ACCP PAH Medical Therapy Guidelines: 2007 Update. David Badesch, MD University of Colorado School of Medicine Denver, CO

ACCP PAH Medical Therapy Guidelines: 2007 Update David Badesch, MD University of Colorado School of Medicine Denver, CO

Disclosure of Commercial Interest Dr. Badesch has received grant/research support from Glaxo Wellcome, United Therapeutics / Lung Rx, Actelion, Encysive, Myogen/Gilead, CoTherix/Actelion, Pfizer, and Lilly/ICOS. He has served as a consultant to Glaxo Wellcome / GlaxoSmithKline, Actelion, Berlex, Myogen/Gilead, Encysive, CoTherix/Actelion, Pfizer, United Therapeutics, MondoBiotech/Biogen IDEC, and PR Pharmaceuticals.

Symptomatic Pulmonary Arterial Hypertension ACCP 2007 General Treatment Measures: Oral anticoagulants [B for IPAH, E/C for other PAH] + diuretics + oxygen [E/A] Acute Vasoreactivity Testing [A for IPAH, E/C for other PAH] Positive Negative Oral CCB [B for IPAH, E/B for other PAH] FC II FC III FC IV Sustained Response? Yes No Continue CCB Sildenafil [A] Treprostinil SC [C] Treprostinil IV [C] Bosentan [A] Sildenafil [A] Epoprostenol [A] Iloprost inh [A] Treprostinil SC [B] Treprostinil IV [C] Epoprostenol IV [A] Bosentan [B] Iloprost inh [B] Sildenafil [C] Treprostinil SC [C] Treprostinil IV [C] Combination Therapy? Prostanoid Bosentan Sildenafil Grade of Recommendation Noted in [ ] Badesch, Abman, Simonneau,et al. Chest 131:1917-1928;131. No Improvement or deterioration Atrioseptostomy + Lung Transplantation

ACCP Guidelines Statement Quality of Evidence, Net Benefit, and Strength of Recommendation Quality of the Evidence Good: based on RCTs or metaanalyses. Fair: based on controlled trials or RCTs with minor flaws. Low: based on nonrandomized, case-control, or other observational studies. Expert opinion: no studies meet the criteria for inclusion in the literature review. Net Benefit: Substantial Intermediate Small/weak None Conflicting Negative Strength of Recommendation: A: Strong recommendation B: Moderate recommendation C: Weak recommendation D: Negative recommendation I: No recommendation possible E/A: Strong recommendation based on expert opinion only E/B: Moderate recommendation based on expert opinion only

ACCP Guidelines Statement Relationship of Strength of the Recommendation Scale to Quality of Evidence and Net Benefits Quality of Evidence Net Benefit Substantial Intermediate Small/Weak None Conflicting Negative Good A A B D I D Fair A B C D I D Low B C C I I D Expert Opinion E/A E/B E/C I I E/D

Determining Pulmonary Vasodilator Reserve Establish the role of vasoconstriction Determine the potential for vasodilator therapy Should be measured in most patients prior to initiating treatment

ACCP Consensus Definition of A Responder Fall in mean PAP by at least 10 mm Hg, to an absolute PAP mean of < 35-40 mm Hg Unchanged or increased CO It is important to follow patients treated with CCBs for both safety and efficacy of the therapy. ACCP=American College of Chest Physicians.

Medical Therapy: Vasoreactivity Testing 1. Patients with IPAH should undergo acute vasoreactivity testing using a short acting agent such as intravenous epoprostenol, adenosine, or inhaled nitric oxide. Level of Evidence: Fair; Benefit: Substantial; Grade of Recommendation: A. 2. Patients with PAH associated with underlying processes, such as scleroderma or congenital heart disease, should undergo acute vasoreactivity testing. Level of Evidence: Expert Opinion; Benefit: Small/Weak; Grade of Recommendation: E/C. 3. Patients with PAH should undergo vasoreactivity testing by a physician experienced in the management of pulmonary vascular disease. Level of Evidence: Expert Opinion; Benefit: Substantial; Grade of Recommendation: E/A.

