The Science Journal of the American Association for Respiratory Care

2005 OPEN FORUM Abstracts

THE VALUE OF AUGMENTATION THERAPY FOR a1-ANTITRYPSIN DEFICIENCY: A META-ANALYSIS

Kenneth R. Chapman, MD†; Robert A. Stockley, MD, DSc‡; Mahlon M. Wilkes, PhD§; and Roberta J. Navickis, PhD§ From the †Asthma & Airway Centre, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada; ‡Lung Investigation Unit, Nuffield House, Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham, UK; and §Hygeia Associates, Grass Valley, California, USA

Background: a1-antitrypsin (a1-AT) is an anti-serine protease that inhibits neutrophil elastase in the lung. a1-AT deficiency is characterized by diminished circulating levels of a1-AT, which predisposes patients to early-onset emphysema. Augmentation with exogenous a1-AT is the only currently available specific therapy for a1-AT deficiency. Augmentation therapy has been shown to raise circulating and lung epithelial-lining fluid a1-AT concentrations, an effect that is thought to protect the lung from emphysematous injury. However, uncertainty persists concerning the effectiveness of augmentation therapy to preserve lung function and improve outcomes as well as identification of patients most likely to benefit from such therapy.

Method: A meta-analysis of controlled clinical studies was conducted to test the hypothesis that augmentation therapy with exogenous a1-AT in patients with a1-AT deficiency slows the decline in pulmonary function, as measured by one-second forced expiratory volume (FEV1). Pertinent studies were sought by computer searches of bibliographic databases (MEDLINE and EMBASE) and other Internet-resident information resources. Supplementary methods, including examination of reference citations in prior publications on a1-AT deficiency, were also employed. FEV1 data extracted from the study reports were quantitatively combined by random effects meta-analysis. Unpublished data were also sought from investigators in the field.

Results: A total of 1509 patients fulfilled the selection criteria and were included in four nonrandomized studies and one randomized trial. Among all patients receiving augmentation therapy, the decline in FEV1 was slower by 13.1 mL/y (CI, 1.6 to 24.7 mL/y; P = 0.026). This overall protective effect was predominantly attributed to the subset of patients with baseline FEV1 percent predicted of 30% to 65%. Augmentation therapy reduced FEV1 decline in that subset by 17.7 mL/y (CI, 9.6 to 25.7 mL/y; P < 0.0005). A significant effect of therapy could not be demonstrated in subsets with baseline FEV1 percent predicted of < 30% or > 65%.

Conclusions: Meta-analysis of data enables a quantitative combination and review of data from smaller studies to increase the precision of size-effective estimates and provides a method to explore the value of augmentation therapy in a1-AT deficiency. This analysis provides confirmation that augmentation therapy effectively slows the progression of lung dysfunction in patients with a1-AT deficiency. Patients with moderate pulmonary impairment are the most likely to benefit from this therapy.

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