Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)

McElvaney, Noel G.; Burdon, Jonathan; Holmes, Mark; Glanville, Allan R.; Wark, Peter; Thompson, Philip J.; Hernández, Paul; Chlumský, J; Teschler, Helmut; Ficker, Joachim H.; Seersholm, Niels; Altraja, Alan; Mäkitaro, Riitta; Chorostowska‐Wynimko, Joanna; Sanak, Marek; Stoicescu, P; Piitulainen, Eeva; Vit, Oliver; Wencker, Marion; Tortorici, Michael A.; Fries, Michael; Edelman, Jonathan M.; Chapman, Kenneth R.

doi:10.1016/s2213-2600(16)30430-1

Cited by 157 publications

(177 citation statements)

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“…Currently, AAT augmentation therapy is recommended for ZZ individuals based on evidence from some observational studies that show improved survival [8,9] and randomised controlled trials that show slower progression of emphysema [10,11].…”

Section: Introductionmentioning

confidence: 99%

COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

Ashry

Strange

2017

Eur Respir Rev

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Since the discovery of severe alpha-1 antitrypsin deficiency as a genetic risk factor for emphysema, there has been ongoing debate over whether individuals with intermediate deficiency with one protease inhibitor Z allele (PiMZ, or MZ) are at some risk for emphysema. This is important, because MZ individuals comprise 2-5% of the general population. In this review we summarise the evidence about the risks of the MZ population to develop emphysema or asthma. We discuss the different study designs that have tried to answer this question. The risk of emphysema is more pronounced in case-control than in population-based studies, perhaps due to inadequate power. Carefully designed family studies show an increased risk of emphysema in MZ smokers. This is supported by the rapid decline in lung function of MZ individuals when compared to the general population after massive environmental exposures. The risk of asthma in MZ subjects is less studied, and more literature is needed before firm conclusions can be made. Augmentation therapy in MZ individuals is not supported by any objective studies. MZ smokers are at increased risk for emphysema that is more pronounced when other environmental challenges are present.

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Section: Introductionmentioning

confidence: 99%

COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

Ashry

Strange

2017

Eur Respir Rev

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“…Recently there has been new supporting evidence for the effectiveness of AT in AATD therapy by a randomized clinical trial [41]. However, our finding of indifferent costs also raises the question how a potentially intensified but standard COPD therapy compares with additional AT and which long-term health and cost benefits might be associated with these options.…”

Section: Discussionmentioning

confidence: 86%

Costs and health-related quality of life in Alpha-1-Antitrypsin Deficient COPD patients

Karl

Holle²,

Bals

et al. 2017

Respir Res

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BackgroundAlpha-1-Antitrypsin Deficiency (AATD) is an economically unexplored genetic disease.MethodsDirect and indirect costs (based on self-reported information on healthcare utilization) and health-related quality of life (HRQL, as assessed by SGRQ, CAT, and EQ-5D-3 L) were compared between 131 AATD patients (106 with, 25 without augmentation therapy (AT)) and 2,049 COPD patients without AATD participating in the COSYCONET COPD cohort. The medication costs of AT were excluded from all analyses to reveal differences associated with morbidity profiles. The association of AATD (with/without AT) with costs or HRQL was examined using generalized linear regression modelling (GLM) adjusting for age, sex, GOLD grade, BMI, smoking status, education and comorbidities.ResultsAdjusted mean direct annual costs were €6,099 in AATD patients without AT, €7,117 in AATD patients with AT (excluding costs for AT), and €7,460 in COPD patients without AATD. AATD with AT was significantly associated with higher outpatient (+273%) but lower inpatient (−35%) and medication costs (−10%, disregarding AT) compared with COPD patients without AATD. There were no significant differences between groups regarding indirect costs and HRQL.ConclusionApart from AT costs, AATD patients tended to have lower, though not significant, overall costs and similar HRQL compared to COPD patients without AATD. AT was not associated with lower costs or higher HRQL.Trial registration NCT01245933 Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0543-8) contains supplementary material, which is available to authorized users.

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“…However, initial clinical trials failed to demonstrate a significant benefit in reducing the rate of decline in lung function but their results were suggestive of some protection against a loss of lung tissue [19, 20]. More recently, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, definitively confirmed the benefits of A 1 -PI therapy in slowing disease progression [21, 22]. …”

Section: Introductionmentioning

confidence: 99%

“…The rate of decline in CT lung density has been shown to correlate with FEV 1 decline [20–22, 31]. During the RAPID/RAPID Extension program, moderate-to-weak 4-year correlations were detected between decline in rate of lung density and spirometry values.…”

Section: Introductionmentioning

confidence: 99%

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Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence

Rahaghi

Miravitlles

2017

Respir Res

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Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released by activated neutrophils during inflammation. Absence or deficiency of A1-PI leads to an imbalance between elastase and anti-elastase activity, which results in progressive, irreversible destruction of lung tissue, and ultimately the development of chronic obstructive pulmonary disease with early-onset emphysema. AATD is under-diagnosed, patients can experience long delays before obtaining an accurate diagnosis, and the consequences of delayed diagnosis or misdiagnosis can be severe. Currently, A1-PI therapy is the only available treatment that addresses disease etiology in patients with AATD; however, demonstrating clinical efficacy of A1-PI therapy is challenging. In order to show therapeutic efficacy with traditional endpoints such as forced expiratory volume in one second and mortality, large sample sizes and longer duration trials are required. However, AATD is a rare, slow progressive disease, which can take decades to manifest clinically and recruiting sufficient numbers of patients into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect of A1-PI therapy in patients with AATD. These findings suggest that the early introduction of treatment in patients with severe emphysema-related AATD may delay the time to death, lung transplantation or crippling respiratory complaints. In addition, there is now limited evidence that A1-PI therapy provides a gain of more than five life-years, supporting previous observations based on registry data. With the clinical efficacy of A1-PI therapy now demonstrated, further studies are required to assess long-term outcomes.

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Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)

Cited by 157 publications

References 21 publications

COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

Costs and health-related quality of life in Alpha-1-Antitrypsin Deficient COPD patients

Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence

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