Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary venous hypertension is synonymous with congestive heart failure, the treatment is to optimize left ventricular function by the use of diuretics, beta blockers, ACE inhibitors, etc., or to repair/replace the mitral valve or aortic valve.
In PAH, lifestyle changes, digoxin, diuretics, oral anticoagulants, and oxygen therapy are considered conventional therapy, but have never been proven to be beneficial in a randomized, prospective manner.
High dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality. The criteria for vasoreactivity have changed. Only those patients whose mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive. Of these, only half of the patients are responsive to calcium channel blockers in the long term.
[edit] Vasoactive substances
Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. Three of these pathways are important since they have been targeted with drugs — endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin derivatives.
[edit] Prostaglandins
Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin, marketed as Flolan®) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. An increased risk of sepsis with intravenous Remodulin® has been reported by the CDC. Iloprost (Ilomedin®) is also used in Europe intravenously and has a longer half life. Iloprost (marketed as Ventavis®) is the only inhaled form of prostacyclin approved for use in the US and Europe. This form of administration has the advantage of selective deposition in the lungs with less systemic side effects. Oral and inhaled forms of Remodulin® are under development. Beraprost is an oral prostanoid available in Japan and South Korea.
[edit] Endothelin receptor antagonists
The dual (ETA and ETB) endothelin receptor antagonist bosentan (marketed as Tracleer®) was approved in 2001. Sitaxsentan, a selective endothelin receptor antagonist that blocks only the action of ETA, has been approved for use in Canada, Australia, and the European Union, to be marketed under the name Thelin®.[10] Sitaxsentan has not been approved for marketing by the US FDA. A new trial to address the FDA's concerns will begin in 2008. A similar drug, ambrisentan is marketed as Letairis® in U.S. by Gilead Sciences.[11] In addition, another dual/nonselective endothelin antagonist, Actelion-1, from the makers of Tracleer®, will enter clinical trials in 2008.
[edit] Phosphodiesterase type 5 inhibitors
Sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), was approved for the treatment of PAH in 2005. It is marketed for PAH as Revatio®. Tadalafil (currently marketed as Cialis® for erectile dysfunction) is currently finishing its Phase III clinical trials and results should be reported very soon.
[edit] Other agents
Vasoactive intestinal peptide by inhalation should enter clinical trials for PAH in 2008. PRX-08066 is a serotonin antagonist currently being developed for hypoxic pulmonary hypertension. A recent study showed benefit as measured by echocardiography. A study using cardiac catheterization with a Swan-Ganz catheter is underway.
[edit] Surgical
Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxia). It is best performed in experienced centers. Lung transplantation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a post-surgical median survival of just over five years.[12]
Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a very difficult, major procedure that is currently performed in a few select centers. Case series show remarkable success in most patients.
Treatment for hypoxic and miscellaneous varieties of pulmonary hypertension have not been established. However, studies of several agents are currently enrolling patients. Many physicians will treat these diseases with the same medications as for PAH, until better options become available. Such treatment is called off-label use.
In PAH, lifestyle changes, digoxin, diuretics, oral anticoagulants, and oxygen therapy are considered conventional therapy, but have never been proven to be beneficial in a randomized, prospective manner.
High dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality. The criteria for vasoreactivity have changed. Only those patients whose mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive. Of these, only half of the patients are responsive to calcium channel blockers in the long term.
[edit] Vasoactive substances
Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. Three of these pathways are important since they have been targeted with drugs — endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin derivatives.
[edit] Prostaglandins
Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin, marketed as Flolan®) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. An increased risk of sepsis with intravenous Remodulin® has been reported by the CDC. Iloprost (Ilomedin®) is also used in Europe intravenously and has a longer half life. Iloprost (marketed as Ventavis®) is the only inhaled form of prostacyclin approved for use in the US and Europe. This form of administration has the advantage of selective deposition in the lungs with less systemic side effects. Oral and inhaled forms of Remodulin® are under development. Beraprost is an oral prostanoid available in Japan and South Korea.
[edit] Endothelin receptor antagonists
The dual (ETA and ETB) endothelin receptor antagonist bosentan (marketed as Tracleer®) was approved in 2001. Sitaxsentan, a selective endothelin receptor antagonist that blocks only the action of ETA, has been approved for use in Canada, Australia, and the European Union, to be marketed under the name Thelin®.[10] Sitaxsentan has not been approved for marketing by the US FDA. A new trial to address the FDA's concerns will begin in 2008. A similar drug, ambrisentan is marketed as Letairis® in U.S. by Gilead Sciences.[11] In addition, another dual/nonselective endothelin antagonist, Actelion-1, from the makers of Tracleer®, will enter clinical trials in 2008.
[edit] Phosphodiesterase type 5 inhibitors
Sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), was approved for the treatment of PAH in 2005. It is marketed for PAH as Revatio®. Tadalafil (currently marketed as Cialis® for erectile dysfunction) is currently finishing its Phase III clinical trials and results should be reported very soon.
[edit] Other agents
Vasoactive intestinal peptide by inhalation should enter clinical trials for PAH in 2008. PRX-08066 is a serotonin antagonist currently being developed for hypoxic pulmonary hypertension. A recent study showed benefit as measured by echocardiography. A study using cardiac catheterization with a Swan-Ganz catheter is underway.
[edit] Surgical
Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxia). It is best performed in experienced centers. Lung transplantation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a post-surgical median survival of just over five years.[12]
Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a very difficult, major procedure that is currently performed in a few select centers. Case series show remarkable success in most patients.
Treatment for hypoxic and miscellaneous varieties of pulmonary hypertension have not been established. However, studies of several agents are currently enrolling patients. Many physicians will treat these diseases with the same medications as for PAH, until better options become available. Such treatment is called off-label use.
