The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint defined by: a) improvement in exercise capacity (6-minute walk test) by at least 10% versus baseline evaluated 30 minutes after dosing, b) improvement by at least one NYHA class versus baseline, and c) no death or deterioration of pulmonary hypertension. Deterioration required two or more of the following criteria: 1) refractory systolic blood pressure < 85 mmHg, 2) worsening of right heart failure with cardiac edema, ascites, or pleural effusion despite adequate background therapy, 3) rapidly progressive cardiogenic hepatic failure (e.g. leading to an increase of GOT or GPT to > 100 U/L, or total bilirubin ≥ 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g. decrease of estimated creatinine clearance to ≤ 50% of baseline), 5) decrease in 6-minute walking distance by ≥ 30% of baseline value, 6) new long-term need for i.v. catecholamines or diuretics, 7) cardiac index ≤ 1.3 L/min/m², 8) CVP ≥ 22 mmHg despite adequate diuretic therapy, and 9) SVO2 ≤ 45% despite nasal O2 therapy.

Although effectiveness was seen in the full population (response rates for the primary composite endpoint of 17% and 5%; p=0.007), there was inadequate evidence of benefit in patients with pulmonary hypertension associated with chronic thromboembolic disease (WHO Group IV); the results presented are therefore those related to patients with PAH (WHO Group I). The response rate for the primary efficacy endpoint among PAH patients was 19% for the iloprost group, compared with 4% for the placebo group (p=0.0033). All three components of the composite endpoint favored iloprost (Figure 1).

Figure 1: Composite Primary Endpoint for PAH Patients (WHO Group I)

The absolute change in 6-minute walk distance (Figure 2) measured (using all available data and no imputation) 30 minutes after inhalation among patients with PAH was greater in the iloprost group compared to the placebo group at all time points. At Week 12, the placebo-corrected difference was 40 meters (p < 0.01). When walk distance was measured immediately prior to inhalation, the improvement compared to placebo was approximately 60% of the effect seen at 30 minutes after inhalation.

Figure 2: Change (Mean ± SEM) in 6-Minute Walk Distance 30 Minutes post Inhalation in PAH Patients (WHO Group I).

The effect of Ventavis in various subgroups is shown in Table 1.

Table 1: Treatment Effects by Subgroup among PAH Patients (WHO Group I)

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