Key Point

Inhaled iloprost has both short- and long-term benefits for patients with various types of PH.

SAN DIEGO—Inhaled iloprost, the newest entry into the prostacyclin class of pulmonary arterial hypertension (PAH) treatments, has been shown to be highly beneficial in the short- and long-term treatment of patients with PAH, according to investigators reporting at the annual meeting of the American Thoracic Society.¹

ILOPROST EFFICACY DEMONSTRATED

Inhaled iloprost is effective for the long-term treatment of pulmonary hypertension (PH), with two-year data suggesting sustained clinical benefit, said Horst Olschewski, MD, Professor and Chair of the Pulmonary Division at Medical University in Graz, Austria.

“Intermittent therapy with inhaled iloprost improves exercise capacity and pulmonary hemodynamics while reducing the risk of developing tolerance and rebound,” Dr. Olschewski pointed out. “It also avoids the inconvenience and complications that are associated with chronic indwelling catheters.”

Prior to the development of inhaled iloprost, prostacyclin therapy required continuous delivery through subcutaneous or intravenous routes, Dr. Olschewski explained. This invasive approach required complicated maintenance and patients found it difficult to tolerate.

Following a series of earlier phase I and II studies, he continued, a randomized, double-blind, multicenter, placebo-controlled, phase III clinical trial was designed to assess the efficacy and safety of inhaled iloprost in 203 adult patients with New York Heart Association (NYHA) class II–IV PAH. The patients were randomly assigned to treatment with inhaled iloprost 2.5 or 5 g given six to nine times a day for 12 weeks or to placebo.

The primary clinical end point of the study was a composite of improvement in NYHA functional class, a 10% increase in six-minute walk test distance, and no clinical deterioration. All aspects of the end point were achieved to a significant degree in the iloprost-treated patients compared to those in the placebo group. The response rate for the composite end point was 19% in the iloprost group versus 4% in the placebo group. Based on these findings, the drug was approved by the FDA on December 29, 2004, for the treatment of PAH in patients with NYHA class III or IV symptoms.

LONG-TERM TREATMENT

To investigate the long-term outcome of therapy with inhaled iloprost, said Dr. Olschewski, 63 patients with NYHA class II-IV PH of different varieties were enrolled from the initial randomized, controlled, phase III trial. These patients, as noted above, had been randomized to receive inhaled iloprost or placebo for 12 weeks. Fifty-two patients who completed the 12-week phase were entered into an open-label treatment phase with inhaled iloprost at the same dosage for two years. Iloprost was administered by intermittent inhalations while patients were awake, with an overnight break.

A total of 36 of the 52 patients suffered from primary pulmonary hypertension (PPH), and all 36 completed 630 days of therapy, Dr. Olschewski noted. Of these, 13% of patients treated with iloprost (4 of 30) who met the clinical composite end point at week 12 of the randomized trial maintained their response over the two-year period. No control patients met the response criteria at week 12, but five patients from this group met the primary composite end point upon long-term, open-label treatment with iloprost. In 31 patients for whom six-minute walk test results were available both at baseline and year 2, estimates showed an increase of 89 meters. Other improvements included a two-year increase from 4.8 to 5.8 on the Mahler dyspnea index. The patients with PPH or idiopathic PH had a two-year survival rate of 91% compared to a predicted survival rate of 63% for an untreated historical cohort, based on the NIH registry.

TREATMENT BENEFIT MAINTAINED AT TROUGH

In a related study, a retrospective analysis of the efficacy data from the pivotal phase III, randomized, placebo-controlled clinical trial showed that inhaled iloprost had a sustained treatment benefit in PH patients as assessed at the point of lowest concentration during the dose cycles, said Lewis J. Rubin, MD, Professor of Medicine at the University of California in San Diego.²

“Despite intermittent dosing, inhaled iloprost had a clinically relevant treatment effect at trough as seen in the six-minute walk distance, improvement in NYHA class, and hemodynamic parameters,” Dr. Rubin stated. “Compared to the trends toward deterioration seen with placebo, the group treated with iloprost had maintenance of stability or trends toward improvement at trough. This is consistent with findings of a sustained treatment effect, including a lower rate of clinical deterioration, and improvement in quality-of-life measures.”

After 12 weeks of therapy, Dr. Rubin noted, six-minute walk distance and hemodynamics using right heart catheterization were measured both preinhalation (trough) and postinhalation (peak). Data for preinhalation were measured at least two hours before an inhalation, while data measured postinhalation were obtained approximately 15 to 30 minutes after inhalation. In some instances, the trough measurements were obtained after the overnight break and prior to the first dose of the day. The change in NYHA class also was analyzed over time, since it is a measure of overall functional improvement that is independent of the timing of daily drug administration.

In all iloprost-treated patients, the mean change in six-minute walk distance measured at trough, from baseline to 12 weeks of therapy, was an increase of 10.9 meters, compared to a decrease of 10.7 meters in the placebo group. This represented a placebo-corrected improvement of 21.6 meters in favor of iloprost treatment. The mean change in six-minute walk distance at trough, from baseline to 12 weeks, showed an increase of 12.7 meters in the patients treated with iloprost versus a decrease of 14.3 meters in the placebo group. The placebo-corrected improvement here in favor of iloprost therapy was 27 meters.

Hemodynamic parameters measured at trough at baseline improved or remained relatively stable at 12 weeks for the patients treated with iloprost. This contrasted with significant deterioration in the placebo group, which showed an 8.7% decrease in pulmonary vascular resistance, a 4.4% decrease in cardiac output, and a 5.2% decrease in slow vital capacity.

—Lawrence M. Prescott, PhD

References
1. Olschewski H, Hoeper MM, Behr J, et al. Safety, dosing, and clinical benefit of 2-year therapy with inhaled iloprost. Presented at: annual meeting of the American Thoracic Society; May 22, 2005; San Diego, Calif.
2. Rubin LJ, Olschewski H, Simonneau G, et al. Maintenance of clinical benefit of inhaled iloprost during trough periods. Presented at: annual meeting of the American Thoracic Society; May 22, 2005; San Diego, Calif.

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