Medical Therapy: Calcium Channel Blockers 4. Patients with IPAH, in the absence of right heart failure, demonstrating a favorable acute response to vasodilator (defined as a fall in mean pulmonary artery pressure of at least 10 mmhg to less than or equal to 40 mmhg, with an increase or unchanged cardiac output), should be considered candidates for a trial of therapy with an oral calcium channel antagonist. Level of Evidence: Low; Benefit: Substantial; Grade of Recommendation: B. 5. Patients with PAH associated with underlying processes such as scleroderma or congenital heart disease, in the absence of right heart failure, demonstrating a favorable acute response to vasodilator (defined as a fall in mean pulmonary artery pressure of at least 10 mmhg to less than or equal to 40 mmhg, with an increase or unchanged cardiac output), should be considered candidates for a trial of therapy with an oral calcium channel antagonist. Level of Evidence: Expert Opinion; Benefit: Intermediate; Grade of Recommendation: E/B.

Medical Therapy: Calcium Channel Blockers 6. In patients with PAH, calcium channel blockers should not be used empirically to treat pulmonary hypertension in the absence of demonstrated acute vasoreactivity. Level of Evidence: Expert Opinion; Benefit: Substantial; Grade of Recommendation: E/A.

ACCP 2007 Acute Vasoreactivity Testing [A for IPAH, E/C for other PAH] Positive Oral CCB [B for IPAH, E/B for other PAH] Sustained Response? Yes Continue CCB No Grade of Recommendation Noted in [ ] Badesch, Abman, Simonneau,et al. Chest 131:1917-1928;131.

Medical Therapy: Anticoagulation and Supplemental Oxygen 7. Patients with IPAH should be anticoagulated with warfarin. Level of evidence: Fair; Benefit: Intermediate; Grade of Recommendation: B. 8. In patients with PAH occurring in association with other underlying processes, such as scleroderma or congenital heart disease, anticoagulation should be considered. Level of Evidence: Expert opinion; Benefit: Small/Weak; Recommendation: E/C. 9. In patients with PAH, supplemental oxygen should be used as necessary to maintain oxygen saturations at > 90% at all times. Level of Evidence: Expert Opinion; Benefit: Substantial; Recommendation: E/A.

PAH: Advanced Therapy SMC A) PGI 2 EC PGI 2 -S Arach. a. PGI 2 camp PGI 2 Prostanoids Epoprostenol Treprostinil Beraprost Iloprost TxA 2 SMC PDE 5 cgmp Vasodilation Antiproliferative B) NO Vasoconstriction EC NO Proliferation L-arginine L-citrulline C) ET-1 SMC G I ET A ET B EC Pre-pro-ET pro-et ET-1 Adapted from Omar Manai.

Epoprostenol in PPH Study Median Change from Baseline in 6-Minute Walk Exercise Test at Week 12 Median Change (meters) 50 40 30 20 10 0-10 -20-30 -40 31.0-29.0 *P<0.002-50 Treatment: Epoprostenol Baseline = 315 Conventional Baseline = 270 Barst RJ et al. NEJM 334: 296-301, 1996.

Cardiopulmonary Hemodynamic Measurements (PPH) Epoprostenol vs. Conventional Therapy Epoprostenol Conventional Change from Change from Variable Baseline Baseline Baseline Baseline PAP m 61 ± 2-4.8 ± 1.3* 59 ± 2 1.9 ± 1.6 PVR 16 ± 1-3.4 ± 0.7* 16 ± 1 1.5 ± 1.2 RAP m 13 ± 1-2.2 ± 1.1* 12 ± 1 0.1 ± 0.9 CI 2.0 ± 0.1 0.3 ± 0.1* 2.1 ± 0.2-0.2 ± 0.2 Mean change ± standard error *Significantly different from conventional therapy Barst RJ et al. NEJM 334: 296-301, 1996.

Survival Among Patients with PPH Epoprostenol vs. Conventional Therapy 100 80 Survival (%) 60 40 20 Epoprostenol (n = 41) Conventional therapy (n = 40) 0 0 2 4 6 8 10 12 Week Barst et al. NEJM 1996;334:296-301. 301.

Survival in PPH 100 % Survival 80 60 40 * * * Observed Expected 20 0 6 12 18 24 30 36 Months *p<0.001. McLaughlin VV et al. Circulation. 2002;106:1477-1482.

