Inhaled Iloprost for Disproportionate Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease (COPD)

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.