Treating alpha-1-antitrypsin deficiency – pro

Alpha1-Proteinase Inhibitor (Human), Prolastin (alpha) is FDA indicated for chronic replacement therapy of individuals having congenital deficiency of alpha1-PI (alpha1-antitrypsin deficiency) with clinically demonstrable panacinar emphysema. Aralast is a similar drug. Studies of Aralast and Zemaira have shown equivalency with Prolastin in achieving and maintaining alpha1-antitrypsin serum levels and alveolar epithelial levels above the target level. No studies of Aralast or Zemaira have been done to show affects on FEV1, rate of decline of FEV1, or survival.

As some individuals with alpha1-antitrypsin deficiency will not go on to develop panacinar emphysema, only those with evidence of such disease should be considered for chronic replacement therapy with Prolastin (alpha) . Prolastin (alpha) is not indicated for use in patients other than those with PiZZ, PiZ(null) or Pi(null)(null) phenotypes becaseu otehr phenotypes have a smaller risk of developing panacinar emphysema.

After the FDA approval had been granted, a meta-anlaysis (Goetzshe et al) came to the conclusion that this drug is ineffective. The two authors independently selected trials, extracted outcome data and assessed the risk of bias. Two trials were included (total 140 patients) that ran for two to three years. All patients were ex- or never-smokers and had genetic variants that carried a very high risk of developing chronic obstructive pulmonary disease. Mortality data were not reported. There was no information on harms in the first trial; in the second trial, serious adverse events were reported to have occurred in 10 patients in the active group and in 18 patients in the placebo group. Annual number of exacerbations and quality of life were similar in the two groups; none of the trials reported on average number of lung infections or hospital admissions. Forced expiratory volume in one second deteriorated a little more in the active group than in the placebo group (difference was -20 ml per year; 95% confidence interval -41 to 1; p = 0.06). For carbon monoxide diffusion, the difference was -0.06 mmol/min/kPa per year (95% confidence interval -0.17 to 0.05; p = 0.31). Lung density measured by CT scan deteriorated a little less in the active group than in the placebo group (difference 1.14 g/l; 95% confidence interval 0.14 to 2.14; p = 0.03) over the total course of the trials. Authors concldued that augmentation therapy with alpha-1 antitrypsin cannot be recommended, in view of the lack of evidence of clinical benefit and the cost of treatment.

This created a difficult situation. No controlled studies have proven that IV augmentation therapy improves survival or slows the rate of emphysema progression. However, results from the NIH patient registry and a comparison of Danish and German registries have been published, and both suggest that augmentation therapy has beneficial effects. Although they were not controlled treatment trials, the similarity of the results suggests that the findings are significant. In the absence of current guidelines, pulmonary physicians require the serum level to be below the threshold protective value and that the patient have one or more of the following: signs of significant lung disease: chronic productive cough or unusual frequency of lower respiratory infection, airflow obstruction, accelerated decline of FEV1, or chest radiographic or CT evidence of emphysema. The ATS recommends starting treatment when the FEV1 is less than 80% of the patient’s predicted value, though the benefits of augmentation therapy for individuals with severe (FEV1 < 35%) or mild (FEV1 >60%) airflow obstruction are less, as shown in studies with Prolastin.

Another potential use is after lung transplantation. Evidence for the use of alpha1-antitrypsin augmentation in patients after lung transplantation for alpha1-antitrypsin deficiency is insufficient. However, observational studies do show that inflammation from acute rejection or infection allows for free elastase activity in the epithelial lining fluid of individuals who have undergone lung transplantation. Therefore, the ATS/ERS Task Force favors the use of augmentation therapy for lung transplant recipients during episodes that provoke inflammation.

Heterozygotes should not be treated at this time due to lack of evidence of benefit.

Prolasta, Prescribing Information

Stoller JK, Aboussouan LS. alpha1-Antitrypsin deficiency . 5: intravenous augmentation therapy: current understanding. Thorax 2004; 59:708.

Chapman KR, Stockley RA, Dawkins C, et al. Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis. COPD 2009; 6:177.

Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev 2010;

Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol. Aug 2008;103(8):2136-41;

Sandhaus RA, Turino G, Stocks J, Strange C, Trapnell BC, Silverman EK, et al. alpha1-Antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note. Chest. Oct 2008;134(4):831-4.

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