al. ATS. San Diego, CA. May 15-20, 2009. ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.

55 PAH Determinants of Patient Risk ACC/AHA Expert Consensus
Low Risk Determinants of Risk High Risk No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III WHO functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min Minimally elevated and stable BNP/NT-proBNP Significantly elevated PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg Minimal RV dysfunction ECHO findings Pericardial effusion, RV dysfunction, RA enlargement RAP < 10 mm Hg; CI > 2.5 L/min/m2 Hemodynamics RAP > 20 mm Hg; CI < 2 L/min/m2 Covers learning objective 4) Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. The American College of Cardiology (ACC) and the American Heart Association (AHA) came to a consensus on which factors can be used to determine a patient’s risk with regard to PAH. The center column lists the factors, or determinants of patient risk. The left column lists the values or answers if the patient is at low risk. The right column lists the values or answers if the patient is at high risk. McLaughlin, et al. Circulation. 2006;114: McLaughlin, et al. J Am Coll Cardiol. 2009;53:

56 Combination Therapy for PAH
To target multiple disease pathways Endothelin pathway (endothelin receptor antagonists) Nitric oxide pathway (PDE-5 inhibitors) Prostacyclin pathway (prostacyclin analogs) Used clinically with little evidence to date Used when therapy needs to be augmented because patient response to monotherapy is inadequate Must consider the drug interaction potential of agents to be combined (risk-benefit analysis) Drug interaction between bosentan and sildenafil Drug interaction between bosentan and tadalafil Covers learning objective 4) Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. Combination therapy is used in PAH to target multiple disease pathways. Endothelin receptor antagonists target the endothelin pathway. PDE-5 inhibitors target the nitric oxide pathway. Prostacyclin analogs target the prostacyclin pathway. Unfortunately, there is very little clinical evidence to support the use of combination therapy. Clinicians make the decision to use combination therapy when response to monotherapy is inadequate. Before a medication is selected, its drug-drug interaction potential must be considered. For example, bosentan has been shown to interact with sildenafil and tadalafil. Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.

57 Combination Therapy for PAH
Clinical Study Agents Study Design N Study Endpoints Statistical Significance Humbert, et al1 Epoprostenol Bosentan Randomized, double-blind, placebo-controlled; 16 weeks 33 Hemodynamics, exercise capacity, functional class NSS findings McLaughlin, et al2 Iloprost Randomized, double-blind, placebo-controlled, multicenter; 12 weeks 67 Hemodynamics, exercise capacity, functional class, TTCW SS improvement in parameters Hoeper, et al3 Randomized, placebo-controlled, multicenter; 12 weeks 40 Exercise capacity, functional class, TTCW Simonneau, et al4 Sildenafil Randomized, double-blind, placebo-controlled, multicenter; 16 weeks 256 Hemodynamics, exercise capacity, TTCW SS improvement in exercise capacity, TTCW Galie, et al5 Tadalafil 405 Hemodynamics, exercise capacity, functional class, TTCW, quality of life SS improvement in all parameters, except functional class Covers learning objective 4) Apply determinants of risk to assess a patient’s prognosis and recognize when therapy needs to be augmented. This table summarizes recently completed controlled clinical studies of combination therapy for PAH. Humbert and colleagues studied epoprostenol and bosentan in 33 patients for a 16-week period. Improvements in hemodynamics, exercise capacity, and functional class were not statistically significant. McLaughlin and colleagues studied iloprost and bosentan in 67 patients for a 12-week period. Improvements in hemodynamics, exercise capacity, functional class, and time to clinical worsening were statistically superior in the combination therapy group. Hoeper and colleagues studied iloprost and bosentan in 40 patients for a 12-week period. Improvements in exercise capacity, functional class, and time to clinical worsening were not statistically significant. Simonneau and colleagues studied epoprostenol and sildenafil in 256 patients for a 16-week period. Improvements in exercise capacity and time to clinical worsening were statistically superior in the combination therapy group. Galie and colleagues studied bosentan and tadalafil in 405 patients for a 16-week period. Improvements in hemodynamics, exercise capacity, time to clinical worsening, and quality of life were statistically superior in the combination therapy group. TTCW = time to clinical worsening; NSS = non-statistically significant; SS = statistically significant 1) Humbert, et al. Eur Respir J. 2004;24: ) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174: ) Hoeper, et al. Eur Respir J. 2006;28: ) Simonneau, et al. Ann Intern Med. 2008;149: ) Galie, et al. Circulation. 2009;119(22):

58 Monitoring Schedule for Patients with PAH
Parameter Baseline (pretreatment) Every 3-6 months 3-4 Months after start or change in therapy If clinical worsening Clinical assessment WHO functional class ECG X 6-MWD Cardiopulmonary exercise testing BNP/NT-proBNP ECHO Right heart catheterization Covers learning objective 5) Compare the side effect profiles and drug interaction potential of available PAH treatments to gauge the risk-benefit ratio of each option and to determine areas for patient monitoring. A proposed monitoring schedule for patients with PAH is presented in the table. Clinical assessment, determination of WHO functional class, ECG, 6-MWD, and BNP/NT-proBNP levels are recommended at baseline, every 3-6 months, 3-4 months after a change in therapy, and if clinical worsening occurs. Cardiopulmonary exercise testing, ECHO, and right heart catheterization are recommended at baseline, 3-4 months after a change in therapy, and if clinical worsening occurs. Galie, et al. Eur Heart J. 2009;30:

59 Summary Comprehensive management of PAH involves optimizing multiple supportive therapies Early, evidence-based treatment of PAH is associated with improved patient outcomes Agents for the treatment of PAH vary with regard to: Indication, administration, adverse effect profile, drug-drug interactions, clinical study data Therefore, a comparison of the risk-benefit ratio of available agents is needed to guide PAH treatment selection To summarize the key points from this grand rounds: Comprehensive management of PAH involves optimizing multiple supportive therapies. Early, evidence-based treatment of PAH is associated with improved patient outcomes. Agents for the treatment of PAH vary with regard to: indication, administration, adverse effect profile, drug-drug interactions, clinical study data. Therefore, a comparison of the risk-benefit ratio of available agents is needed to guide PAH treatment selection.


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