PAH Associated with Scleroderma: Median Change from Baseline in 6-Minute Walk Test Median Change (meters) 90 80 70 60 50 40 30 20 10 0-10 -20-30 -40-50 Treatment: 13.3-7.0 Week 1 Week 6 Week 12 Epoprostenol Baseline = 271.5m Badesch, et al. Ann Intern Med, 2000;132:425-434 434 48.5* - 14.0 63.5* *P<0.003-36.0 Conventional Baseline = 240.0m

PAH Associated with Scleroderma Cardiopulmonary Hemodynamic Measurements Epoprostenol Conventional Change from Change from Variable Baseline Baseline Baseline Baseline PAP m 50.9 ± 1.41-5.03 ± 1.09* 49.1 ± 1.37 0.94 ± 1.10 PVR 14.2 ± 0.95-4.58 ± 0.76* 11.2 ± 0.73 0.92 ± 0.56 RAP m 13.1 ± 0.67-1.26 ± 0.82* 11.1 ± 0.74 1.20 ± 0.69 CI 1.9 ± 0.08 0.50 ± 0.08* 2.2 ± 0.09-0.10 ± 0.08 Mean change ± standard error *Significantly different from conventional therapy Badesch,, et al. Ann Intern Med, 2000;132:425-434 434

Treprostinil in PAH Exercise Capacity: Six Minute Walk Change from Baseline UT-15 Placebo Effect* p-value Exercise (meters) Week 12 +10 0 +16 0.0064 Week 6 +13 +4 +11 0.032 Week 1 +11 +8 +5 0.27 *Non-parametric Analysis of Covariance (Hodges-Lehmann estimate) Last Rank Carried Forward for AE Lowest Rank for Death/Deterioration Simonneau G et al. AJRCCM 165:800-4; 2002.

Treprostinil in PAH Change in Exercise Versus Dose(Week 12) Mean ± SE Change from Baseline (meters) Meters 40 35 30 25 20 15 10 5 0 +3.3 ± 10 (N=45) +1.4 ± 9 (N=55) +20 ± 8 (N=49) 1st 2nd 3rd Quartile < Quartile 5 Quartile 5.0 to <8.1 8.1 to 13.8 +36.1 ± 31 (N=58) 4th Quartile >13.8 (2.5 ± 0.2) (5.6 ± 0.1) (9.4 ± 0.2) (16.2 ± 0.4) mg/kg/min Simonneau G et al. AJRCCM 165:800-4; 2002. p-value 0.03

Chronic Inhaled Iloprost in PAH Effect of Inhaled Iloprost and Placebo on the Mean ({+/-}SE) Change from Base Line in the Distance Walked in Six Minutes, According to an Intention-to-Treat Analysis Olschewski, H. et al. N Engl J Med 2002;347:322-329

PAH: Advanced Therapy SMC camp A) PGI 2 EC PGI 2 -S Arach. a. PGI 2 PGI 2 TxA 2 SMC PDE 5 cgmp Vasodilation Antiproliferative B) NO Vasoconstriction EC NO Proliferation L-arginine L-citrulline C) ET-1 Adapted from Omar Manai. SMC EC Pre-pro-ET pro-et G I ET A ET B ET-1 Bosentan Sitaxsentan Ambrisentan

Endothelin Met Leu Ser Ser Cys Ser Cys NH 2 Asp Lys Glu Cys Val Tyr Phe Cys His Leu Asp Ile Ile Trp CO 2 First identified in 1988; at the time, the most potent endogenous vasoconstrictor known Also has effects on inflammation, proliferation, and fibrosis. Present within the plexiform lesions of IPAH/PPH. (Giaid( Giaid A et al. New Engl J Med. 1993; 328:1732)

Pilot Study of Bosentan in PAH: 6-Minute Walk Test Change From Baseline Over Time 100 Placebo (n = 11) Bosentan (n = 21) P = 0.02 Meters 50 0-50 Channick et al. Lancet 358:1119-23. 4 8 12 Weeks Primary Endpoint

Pilot Study of Bosentan in PH: Change in Hemodynamics From Baseline to Week 12 Cardiac Index Mean Pulmonary Arterial Pressure Pulmonary Vascular Resistance L/min/m 2 0.8 0.4 0-0.4-0.8 P < 0.0001 Week 12 mm Hg 10 5 0-5 P = 0.013 Week 12 Dyn.sec.cm -5 400 200 0-200 -400 P = 0.0001 Week 12 Placebo (n = 10) Bosentan (n = 20) Channick et al. Lancet 358:1119-23.

