Inhaled Iloprost for Severe Pulmonary Hypertension

Horst Olschewski et al. N Engl J Med 2002; 347: 322–329

The Aerosolized Iloprost Randomized (AIR) Study was a double-blind, randomized trial in which an aerosolized form of iloprost, a stable analogue of the pulmonary vasodilator prostacyclin, was assessed over a 12-week period. A total of 203 patients with primary pulmonary hypertension (102 patients) as well as other selected forms of pulmonary hypertension (secondary to appetite suppressants 19, collagen vascular disease 25, chronic pulmonary thromboembolism 57—a total of 101 patients) were included in the study. The inclusion criteria were a mean pulmonary artery pressure greater than 30 mmHg, ability to cover between 50 and 500 m in the 6-minute walk test and NYHA functional class III or IV. The exclusion criteria were a pulmonary artery wedge pressure of more that 15 mmHg at rest, a cardiac index of <1.5 or >4 L/min, bleeding disorders, bilirubin level >3 mg/dl, renal dysfunction, a forced vital capacity below 50% and clinical instability. The 203 patients were randomized to receive iloprost or a placebo after stratification according to the NYHA functional class (III or IV), hemodynamic parameters and type of pulmonary hypertension. Iloprost diluted with saline was delivered in short pulses by means of a nebulizer to achieve a total dose of 5 µg six or nine times daily (median inhaled dose of 30 µg/day). Right heart catheterization was performed at baseline and at 12 weeks, and the patients were evaluated 4-weekly. The primary end-point was a 10% increase in the distance walked in the 6-minute test and an improvement in the NYHA functional class. Iloprost treatment was found to be favorable, with the estimated odds of an effect being 3.97 compared with the placebo (97% CI). There was no difference among the subgroups (type of pulmonary hypertension and functional class at randomization). Treatment with iloprost was superior to that with the placebo, with the combined clinical end-point being met by 16.8% compared with 4.9%, respectively (p= 0.007). The absolute change in the distance walked in 6 min was significantly greater (by 36.4 m) in the iloprost group than in the placebo group (p=0.0004). There was an improvement in all the hemodynamic parameters and also in the functional class (p=0.03), dyspnea (p=0.015), and quality of life (p=0.026). Fewer treated patients died (1) or deteriorated (4.9%) in the iloprost group compared with 4 deaths and 8.8% deterioration in the placebo group. The frequency of occurrence of syncope in both the subgroups was similar. Transient flushing and jaw pain were common but well tolerated.

Pulmonary hypertension is a vexing condition to treat. Reduction in mortality was first demonstrated by therapy with intravenous prostacyclin in a controlled study of patients with severe pulmonary hypertension. However, systemic side-effects, tolerance and recurrent catheter infections with intravenous prostacyclin led to the development of aerosolized prostacyclin which was found to be effective in the treatment of acute respiratory failure.  Iloprost is a stable analogue of prostacyclin and has a longer vasodilatory action which lasts for 30–90 min. The results of this study demonstrated that nearly 40% of treated patients increased their 6-minute walk distance by at least 10%; however, only half as many patients also showed improvement in the NYHA functional class. Although only 17% of patients in the iloprost group reached the combined end-point, there was clinical improvement in a substantial number of other patients. The benefit was greatest among patients with primary pulmonary hypertension—49% of the patients with primary pulmonary hypertension showed a more than 10% increase in the 6-minute walk distance compared with only 25% of the patients with nonprimary pulmonary hypertension. The issue of the paradoxically increased frequency of syncope has been explained by the authors as being due to the patients challenging the limits of their cardiac reserve with the clinical improvement following iloprost therapy and also due to the increased time interval from the last administered dose. However, the fact remains that 8 patients in the iloprost group fainted compared to 5 in the placebo group. None of the syncopal attacks in the placebo group was categorized as serious while 5 out of the 8 episodes in iloprost-treated patients were. Also, the dosage is not clear and varied from 6 to 9 times a day. As the device is not battery-driven, inadvertent decreased inhalation is likely to be a common occurrence. Techniques that shorten the inhalation time would ensure adequate dose and increase compliance. The short duration of the study and the fact that survival was not used as an end-point are other shortcomings. To conclude, this trial has demonstrated the efficacy and safety of iloprost for the treatment of pulmonary hypertension.