Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease (COPD)
Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease (COPD)
Pulmonary hypertension is frequently present in COPD and it is generally limited to a mild
 increase in mean pulmonary artery pressure. However some COPD patients are characterized by
 higher levels of mPAP at rest, fulfilling the definition of moderate or severe PH
 disproportionate PH .

 In these patients the elevated pulmonary pressures adversely affect the prognosis.At the
 present time the evidence for the the use of specific pulmonary vasodilators in the
 management of these patients are scarce and cannot be recommended.the aim of this study is to
 evaluate the medium term efficacy and safety of the inhaled prostacyclin stable analog,
 iloprost in patients with COPD and moderate to severe pulmonary hypertension
While pulmonary hypertension is frequently present in COPD, particularly in the presence of
 hypoxemia, it is generally limited to a mild increase in mean pulmonary artery pressure in
 the face of a normal cardiac output.

 Apart from this classical and widely observed profile of PH with modestly elevated mPAP, some
 COPD patients are characterized by higher levels of mPAP at rest, fulfilling the definition
 of moderate or severe PH . This kind of PH may be observed in patients presenting with a
 severe obstructive disease, but sometimes contrasts with a mild or moderate obstruction. In
 the latter case, the term disproportionate PH has been proposed, but it can be extended to
 describe all COPD patients with moderate to- severe PH.

 Therefore, it is possible that in some patients with COPD, pulmonary hypertension contributes
 to the clinical picture because of right ventricular output limitation and is responsible for
 the poor prognosis of these patients, which is similar to that in primary pulmonary arterial
 hypertension.

 The exact incidence of clinically significant pulmonary hypertension, defined as pulmonary
 hypertension that contributes to symptomatology and prognosis, is difficult to estimate in
 COPD. A prevalence of 5.8%- 13.5% in patients seems reasonable which would suggest an
 incidence of 1-3/10,000, which is 100 times the incidence of idiopathic pulmonary arterial
 hypertension.

 These patients are characterized by marked effort dyspnea , profound hypoxemia, hypocapnia,
 moderate airway obstruction and a very low DLCO.

 PH in COPD was an independent prognostic factor. Indeed, patients with similar airflow
 limitation had lower life expectancy when PH was resent. Patients with PH had a significantly
 lower survival rate at 5 yrs compared with patients without PH (33 versus 66%). Pathologic
 studies that stemmed from long-term oxygen trials pointed to the fact that pulmonary vascular
 remodeling in chronic obstructive pulmonary disease (COPD) is more than just medial
 hypertrophy from long-lasting hypoxic vasoconstriction. In these patients, all vessel wall
 layers appear to be involved, with intimal changes actually being the most prominent. Major
 remodeling of all pulmonary arterial vessel layers explains why pulmonary hypertension in
 COPD is often not,or minimally, reversible by supplemental oxygen, acutely or chronically.
 The pathobiology of pulmonary artery remodeling in advanced COPD remains incompletely
 explored. There are data supporting an endothelium-derived vasoconstrictor-dilator imbalance,
 mainly from a decreased endothelial nitric oxide expression. Plasma levels of ET-1 are
 increased both in patients with severe COPD and there is evidence that ETA and ETB receptor
 expression is increased in the pulmonary arteries of patients with COPD.

 The major unmet medical need is the absence of a simple drug therapy that relieves the
 breathlessness or muscle fatigue, reduces pulmonary vascular resistance and the overloaded
 right ventricles that severely limits exercise tolerance in COPD and affects survival.

 The only validated therapeutic approach of the 'common' PH in COPD patients is long-term
 oxygen therapy. A large variety of vasodilators has been tested in numerous studies both
 after short- and medium-term administration. The early enthusiasm vanished subsequently for
 several reasons: modesty of the vasodilator effect, inability for some drugs to sustain the
 acute benefit, no specificity of the vasodilator effect with concomitant systemic
 vasodilatation, deleterious effect on gas exchange due to a diminution of the
 ventilation/perfusion ratio and no demonstration of a survival benefit. At the present time
 vasodilators cannot be recommended in the management of COPD.

 Treatments of PAH have shown a dramatic change in the past few years. Synthetic prostacyclin
 (epoprostenol), prostacyclin analogues, endothelin-1 receptor antagonists and
 phosphodiesterase-5 inhibitors are in use in group I PAH with improve clinical outcome.

 Based on analogy to primary pulmonary hypertension, a specific interventions aiming at the
 restoration of endothelial vasoconstrictor- dilator imbalance could be undertaken.

 Selective pulmonary vasodilatation by inhalation of the vasorelaxant agent is an appealing
 concept to circumvent some of the hazards inherent in systemic vasodilator therapy in COPD
 patients with PH. Treatment of these patients with aerosolization of iloprost may reduce
 pulmonary vascular resistance , increases cardiac output while conserving
 ventilation-perfusion matching and and shunt preventing worsening of arterial hypoxia and
 wasting of the small ventilatory reserve of these patients.

 In order to resolve these uncertainties we suggest evaluating the effectiveness of an inhaled
 iloprost in COPD patients with moderate to severe pulmonary hypertension. This evaluation
 would include monitoring and measurement of all the relevant cardio-respiratory variables as
 set out in detail below.
Inclusion Criteria:

 1. Patient with COPD and increased SPAP >55 on echocardiogram will be screened for the
 study.

 2. Patients with normal wedge pressure ( [PCWP] ≤ 15 mm Hg), mean PAP ≥ 35 mm Hg and a
 pulmonary vascular resistance (PVR- 3.0 wood unit)on right heart catheterization.

 3. Diagnosis of COPD according to GOLD guidelines

 4. The patient can read, understand and sign the informed consent.

 Exclusion Criteria:

 1. Other identified cause for pulmonary hypertension