BREATHE-1: Walk Test ITT Change From Baseline to Week 16 Walk Distance (meters) 80 Placebo (n = 69) Bosentan (n = 144) 60 40 20 0-20 P = 0.0002 Mean ± SEM -40 Baseline Week 4 Week 8 Week 16 62.5 mg/bid 125 or 250 mg/bid Rubin et al. NEJM 346:896-903l 2002.

Event-Free (%) 100 75 50 25 0 BREATHE-1 Time to Clinical Worsening Up to 28 Weeks P = 0.0015 0 4 8 12 16 20 24 28 Time (weeks) 89 % 63 % Bosentan n = 144 n = 103 n = 20 Placebo n = 69 n = 51 n = 17 Rubin et al. NEJM 346:896-903l 2002.

BREATHE-1 Summary of Adverse Events During Study Treatment Placebo Bosentan (n = 69) (n = 144) % % Nasopharyngitis 7.2 11.8 Headache 18.8 20.8 Flushing 4.3 9.0 Hypotension 4.3 6.9 Syncope 5.8 9.0 Hepatic Funct.. Abnormal 2.9 9.7 Incidence of events: bosentan > placebo Rubin et al. NEJM 346:896-903l 2002.

Bosentan as Initial Therapy* Observed and Predicted Survival Kaplan-Meier survival estimates with 99.9% CI % of event-free patients 100 90 80 70 60 50 40 30 20 10 0 Observed Predicted (NIH) Event Rate / year (exponential): 5.5% 0 6 12 18 24 30 36 months 169 167 163 153 113 23 16 Patients at risk McLaughlin V. Eur Respir J 25:244-9; 2005 *As first-line treatment for PPH. Some patients may have been switched to alternative therapies.

Sitaxsentan in PAH STRIDE 1: Six-Minute Walk Distance 30 20 * * Placebo 100 mg 300 mg Meters 10 0-10 -20 Week 6 Week 12 *p<0.01; mean +/- SE. Barst RJ et al. Am J Respir Crit Care Med. 2004;169:441-447.

Sitaxsentan in PAH STRIDE 1: Change in Hemodynamics Placebo 100 mg 300 mg 1 0-1 mpap (Mm Hg) 0.5 0.4 0.3 CI (L/min/m 2 ) * ** 100 0 PVR (dyn sec cm-5) -2 0.2 0.1-100 -3 0.0-4 -0.1-200 -5-6 * *p<0.001 vs placebo; Mean +/- SE -0.2-0.3 *p<0.02 vs placebo; **p<0.001 vs placebo Barst RJ et al. Am J Respir Crit Care Med. 2004;169:441-447. -300 * *p<0.001 vs placebo *

Sitaxsentan in PAH STRIDE 1 : Most Frequent Adverse Events Adverse Event Placebo n=59 (%) Sitaxsentan 100 mg n=56 (%) Sitaxsentan 300 mg n=63 (%) Headache 20 (34) 25 (45) 29 (46) Peripheral edema 10 (17) 9 (16) 16 (25) Nausea 11 (19) 13 (23) 11 (17) Increased INR 3 (5) 8 (14) 15 (24) Nasal congestion 6 (10) 9 (16) 13 (21) Dizziness 6 (10) 8 (14) 6 (10) Barst RJ et al. Am J Respir Crit Care Med. 2004;169:441-447.

Sitaxsentan in PAH STRIDE 1: LFT Results STRIDE 1/1x (Longer-term Exposure) % patients with LFT elevations >3x ULN 40 35 30 25 20 15 10 5 0 (2/59) STRIDE-1 (12 weeks) (0/56) (6/63) Chronic Exposure (median 24 weeks; Mean ± SD: 26 ± 14 weeks; Range 1 day 58 weeks) (4/79) (19/91) Placebo 100 mg 300 mg 100 mg 300 mg Barst RJ et al. Am J Respir Crit Care Med. 2004;169:441-447.

