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1-Antitrypsin*
* From the Departments of Pulmonary and Critical Care Medicine (Dr. Stoller) and Biostatistics (Dr. O’Brien and Mr. Connor), Cleveland Clinic Foundation, Cleveland, OH; California Pacific Medical Center (Dr. Fallat), San Francisco, CA; Department of Biostatistics (Dr. Schluchter), Case Western Reserve University School of Medicine, Cleveland, OH; Department of Pulmonary and Critical Care Medicine (Dr. Crystal), Weill Medical College of Cornell University, New York, NY; Pulmonary Service (Dr. O’Neil), National Naval Medical Center, Bethesda, MD; Department of Medicine (Dr. Gross), Stritch-Loyola School of Medicine, Chicago, IL; University of Colorado Health Sciences Center (Dr. Sandhaus), and National Jewish Medical and Research Center, Denver, CO.
Correspondence to: James K. Stoller, MS, MD, FCCP, Department of Pulmonary and Critical Care Medicine, A 90, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: stollej{at}ccf.org
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Observational cohort study with follow-up visits every 6 to 12 months for up to 7 years.
Measurements: The rate and dosing frequency with which Registry participants were prescribed to receive augmentation therapy by their managing physicians, and the type and frequency of adverse events, classified in two ways: severity of self-reported symptoms, and actions taken as a consequence of the symptom.
Results: Over the course of Registry follow-up, 66% (n = 747) of the participants received augmentation therapy at some time. In keeping with recommendations made in the 1989 American Thoracic Society (ATS) statement, 75% of participants with airflow obstruction at first visit (defined as FEV1 < 80% predicted) received augmentation therapy within 3 years, though some participants with FEV1 
80% predicted (14%) also received augmentation therapy. Among those with COPD for whom augmentation therapy was not prescribed, financial constraints were the reported cause in 30%. Observed patterns also varied from approved practice, in that dosing frequencies other than the US Food and Drug Administration-approved, once-weekly regimen were frequently prescribed. The overall rate of reported adverse events was 0.02 per patient-month, with 83% of participants reporting no events. This overall rate was composed of 16% considered mild events, 76% moderate events, and 9% severe events.
Conclusions: We conclude that augmentation therapy was generally well tolerated and, consistent with ATS guidelines, physicians generally did not prescribe augmentation therapy for subjects with FEV1 80% predicted. However, the large percentage of subjects with FEV1 <80% predicted not receiving augmentation therapy and the frequent use of 2- to 3-week or monthly dosing reflects variation of practice from suggested treatment guidelines.
Key Words: 
1-antiprotease • 1-antitrypsin • augmentation therapy • COPD
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-antitrypsin deficiency is an underrecognized condition in which inadequate levels of 1-antiprotease in the blood and lung predispose to early onset panacinar emphysema.1
2
3
4
In addition to conventional therapies for COPD, specific therapy of 1-antitrypsin deficiency is directed at augmenting the levels of this antiprotease in the blood from which lung levels derive. Current therapy for individuals with established 1-antitrypsin deficiency-related emphysema has focused on exogenous augmentation by infusing purified 1-antiprotease IV in amounts sufficient to raise serum levels above a "protective threshold" value at which pulmonary risk is deemed minimal. On the strength of evidence supporting the "biochemical efficacy" of IV augmentation therapy to raise serum and lung levels adequately,5
a form of purified pooled human plasma 1-antiprotease achieved US Food and Drug Administration (FDA) approval in 1989 for once-weekly dosing (60 mg/kg) [Prolastin; Bayer Laboratories; West Haven, CT].6
Based on observational cohort studies showing a slower rate of FEV1 decline in recipients with moderate airflow obstruction and enhanced survival in some augmentation therapy recipients,7
8
weekly IV augmentation therapy has since been recommended9
and prescribed7
for some individuals with severe deficiency of 1-antitrypsin complicated by established COPD.
