National Heart, Lung and Blood Institute (NHLBI) Registry

A long-term post-marketing surveillance program under the direction of the National Heart, Lung and Blood Institute (NHLBI) was initiated in 1988.^1-4 The objective of this prospective registry was to help define the natural history and clinical course of alpha₁-antitrypsin (AAT) deficiency. Thirty-six clinical centers in the United States and one in Canada participated in the registry. A total of 1,129 adult patients (18 years of age or older) with severe AAT deficiency (defined as having serum AAT level ≤80 mg/dL (11 micromoles (μM)) or a ZZ or Z-null genotype identified by genomic DNA analysis) were enrolled in the registry. The majority of registry participants were symptomatic patients in their fourth to sixth decade, with a ZZ genotype (97.3%), a history of having smoked cigarettes, and pulmonary function test results consistent with emphysema. The mean baseline FEV₁ was 47% of predicted.⁵ The decision to prescribe Prolastin^® (Alpha₁- Proteinase Inhibitor [Human]) and the dose used were left to the discretion of the subjects’ managing physicians. Of the 1,129 subjects enrolled, 382 (34%) never received Prolastin^®, 390 (35%) always received Prolastin^®, and 357 (32%) received Prolastin^® at some time during the study period. The last group received Prolastin^® for an average 66% of the total study period.⁶ As their results did not differ from those always receiving Prolastin^®, the two groups were combined for most analyses.

Patient follow-up included spirometry at 6-month or yearly intervals, and continued through April 1996. Depending upon date of enrollment in the registry, follow-up times for individual subjects ranged from 3.5 to 7 years. Of the 1,129 patients in the study, 204 (18.1%) died, 39 (3.5%) dropped out, and 886 (78.5%) remained in the study until its conclusion.⁶

Survival

Age and baseline FEV₁ were significant predictors of mortality. Overall, patients receiving Prolastin^® had decreased mortality (P=0.02). This difference in mortality remained significant when the multivariate Kaplan-Meier survival analysis was adjusted for covariates, such as age and baseline FEV₁, which were independent predictors of mortality (P=0.02). Among all patients with initial FEV₁ <50%, mortality was significantly higher (P≤0.001) for those who never received Prolastin^®. Mortality rates for those with initial FEV₁ ≥50% were low and did not differ between groups.⁶

Decline in FEV₁

The majority of subjects, whether or not they received Prolastin^®, experienced a decline in FEV ₁ during the study period. The average ΔFEV ₁ (ie, change between baseline FEV ₁ and all subsequent measurements) among 927 subjects with at least two spirometry results ≥1 year apart was 54 mL per year.⁶ Significant predictors of a more rapid decline in FEV₁ included male gender, age 30 to 44 years, current smoker, baseline FEV₁ between 35% and 79% of predicted, bronchodilator responsiveness, decreased serum AAT level, and nonuse of augmentation therapy. The effects of Prolastin^® in these 927 subjects were evaluated based on mean FEV₁% of predicted and baseline FEV₁% of predicted. Among all 927 subjects, mean rates of FEV₁ decline did not differ between those receiving and those not receiving Prolastin^® (difference in means of 4 mL per year; P=0.40). However, the rate of FEV₁ decline among subjects with mean FEV₁ values of 35% to 49% of predicted was significantly slower in those receiving Prolastin^® compared to those not receiving therapy (difference in means of 27 mL per year, P=0.03). Similar results were obtained for subjects with initial FEV₁ values of 35% to 45% of predicted, (ie, difference in means of 22 mL/year, P=0.04).

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