Change in Six-Minute Walk Distance (m) 40 30 20 10 0-10 STRIDE-2: Change in 6-MWD from Baseline to Week 18 Sitax 100mg * OL Bosentan ** Sitax 50mg Placebo -20 6 12 18 Week * p=0.03 sitax 100mg vs. placebo p=0.07 sitax 50mg vs. placebo ** p=0.05 OL bosentan vs. placebo m ± SE Barst et al. J Am Coll Cardiol 2006;47:2049 56.

Ambrisentan in PAH: 6-Minute Walk Distance Change from Baseline at Week 12 Change in 6MWD (meters) 60 50 40 30 20 10 0 1 mg 2.5 mg 5 mg 10 mg All Doses n=16 n=19 n=16 n=13 n=64 p=0.0029 p=0.0004 p=0.0112 p=0.0082 p=0.0001 Nazzareno Galié MD, David Badesch MD, Ronald Oudiz MD, Gérald Simonneau MD, Michael D. McGoon MD, Anne M. Keogh MD, Adaani E. Frost MD, Diane Zwicke MD, Robert Naeije MD, Shelley Shapiro MD, PhD, Horst Olschewski MD and Lewis J. Rubin MD. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005 Aug 2;46(3):529-35.

Ambrisentan in PAH: Hemodynamics Week 0 (n=34) and Week 12 (n=29) mmhg dynes sec cm -5 Mean Pulmonary Artery Pressure Cardiac Index 54 3.0 = -5.2 = +0.33 50 2.8 46 42 38 34 p<0.001 Week 0 Week 12 L/min/m 2 2.6 2.4 2.2 2.0 Week 0 Week 12 Pulmonary Vascular Resistance Mean Right Atrial Pressure 1500 8.5 = -226 1200 8.0 = -0.45 900 7.5 600 7.0 300 6.5 p<0.001 p=ns 0 6.0 Week 0 Week 12 Week 0 Week 12 mmhg p<0.001

Ambrisentan in PAH: Adverse Events 12-Week Blinded Treatment Period Peripheral Edema Upper Respiratory Tract Infection Nasal Congestion Headache Nausea Flushing LFTs >3X LFTs >8X 0 5 10 15 20 25 30 Percent of Subjects with AE (%)

Ambrisentan ARIES-1 Primary Endpoint: Change in 6MWD at Week 12 Change in 6MWD (m) 50 +43.6 m 25 +22.8 m 0-7.8 m -25 Week 0 Week 4 Week 8 Week 12 N=202. Placebo-adjusted changes: 10 mg = +51.4 m (P=0.0001) 5 mg = +30.6 m (P=0.0084) Oudiz RJ, et al. Chest. 2006;130:Abstract 121S. Placebo 5 mg 10 mg

Ambrisentan ARIES-2 Primary Endpoint: Change in 6MWD at Week 12 Mean Change in 6MWD (m) 60 40 20 0-20 Week 0 Week 4 Week 8 Week 12 N=192. Placebo-adjusted changes: 2.5 mg = 32.3 m (P=0.022) 5 mg = 59.4 m (P<0.001) Olschewski H, et al. ATS 2006. San Diego. +49.4 m +22.2 m -10.1 m Placebo 2.5 mg 5 mg

ARIES-2: Time to Clinical Worsening With Ambrisentan Probability of No Clinical Worsening of PAH 1.0 0.9 0.8 0.7 Placebo Ambrisentan 2.5 mg Ambrisentan 5 mg Ambrisentan combined dosages 5 mg (P=0.008) 2.5 mg (P=0.005) Week 0 Week 4 Week 8 Week 12 2.5 & 5 mg (P <0.001) Placebo Week 16 Time to clinical worsening = Combined endpoint of death, lung transplantation, atrial septostomy, hospitalization for PAH, addition of other drugs for PAH, or early escape from clinical trial. Olschewski H, et al. ATS 2006. San Diego.

