1	Approved Therapy of Pulmonary Arterial Hypertension Michael D. McGoon, MD
2	Goals of Treatment Efficacy Safety Minimal Side Effects Minimal Interactions or Beneficial Interactions Convenient Affordable
3	Information-Gathering about Effects of Treatment
4	Timeline of FDA Approval of PAH Medications
5	Epoprostenol (Flolan^®) Synthetic salt of prostacyclin Rapid efficacy; short, 3- to 5-min half-life Approved for Class III and IV Invasive: requires continuous IV infusion Individualized dosing regimen required Two RCTs showing efficacy
6	IV Epoprostenol in IPAH: Change From Baseline in 6MW Test
7	Effect of Flolan on 6 Minute Walk
8	Effect of Flolan on 6 Minute Walk
9	Effect of Flolan on 6 Minute Walk
10	Effect of Flolan on 6 Minute Walk
11	Effect of Flolan on 6 Minute Walk
12	IV Epoprostenol in PAH Due to Scleroderma: Change from Baseline in 6MW Test
13	Survival Among Patients With IPAH
14	Long-term Outcome in IPAH With Epoprostenol
15	Epoprostenol: Side 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
16	Epoprostenol (Flolan^®) The Good Potent and short-acting Improves exercise tolerance Improves survival Improves symptoms The Bad Side effects Risks of intravenous route And The Ugly Expensive Inconvenient
17	Timeline of FDA Approval of PAH Medications
18	Bosentan (Tracleer^®) Oral, dual (ET_A and ET_B) endothelin receptor antagonist Two RCTs showing efficacy Approved doses: 62.5 mg bid starting dose for 4 weeks increased to 125 mg bid maintenance dose Approved for Class III and IV
19	Bosentan: 6-Minute Walk Test
20	Effect of Bosentan on 6 Minute Walk
21	Effect of Bosentan on 6 Minute Walk
22	Effect of Bosentan on 6 Minute Walk
23	Effect of Bosentan on 6 Minute Walk
24	Effect of Bosentan on 6 Minute Walk
25	Bosentan: Hemodynamic Effects Mean Change From Baseline to Week 12
26	Bosentan: Time to Clinical Worsening (BREATHE-1)*
27	Survival With First-Line Bosentan in Patients With IPAH
28	Bosentan: Side Effects Headache Nasopharyngitis Flushing Abnormal hepatic function reversible transaminase elevations >3X ULN in up to 11% of patients: monthly LFTs required Edema lower extremity edema may require diuretic adjustment Hypotension Palpitations Dyspepsia Fatigue Pruritis Use requires dual contraceptive methods (hormonal plus barrier)
29	Bosentan (Tracleer^®) The Good Oral Improves exercise tolerance Improves survival The Bad Side Effects Drug Interactions Increases sildenafil level And The Ugly Expensive
30	Timeline of FDA Approval of PAH Medications
31	Treprostinil Longer-acting prostacyclin analogue (~4-h half-life) Subcutaneous infusion; recently approved for IV use (limited data) Approved for Class II-IV Efficacy slower than epoprostenol, requires higher doses Site pain problematic with subcutaneous infusion
32	Subcutaneous Treprostinil: Change From Baseline in 6MW Test by Dose Quartile
33	Effect of Treprostinil on 6 Minute Walk
34	Effect of Treprostinil on 6 Minute Walk
35	Effect of Treprostinil on 6 Minute Walk
36	Effect of Treprostinil on 6 Minute Walk
37	Effect of Treprostinil on 6 Minute Walk
38	Treprostinil: Side Effects Infusion site pain Infusion site reaction Headache Diarrhea, nausea Rash Jaw pain Vasodilatation Dizziness Edema Pruritus Hypotension Delivery site complications
39	Site Reaction to Treprostinil
40	Treprostinil (Remodulin^®) The Good Improves exercise tolerance Improves survival The Bad Side Effects – s.c. site pain Risks of intravenous route And The Ugly Expensive Inconvenient
41	Timeline of FDA Approval of PAH Medications
42	Iloprost Longer-acting prostacyclin analogue (20- to 30-min half-life) Aerosolized delivery system Approved for Class III and IV Requires frequent inhalations (6-9x/d)
43	Inhaled Iloprost: Change from Baseline in 6MW Test (AIR Trial)
44	Effect of Iloprost on 6 Minute Walk
45	Effect of Iloprost on 6 Minute Walk
46	Effect of Iloprost on 6 Minute Walk
47	Effect of Iloprost on 6 Minute Walk
48	Effect of Iloprost on 6 Minute Walk
49	Inhaled Iloprost: Event-Free Survival* in Patients with IPAH
50	Inhaled Iloprost: Overall Survival in Comparison to Estimated Survival (NIH)
51	Iloprost: Side Effects Vasodilation (flushing) Increased cough Headache Trismus Insomnia Nausea, vomiting Alk phos increased Flu syndrome Back pain Abnormal labs Tongue pain Palpitations Syncope GCT increased Muscle cramps Hemoptysis Pneumonia
52	Iloprost (Ventavis^®) The Good Improves exercise capacity The Bad Side Effects And The Ugly Expensive Inconvenient
53	Timeline of FDA Approval of PAH Medications
54	Sildenafil Oral, phosphodiesterase type-5 inhibitor One RCT demonstrating efficacy Approved dose: 20 mg tid Approved for PAH (all classes)
55	Sildenafil: Change from Baseline in 6MW Test
56	Effect of Sildenafil on 6 Minute Walk
57	Effect of Sildenafil on 6 Minute Walk
58	Effect of Sildenafil on 6 Minute Walk
59	Effect of Sildenafil on 6 Minute Walk
60	Effect of Sildenafil on 6 Minute Walk
61	Sildenafil: Hemodynamic Effects Change From Baseline to Week 12
62	Sildenafil: Incidence of Clinical Worsening
63	Sildenafil Side Effects Nose bleed Headache Dyspepsia Flushing Insomnia Erythema Dyspnea exacerbated Rhinitis Diarrhea Myalgia Pyrexia Gastritis Sinusitis Paresthesia
64	Sildenafil (Revatio^®) The Good Oral Improves exercise capacity The Bad Generally mild side effects – Nosebleeds Stuffiness Headache Decrease bosentan level And The Ugly Not cheap
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