Cost-minimisation analysis of sivelestat for acute lung injury associated with systemic inflammatory response syndrome.

OBJECTIVES: To conduct a cost-minimisation analysis of sivelestat sodium hydrate treatment for patients in the intensive care unit (ICU) with acute lung injury (ALI) associated with systemic inflammatory response syndrome (SIRS) caused by infection. DESIGN: The analysis was performed based on data from a phase III randomised, multicentre, double-blind, controlled clinical study of up to 14 days treatment with sivelestat, in which the effect of intravenous sivelestat at a high dose (0.20 mg/kg/h; the sivelestat group) was compared with that at a low dose (0.004 mg/kg/h, effectively a placebo; the control group). PATIENTS: Patients with ALI associated with SIRS caused by infection, who began their treatment under mechanical ventilation management in the ICU. METHODS: A four-stage Markov model was constructed to represent the possible conditions of an ALI patient: ICU plus intubated mechanical ventilation; ICU plus weaned from a mechanical ventilator; admission to the general ward; and death. The base-case analysis used a mechanical ventilator weaning daily rate of 2.9% for the control group and 4.0% for the sivelestat group, and the same mortality (1.2%) for both groups at all stages of the Markov model. Medical costs were estimated from standard fees and Japanese National Health Insurance drug prices included fees for hospitalisation within the ICU and general wards, mechanical ventilation, examinations and drug expenditure. Costs were in 2001 values. Sensitivity analyses were performed by varying the weaning rate, mortality, time between weaning and discharge to the general ward, and drug costs. PERSPECTIVE: Payers of healthcare costs. MAIN OUTCOMES: The expected 30-day medical costs per patient in the control and sivelestat groups were Japanese yen (yen) 4,144,887 and 3,975,451 yen, respectively; a difference of 169,436 yen. Drug expenditure accounted for more than half of the medical costs for each group. The periods under mechanical ventilation management and in the ICU for the sivelestat group were shorter than those for the control group by 2 and 1.8 days, respectively. This was of significance in the reduction of the medical costs. A sensitivity analysis suggested that the expected costs for the sivelestat group exceeded those for the control group when the daily weaning rate for the sivelestat group was <3.5%, and also when mortality rates were set at 0.9% in the sivelestat group and 1.4% in the control group. CONCLUSIONS: This analysis suggests that from the Japanese healthcare payer perspective, treatment with sivelestat may reduce medical costs compared with standard care for patients with ALI associated with SIRS caused by infection.

Relationship between neutrophil elastase and acute lung injury in humans.

We conducted clinical trials in patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome using a selective neutrophil elastase inhibitor, sivelestat sodium hydrate (Sivelestat), to investigate the involvement of neutrophil elastase in ALI. In the phase III double-blind study (Study 1) in 230 patients, the efficacy of Sivelestat was evaluated with the pulmonary function improvement (PFI) rating as the primary endpoint, and the weaning rate from mechanical ventilator, the discharge rate from intensive care unit (ICU), and the survival rate as secondary endpoints. Afterwards, an unblinded study (Study 2) in 20 patients was conducted using procedures for weaning from mechanical ventilation to reevaluate its efficacy with ventilator-free days (VFD) value, the primary endpoint, and to compare with that of Study 1 subgroup, which met the selection criteria used in Study 2. Sivelestat increased PFI rating, reduced duration of mechanical ventilation, and shortened stay in ICU in Study 1, although there was no significant efficacy on the survival rate. VFD value in Study 2 was comparable to that in the optimal-dose group of Study 1 subgroup, and increase in VFD value correlated with PFI rating and increase in ICU free days. It was concluded that neutrophil elastase may be involved in the pathogenesis of ALI in humans.

Elastase inhibition reduced death associated with acid aspiration-induced lung injury in hamsters.

This study examined whether the specific inhibition of neutrophil elastase by sivelestat sodium hydrate (sivelestat) reduced deaths associated with severe acute lung injury after hydrochloric acid (HCl) aspiration in hamsters. Animals that received a single intratracheal instillation of HCl (0.2 N, 200 microL) time-dependently died by occlusion of their trachea with inflammatory exudate. In a time course study, these animals developed severe lung injury, peaking 12 to 24 h after HCl instillation, as indicated by hemorrhage and a massive increase in the protein concentration of bronchoalveolar lavage fluid. These changes were closely correlated with neutrophil elastase activity in bronchoalveolar lavage fluid. Sivelestat (0.01, 0.1 and 1 mg/kg/h), when intravenously infused during the first 48 h post-HCl instillation, dose-dependently reduced death in HCl-instilled hamsters. In a separate experiment, analysis of bronchoalveolar lavage fluid parameters and partial pressure of arterial oxygen (PaO(2)) 8 h post-HCl instillation showed that sivelestat at 1 mg/kg/h, i.v. significantly improved both bronchoalveolar lavage fluid parameters and PaO(2) levels with evidence of the inhibition of neutrophil elastase activity in bronchoalveolar lavage fluid. These results suggest that neutrophil elastase plays a significant role in this type of severe acute lung injury that leads to death by respiratory failure.