PAH: Advanced Therapy A) PGI 2 SMC EC PGI 2 -S Arach. a. PGI 2 camp PGI 2 Sildenafil TxA 2 SMC PDE 5 cgmp Vasodilation Antiproliferative B) NO EC L-arginine L-citrulline NO Vasoconstriction Proliferation C) ET-1 SMC G I ET A ET B EC Pre-pro-ET pro-et ET-1 Adapted from Omar Manai.

Sildenafil in PAH SUPER-1: Study Design Screening Randomization 4 Weeks 8 Weeks 12 Weeks Placebo tid 20 mg tid 40 mg tid 80 mg tid 6-min-walk BORG 6-min-walk BORG 6-min-walk BORG Clinical Worsening 6-min-walk BORG Clinical Worsening 6-min-walk BORG Clinical Worsening Hemodynamics Hemodynamics Galiè N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. NEJM 353:2148-2157;2005.

Sildenafil in PAH SUPER-1: Improvements in 6-MWD Change from baseline (m) 70 60 50 40 30 20 10 0-10 -20-30 Week 4 Week 8 Week 12 *p<0.0001 * * * 45 m 46 m 50 m Placebo Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg Galiè N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. NEJM 353:2148-2157;2005.

Sildenafil in PAH SUPER-1: Hemodynamics Change from baseline at Week 12 3 2 1 0-1 -2-3 -4-5 -6-7 -8 mpap (mm Hg) -2.7 p=0.04-3.0-5.1 p=0.01 p<0.001 1.2 1 0.8 0.6 0.4 0.2 0-0.2-0.4-0.6 Cardiac Output (L/min) 0.5 0.5 p=0.04 0.8 p=0.03 p<0.001 200 100 0-100 -200-300 -400 PVR (dyne.s/cm 5 ) -171-192 p=0.01-310 p=0.006 p<0.0001 Week 4 Week 4 Week 4 Placebo Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg Galiè N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. NEJM 353:2148-2157;2005.

Sildenafil in PAH SUPER-1: AEs 3% and Sildenafil > Placebo Percentage of patients reporting event Adverse event Sildenafil (N=207) Placebo (N=70) Headache 46 39 Flushing 12 4 Dyspepsia 12 7 Back Pain 12 11 Diarrhea 11 6 Limb pain 10 6 Myalgia 9 4 Cough 7 6 Epistaxis 7 1 Pyrexia 6 3 Influenza 5 3 Gastritis 3 0 Vertigo 3 1 Erythema 3 0 Galiè N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. NEJM 353:2148-2157;2005.

Medical Therapy: Functional Class II 10. PAH patients in functional class II who are not candidates for, or who have failed, CCB therapy, may benefit from treatment with: a. Sildenafil (Level of Evidence: Good; Benefit: Substantial; Grade of Recommendation: A). b. Subcutaneous treprostinil (Level of Evidence: Low; Benefit: Small/Weak; Grade of Recommendation: C). c. IV treprostinil (Level of Evidence: Low; Benefit: Small/Weak; Grade of Recommendation: C). Although treprostinil is FDA approved for use in patients in FC II, it would seldom be recommended in such patients due to the complexity of administration, side effects, and cost. Data pertaining to the treatment of FC II patients remain limited, and enrollment in clinical trials is encouraged.

Medical Therapy: Functional Class III 11. PAH patients in functional class III who are not candidates for, or who have failed, calcium channel blocker therapy, are candidates for longterm therapy with: a. Endothelin receptor antagonists (bosentan), or sildenafil, in no order of preference. Level of Evidence: Good; Benefit: Substantial; Grade of Recommendation: A. b. IV epoprostenol. Level of Evidence: Good; Benefit: Substantial; Grade of Recommendation: A. c. Inhaled iloprost. Level of Evidence: Good; Benefit: Intermediate; Grade of Recommendation: A. d. Subcutaneous treprostinil. Level of Evidence: Fair; Benefit: Intermediate; Grade of Recommendation: B. e. IV trepostinil. Level of Evidence: Low; Benefit: Intermediate; Grade of Recommendation: C. With the approval of ambrisentan by the FDA, the recommendations for FC II and III patients will need to be updated again.