The National Heart, Lung, and Blood Institute (NHLBI) Registry of Individuals with Severe Deficiency of Alpha1-Antitrypsin is an observational cohort study in which 1,129 subjects with severe 1-antitrypsin deficiency were followed up longitudinally while treated by their managing physicians (rather than by protocol). This study provides an opportunity to examine the frequency and patterns with which IV augmentation therapy was prescribed by physicians managing Registry participants.9
10
11
12
In this context, this report describes two important aspects of IV augmentation therapy use in the Registry experience: (1) the patterns of use in comparison with recommended guidelines, and (2) the frequency and nature of adverse events ascribed to IV augmentation therapy.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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18 years and a serum 1-antitrypsin level 
11 µmol/L confirmed by the Central Phenotyping Laboratory of the Registry or a ZZ or Znull phenotype confirmed by genomic DNA analysis (GeneScreen; Dallas, TX). Beginning in 1989, a total of 1,129 Registry participants were recruited and followed up at 37 participating clinical centers over an interval of 3.5 to 7 years. As previously described,9
10
11
12
information gathered at baseline and at 6- to 12-month intervals thereafter included demographic data, pulmonary function tests (including prebronchodilator and postbronchodilator spirometry), and available laboratory tests (eg, complete blood counts, liver function tests, etc). Spirometric tracings were centrally reviewed and graded to achieve a high degree of acceptability and reproducibility of measurements, in accordance with American Thoracic Society (ATS) standards.13
Also in accordance with ATS recommendations, severity of COPD was classified by ATS stages14
as follows: stage I, postbronchodilator FEV1 50% predicted; stage II, FEV1 35 to 49% predicted; stage III, FEV1 < 35% predicted. For purposes of analysis, subjects with postbronchodilator FEV1 80% predicted were considered to have normal airflow.
Participants were encouraged to maintain augmentation therapy logs in which they maintained records regarding the dose, frequency of infusion (eg, weekly, monthly, etc.), lot number, and any adverse experiences they ascribed to their infusions. Participants were categorized as to whether they received augmentation therapy: (1) "always" throughout the Registry, defined as beginning < 3 months after enrollment and lasting continuously thereafter; (2) "sometimes" throughout the Registry, defined as beginning > 3 months after enrollment, or interrupting augmentation therapy for > 1 month; or (3) "never" while in the Registry.
Data regarding adverse events were based on self reports as remembered over the interval since the participant’s last Registry follow-up visit in the prior 6 to 12 months. Adverse experiences were recorded based on the participant’s response to the following question: "Have you experienced any problems related to the augmentation therapy since your last visit?" Participants who were unable to return to a clinical center for follow-up were contacted by telephone to obtain updated information regarding interval medical histories and augmentation therapy (ie, receipt, dose and interval, and any adverse experiences).
Classification of Adverse Events Attributed to Augmentation Therapy
Two different classifications of adverse events to augmentation therapy were used over the course of the Registry. Initially, events were assessed according to severity (mild, moderate, severe) using a list of sample signs and symptoms as a classification guide. Examples of severe symptoms included hypotension, wheezing, or acute shortness of breath accompanying the infusion. Examples of "moderate" symptoms included headache and dizziness, and "mild" symptoms included nausea, anxiety, or mild pain. In November 1993, an alternative, "consequence-based" classification scheme for adverse events was introduced. Specifically, events were classified as to whether they led to the following: (1) acute hospitalization or an emergency department visit, (2) physician visit (other than in the emergency department or during an acute hospitalization) and/or using medications (whether prescribed or self-administered as an over-the-counter medication), or (3) permanent discontinuation of augmentation therapy. Adverse events recorded before November 1993 (which comprised 38% of all adverse events) were classified retrospectively using the consequence-based scheme classification, based on available information provided in comments on the data collection forms. Cross-tabulations were done to compare how events were categorized by the two schemes.
