Presentation Outline ICHP Annual Meeting September 13-15
Presentation Outline ICHP Annual Meeting September 13-15
Presentation Outline ICHP Annual Meeting September 13-15
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ACCF/AHA Consensus PAH Treatment<br />
Algorithm<br />
Anticoagulate ± Diuretics ±<br />
Oxygen ± Digoxin<br />
Oral CCB<br />
Sustained<br />
Response<br />
Yes<br />
Continue<br />
CCB<br />
No<br />
Positive<br />
Modified from McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:<strong>15</strong>73-1619.<br />
Pre-proendothelin<br />
Endothelin<br />
receptor A<br />
Endothelinreceptor<br />
antagonists<br />
Acute Vasoreactivity Testing<br />
Negative<br />
Lower Risk Higher Risk<br />
ERAs or PDE-5 Is (oral)<br />
Epoprostenol or Treprostinil (IV)<br />
Iloprost (inhaled)<br />
Treprostinil (SC, inhaled)<br />
Reassess: consider<br />
combo-therapy<br />
Investigational Protocols<br />
Epoprostenol or Treprostinil (IV)<br />
Iloprost (inhaled)<br />
ERAs or PDE-5 Is (oral)<br />
Treprostinil (SC)<br />
Atrial septostomy<br />
Lung transplant<br />
Approved Therapeutic Targets<br />
Endothelin<br />
Pathway<br />
Endothelin Endothelin-11<br />
Smooth muscle cells<br />
Endothelial cells<br />
Proendothelin<br />
Endothelin<br />
receptor B<br />
Vasoconstriction<br />
and proliferation<br />
Humbert M, et al. N Engl J Med. 2004;351:1425-1436.<br />
Nitric Oxide<br />
Pathway<br />
L-arginine<br />
Phosphodiesterase<br />
type 5<br />
Nitric Oxide<br />
cGMP<br />
L-citrulline<br />
Prostacyclin<br />
Pathway<br />
Endothelial cells<br />
Arachidonic acid<br />
Exogenous<br />
nitric oxide<br />
Vasodilation<br />
and antiproliferation<br />
Phosphodiesterase<br />
type 5 inhibitor<br />
Prostaglandin I 2<br />
Prostacyclin (prostaglandin I I2) )<br />
cAMP<br />
Vasodilation<br />
and antiproliferation<br />
Smooth muscle cells<br />
Endothelin Receptor Antagonists:<br />
Pivotal Trials<br />
Study Name<br />
Drug<br />
BREATHE-1<br />
Oral bosentan*<br />
vs placebo<br />
EARLY<br />
Oral bosentan<br />
vs placebo<br />
ARIES-1&2<br />
Oral ambrisentan §<br />
vs placebo<br />
N<br />
Etiology<br />
Class Design<br />
2<strong>13</strong><br />
PAH<br />
III, IV<br />
185<br />
PAH<br />
II<br />
394<br />
PAH<br />
II, III<br />
Double-blind<br />
16-week<br />
Double-blind<br />
6-month<br />
Double-blind<br />
12-week<br />
Positive<br />
Results<br />
•6MWD<br />
• Delay clinical worsening<br />
• Symptoms<br />
• Delay clinical worsening<br />
• Hemodynamics<br />
•6MWD<br />
• Delay clinical worsening<br />
*Bosentan = Tracleer ® . Approved for FC II-IV. 62.5-125 mg po bid.<br />
§ Ambrisentan = Letairis ® . Approved for FC II-III. 5-10 mg po qd<br />
Rubin L, et al. N Engl J Med. 2002;346:896-903.<br />
Channick RN, et al. Lancet. 2001;358:1119-1123.<br />
Galiè N, et al. Lancet, 2008;371:2093-2100.<br />
Galiè N, et al. Circulation. 2008;117:3010-3019.<br />
Prostacyclin<br />
derivatives<br />
<strong>15</strong>
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