Symptomatic Pulmonary Arterial Hypertension ACCP 2007 General Treatment Measures: Oral anticoagulants [B for IPAH, E/C for other PAH] + diuretics + oxygen [E/A] Acute Vasoreactivity Testing [A for IPAH, E/C for other PAH] Positive Negative Oral CCB [B for IPAH, E/B for other PAH] FC II FC III Sustained Response? Yes No Continue CCB Sildenafil [A] Treprostinil SC [C] Treprostinil IV [C] Bosentan [A] Sildenafil [A] Epoprostenol [A] Iloprost inh [A] Treprostinil SC [B] Treprostinil IV [C] Grade of Recommendation Noted in [ ] Badesch, Abman, Simonneau,et al. Chest 131:1917-1928;131.

Medical Therapy: Functional Class IV 12. PAH patients in functional class IV who are not candidates for, or who have failed, calcium channel blocker therapy, are candidates for long-term therapy with intravenous epoprostenol (treatment of choice). Level of Evidence: Good; Benefit: Substantial; Grade of Recommendation: A. 13. Other treatments available for the treatment of functional class IV PAH patients include, in no hierarchal order: a. Endothelin receptor antagonists (bosentan). Level of Evidence: Fair; Benefit: Intermediate; Grade of Recommendation: B. b. Inhaled iloprost. Level of Evidence: Fair; Benefit: Intermediate; Grade of Recommendation: B. c. Subcutaneous treprostinil. Level of Evidence: Fair; Benefit: Intermediate; Grade of Recommendation: B. d. Sildenafil. Level of Evidence: Low; Benefit: Intermediate; Grade of Recommendation: C. e. IV treprostinil. Level of Evidence: Low; Benefit: Intermediate; Grade of Recommendation: C.

Symptomatic Pulmonary Arterial Hypertension ACCP 2007 General Treatment Measures: Oral anticoagulants [B for IPAH, E/C for other PAH] + diuretics + oxygen [E/A] Acute Vasoreactivity Testing [A for IPAH, E/C for other PAH] Positive Negative Oral CCB [B for IPAH, E/B for other PAH] FC II FC III FC IV Sustained Response? Yes No Continue CCB Sildenafil [A] Treprostinil SC [C] Treprostinil IV [C] Bosentan [A] Sildenafil [A] Epoprostenol [A] Iloprost inh [A] Treprostinil SC [B] Treprostinil IV [C] Epoprostenol IV [A] Bosentan [B] Iloprost inh [B] Sildenafil [C] Treprostinil SC [C] Treprostinil IV [C] Grade of Recommendation Noted in [ ] Badesch, Abman, Simonneau,et al. Chest 131:1917-1928;131.

STEP Study of Inhaled Iloprost in Patients Already Receiving Bosentan: Post-inhalation change in 6-MWD (Week 12) Iloprost Placebo Meters Change Meters Change Walked from Baseline Walked from Baseline Baseline (m) Mean 336 + 61 340 + 73 Week 12 (m) Mean 367 + 84 30 m 343 + 99 4 m p-value 0.001 0.69 (vs. baseline) Placebo-adjusted Difference: +26 m (p = 0.051) McLaughlin et al: In press, AJRCCM.

PAH Study of Sildenafil added to Background Epoprostenol Therapy Change from Baseline in 6-MWD Simonneau et al. Presented at ATS 2006.

Medical Therapy: Children and Pregnancy 15. In children with PAH, the recommendations for medical therapy (other than anticoagulation) in adults also apply. Quality of Evidence: Low; Net Benefit: Substantial; Strength of Recommendation: B. 16. a. Children with PAH with right heart failure, or with a hypercoagulable state, should be anticoagulated with warfarin. Level of Evidence: Expert Opinion; Net Benefit: Intermediate; Strength of Recommendation: E/B. b. Children with PAH without right heart failure or a hypercoagulable state, may be anticoagulated with warfarin; for children less than 5 years of age, lower target INRs are recommended. Level of Evidence: Expert Opinion; Net Benefit: Small/Weak; Strength of Recommendation: E/C. 17. In patients with PAH, pregnancy should be avoided, or termination recommended. Level of Evidence: Good; Benefit: Substantial; Grade of recommendation: A.