Statistical Analysis
The three groups (always, sometimes, and never receiving therapy) were compared using analyses of variance for continuous measures, logit analyses for binary measures, and proportional odds modeling for ordinal measures. The overall test of three-group equality was performed, as were two distinct planned contrasts: never receiving vs sometimes or always receiving therapy, and sometimes receiving vs always receiving therapy. Time from enrollment until starting augmentation therapy was estimated using the Kaplan-Meier method, and comparisons between the four post-FEV1 predicted groups were performed using the log-rank test. Logistic regression was used to relate initial values of postbronchodilator FEV1 percentage of predicted to whether augmentation therapy was started within 3 years of entering the study. All such analyses used the SAS System (SAS Institute; Cary, NC).15
BUGS software (MRC Biostatistics Unit; Cambridge, UK)16
was used to fit an empirical Bayes model to the counts of reported adverse events in order to estimate and compare the adverse event rates for patients receiving infusions weekly, two to three times per month, or monthly. Specifically, the model assumed that the number of adverse events for individual i under infusion frequency j comes from a Poisson distribution with mean 
jDaysij, where j is the adverse event rate at infusion rate j and Daysij is the number of days patient i was on infusion rate j. Thus, a participant who was treated both weekly and 2 to 3 times per month contributed to the estimates of two of the js. A conjugate prior distribution with shape and scale parameters found empirically was used for the js.17
Convergence of the posterior distributions was verified.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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80 predicted. Of 1,129 Registry enrollees, 747 participants (66%) received augmentation therapy at some point over the course of Registry follow-up; 390 participants (34%) were classified as always receiving augmentation therapy and 357 participants (32%) as sometimes receiving augmentation therapy. Comparing those never receiving augmentation therapy vs those who were sometimes or always receiving therapy by baseline characteristics at Registry enrollment (Table 1
) shows that those never receiving augmentation therapy tended to be younger, have somewhat lower family income, be less likely to have insurance coverage, less likely to have ever smoked, less likely to be an index case (ie, participants who came to Registry attention for reasons other than pulmonary symptoms), have better preserved lung function (ie, mean FEV1 65% predicted), and have lower baseline rates of bronchodilator responsiveness. Furthermore, comparing those who sometimes vs always receiving augmentation therapy showed many similarities, though those always receiving therapy reported a higher degree of education, slightly greater family incomes, and more frequent insurance coverage.
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80% predicted) were prescribed to receive augmentation therapy than participants with lower values of FEV1 percentage of predicted.
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80% predicted were not recommended to receive such therapy by their managing physician. However, augmentation therapy was also reportedly not recommended for 32% and 8% of participants with FEV1 values 35 to 79% predicted and < 35% predicted, respectively. For 30% (38 of 128 participants) with FEV1 79% predicted, financial issues were credited as the reason for their not receiving augmentation therapy. For 5% of nonrecipients, patient choice was cited, either because the participant was unconvinced of the efficacy of augmentation therapy or reported concern about contracting a blood-borne illness.
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Among the 137 subjects who permanently discontinued augmentation therapy during Registry follow-up, medical reasons accounted for 64%, most commonly because a transplant had been performed (58%). Financial reasons were cited as the cause for 12% of discontinuations, adverse events for 3%, and other/unknown reasons for 22%. Other causes for discontinuing augmentation therapy included subject refusal (18%, usually because of concern over receiving infusions), or subject uncertainty about clinical efficacy (4%).
Variations in the rates of augmentation therapy use among the 37 clinical centers were investigated. For each center, the observed number of subjects ever receiving augmentation therapy was compared to the expected number for that center. The expected number was obtained by applying the rates of augmentation therapy use observed for the other 36 centers in three FEV1 strata (< 35% predicted, 35 to 79% predicted, and 80% predicted) to the number of subjects in these three strata at that center. Notably, no significant differences were found between observed vs expected rates in any of the 37 centers (p > 0.05 for each comparison).
Dosing frequencies for augmentation therapy were commonly modified over the course of Registry follow-up. Among 633 participants ever receiving augmentation therapy while in the Registry for whom multiple reports of augmentation dosing frequency were available, the most common initial infusion frequency was weekly (51%), followed by every 2 to 3 weeks (26%), and monthly (23%). In contrast, the most common dosing frequency at the latest follow-up visit was every 2 to 3 weeks (43%), followed by weekly (33%), and monthly (24%). Altogether, the dosing frequency was changed for 34% of participants who ever received augmentation therapy, increasing in 25% (eg, changing from monthly to weekly), and decreasing in 9%.
