P12 Alpha1-antitrypsin deficiency

A systematic review of three randomised controlled trials studying a total of 283 patients, concluded that there was a lack of evidence of clinical benefit from alpha-1 antitrypsin augmentation therapy (Gøtzsche 2016) [evidence level I]. Alpha-1 antitrypsin augmentation therapy is not routinely available in Australia.

In the RAPID trial RCT, which contributed the majority of patients to the above systematic review, intravenous augmentation therapy was studied in 177 adults with COPD and severe alpha1-antitrypsin (AAT) deficiency (serum level <11µM), FEV1 35-70% predicted and no smoking in the prior six months (Chapman 2015). Intravenous AAT 60 mg/kg from pooled human plasma was given weekly in the intervention group, vs. matched placebo in the control group, for 24 months. Open label augmentation was then offered for a further 24 months. 10% of the intervention group withdrew prematurely, compared to 21% of the control group. The annual rate of lung density loss, measured by CT chest at total lung capacity (TLC), was statistically significantly less in the patients receiving AAT augmentation (mean –1.45 g/L per year, SE 0.23), compared to the placebo group (–2.19 g/L per year, SE 0.25), with difference of 0.74 g/L per year (95% CI 0.06–1.42). There were no changes in annual rate of lung density loss when measured at a combination of TLC and FRC, or at FRC alone. There were no statistically significant differences in mortality, exacerbations, FEV1 or adverse effects. Post-hoc exploratory analysis showed a reduced rate of lung density loss with higher trough serum AAT levels achieved. Benefits in patient-orientated outcomes were not demonstrated, although this study was not powered to show this.

A two year, open label extension trial of 140 patients who had participated in the previous trial (Chapman 2015) showed that the decrease in rate of lung density loss was maintained in patients who continued this dose of active AAT augmentation therapy, and was achieved by patients who started therapy during the extension trial (McElvaney 2017).

It is noted that the optimal dosing regimen has not yet been determined, but that in the trials described above patients underwent weekly intravenous infusions. The evidence to date demonstrates that AAT augmentation modifies the development of emphysema.  It is unclear if AAT therapy improves clinical outcomes.  Studies of cost-effectiveness have not yet been conducted.