Long-term effects of intravenous iloprost in patients with idiopathic pulmonary arterial hypertension deteriorating on non-parenteral therapy

Abstract

Background: The majority of patients with idiopathic pulmonary arterial hypertension (IPAH) in functional classes II and III are currently being treated with non-parenteral therapies, including endothelin receptor antagonists (ERA), phosphodiesterase (PDE)-5 inhibitors, inhaled iloprost or combinations of these substances. If these treatments fail, current guidelines recommend the addition of parenteral prostanoid therapy. There is, however, limited evidence for the efficacy of parenteral prostanoids when added to combinations of non-parenteral therapies.

Methods: In this retrospective, multicentre study we collected data from consecutive IPAH patients receiving intravenous iloprost in addition to optimized non-parenteral therapy between Jan 2002 and Dec 2009. Analyses included 6 min walk distance (6MWD), functional class, need for transplantation, and survival.

Results: During the observation period, 50 patients were treated with intravenous iloprost in addition to non-parenteral therapy; 44% of the patients were on dual combination therapy and 52% on triple combination. Three months after initiation of iloprost, functional class had improved in 24% of the patients and the median 6MWD had increased from 289 m to 298 m (n.s.). During the observation period, 22 patients (44%) died and 14 (28%) underwent lung transplantation. The probabilities of LuTx-free survival at 1, 3 and 5 years following iloprost initiation were 38%, 17% and 17%, respectively. A 6MWD < 300 m and persistent functional class IV at 3 months after initiation of intravenous iloprost were predictors of an adverse outcome.

Conclusion: In essence, late initiation of intravenous iloprost in IPAH patients who previously failed to respond to non-parenteral therapies appears to be of limited efficacy in the majority patients. Alternative therapeutic options are currently not available, underlying the need for the development of new drugs.

Figure 1

Available data of 6MWD for each patient at different time points e.g. start of iloprost (BL-ilo), 3 months (3 Mo) and 12 months (12 Mo) after iloprost initiation. The median of the 6MWD increased from BL-ilo to 3 Mo and 12 Mo (289 m vs. 298 m vs. 345 m). However, the between group differences were not statistical significant (one-way ANOVA: p = 0.09)

Figure 2

Kaplan-Meier curves showing the expected survival in comparison to the observed LuTx-free (A) and observed overall (LuTx censored) (B) survival from the time of diagnosis. Patients at risk were n = 50, n = 47, n = 41, n = 32, n = 21, n = 16 and n = 14 at diagnosis, 12, 24, 36, 48, 60 and 72 months after diagnosis (observed survival). Level of significance: LuTx-free survival vs. expected survival: p = 0.15. Overall survival vs. expected survival: p < 0.01. |: censored patients.

Figure 3

Kaplan-Meier curves showing the observed LuTx-free (A) and observed overall (B) survival from initiation of continuous intravenous iloprost. Patients at risk n = 50, n = 16, n = 10, n = 6, n = 5, n = 5, n = 3 at BL-ilo, 12, 24, 36, 48, 60 and 72 months after initiation of iloprost therapy (observed survival). |: censored patients.

Figure 4

Kaplan-Meier curves demonstrating the impact of functional class (A and B) and 6MWD (C and D) 3 months after introduction of intravenous iloprost on the LuTx-free and overall survival from the time point iloprost-start. LuTx-free survival: Hazard ratio NYHA IV vs. III 3.87; 95% CI 1.38-10.84; Hazard ratio 6MWD < 300 m vs. > 300 m 3.14, 95% CI 1.17-8.45. Overall survival: Hazard ratio of NYHA IV vs. NYHA III: 8.39, 95% CI 2.28-30.83; Hazard ratio of 6MWT < 300 m vs. > 300 m: 8.76, 95% CI 2.05-37.5. |: censored patients.