Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline-A Multinational Registry Analysis

Abstract

Rationale: Intravenous plasma-purified alpha-1 antitrypsin (IV-AAT) has been used as therapy for alpha-1 antitrypsin deficiency (AATD) since 1987. Previous trials (RAPID and RAPID-OLE) demonstrated efficacy in preserving computed tomography of lung density but no effect on FEV₁. This observational study evaluated 615 people with severe AATD from three countries with socialized health care (Ireland, Switzerland, and Austria), where access to standard medical care was equal but access to IV-AAT was not. Objectives: To assess the real-world longitudinal effects of IV-AAT. Methods: Pulmonary function and mortality data were utilized to perform longitudinal analyses on registry participants with severe AATD. Measurements and Main Results: IV-AAT confers a survival benefit in severe AATD (P < 0.001). We uncovered two distinct AATD phenotypes based on an initial respiratory diagnosis: lung index and non-lung index. Lung indexes demonstrated a more rapid FEV₁ decline between the ages of 20 and 50 and subsequently entered a plateau phase of minimal decline from 50 onward. Consequentially, IV-AAT had no effect on FEV₁ decline, except in patients with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 lung index. Conclusions: This real-world study demonstrates a survival advantage from IV-AAT. This improved survival is largely decoupled from FEV₁ decline. The observation that patients with severe AATD fall into two major phenotypes has implications for clinical trial design where FEV₁ is a primary endpoint. Recruits into trials are typically older lung indexes entering the plateau phase and, therefore, unlikely to show spirometric benefits. IV-AAT attenuates spirometric decline in lung indexes in GOLD stage 2, a spirometric group commonly outside current IV-AAT commencement recommendations.

Keywords: Kaplan-Meier survival curve; forced expiratory volume; universal health care; α 1-proteinase inhibitor.

Figure 1.

(A) FEV₁ (in liters; L) at age of pulmonary function testing (PFT) in all study participants. (B) FEV₁ (L) at age of PFT stratified by lung index status. (C) FEV₁ percent predicted at age of PFT in all study participants. (D) FEV₁ percent predicted at age of PFT stratified by lung index status. Gray shading represents 95% confidence interval of the mean.

Figure 2.

(A) Kaplan-Meier survival analysis categorized by lung index status showing an increased survival probability for non–lung index individuals compared with lung-index individuals (P = 0.009). (B) Kaplan-Meier survival analysis categorized by country showing an increased survival probability, mainly among Austrian individuals compared with Irish individuals (including lung index and non–lung index individuals) (P = 0.035).

Figure 3.

(A) Kaplan-Meier survival analysis of lung-index individuals categorized by country showing an increased survival probability, mainly among Austrian lung-index individuals compared with Irish lung-index individuals (P = 0.004). (B) Kaplan-Meier survival analysis of non–lung index individuals categorized by country showing a similar survival probability among non–lung index individuals across all three countries (P = 0.4).

Figure 4.

(A) Kaplan-Meier survival analysis categorized by augmentation status across all three countries showing an increased survival probability conferred by augmentation therapy (P = 0.00076). Those who were previously receiving augmentation therapy but stopped receiving it were excluded from analysis. (B) Kaplan-Meier survival analysis of individuals who never received intravenous alpha-1 antitrypsin, categorized by country, showing no difference in survival probability in those who never received augmentation therapy (P = 0.14).