Adverse Events While Receiving Augmentation Therapy
A total of 720 adverse event episodes were reported, excluding 10 episodes among seven participants associated with flawed lots of the commercially available 1-antiprotease preparation (Prolastin; Bayer; West Haven, CT) that resulted in short-lived drug recalls. Table 3
presents the types of reported symptoms stratified by severity. The four most commonly reported events were headache (47%), dizziness (17%), nausea (9%), and dyspnea (9%), which was classified as severe. Notably, no instance of newly contracted hepatitis (A, B, C, or 
), HIV, or prior disease was reported.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1-antitrypsin deficiency consists of IV infusion of purified-pooled human plasma antiprotease and has been available since FDA approval was granted in 1989. Currently, a single commercial preparation is available in the United States (Prolastin). On the strength of evidence supporting its biochemical efficacy (ie, that IV infusion raises serum levels above the protective threshold value5
), this drug has achieved FDA approval at a dose of 60 mg/kg once weekly, although alternative dosing regimens have been employed.18
19
In the absence of a definitive randomized controlled clinical trial demonstrating the clinical efficacy of augmentation therapy,20
discordant recommendations from official societies have emerged, with the ATS issuing an official statement in 1989 advocating augmentation therapy for patients with established emphysema from 1-antitrypsin deficiency on the strength of available evidence.6
In contrast, in 1992, the Canadian Thoracic Society recommended restraint in the use of augmentation therapy pending definitive evidence from a randomized controlled trial21
and, more recently, observed "possible benefit to selected patients" while again advocating a placebo-controlled, randomized clinical trial.9
Because such a randomized trial had been deemed infeasible in terms of cost and the required number of study subjects,22
23
the NHLBI initiated the Registry for Individuals with Severe Deficiency of Alpha1-Antitrypsin in 1989. The Registry is an observational cohort study to evaluate the natural history of 1-antitrypsin deficiency, whether or not the subject is receiving augmentation therapy.10
As treatment with augmentation therapy was at the discretion of Registry participants’ regular managing physicians, the Registry also afforded an opportunity to describe prescribing patterns and adverse events. Because the Registry was not population based, most enrollees (72%) were ascertained because of symptoms and, not surprisingly, had COPD (mean baseline FEV1 47% predicted).
In the context that most Registry subjects had COPD, patterns of augmentation therapy are likely to reflect patterns of actual practice. Overall, 66% of Registry participants received augmentation therapy at some point during Registry follow-up. At the time of Registry enrollment, 23% were receiving augmentation therapy and, within 3 months thereafter, 45% had received augmentation therapy.
Observed patterns of prescribing augmentation therapy generally complied with ATS guidelines,6 but not entirely. Specifically, augmentation therapy was largely reserved for subjects with established airflow obstruction, in that only 14% of Registry subjects with FEV1 80% predicted received augmentation therapy over the course of Registry follow-up. It is possible that prescribing physicians were influenced in this decision by subnormal values of diffusing capacity (< 80% predicted in 78% of these participants) or by participants’ self-reports of COPD.
However, many subjects with established airflow obstruction were not prescribed to receive augmentation therapy by their managing physicians. For example, only 77% of all individuals with FEV1 < 80% predicted and only 79% of those with FEV1 < 60% predicted reported receiving augmentation therapy over the course of Registry follow-up. At the same time, the frequency with which augmentation therapy was prescribed generally increased as FEV1 percentage of predicted decreased. Finally, the fact that 5% of Registry patients always receiving augmentation therapy were current smokers indicates the willingness of some physicians to prescribe augmentation therapy to active smokers.
Although reported reasons for nonreceipt of augmentation therapy were available for only 70% of these 184 individuals, the most common reason reported for not initiating augmentation therapy was financial (30%). Univariate comparison of those receiving vs not receiving augmentation therapy suggested that augmentation therapy recipients were older, were more likely to have smoked or to be ascertained as an index case, had lower FEV1 values, were more likely to show a bronchodilator response, had a lower 1-antitrypsin level, were more likely to have insurance coverage, and had higher family income.
These observations regarding patterns of augmentation therapy use invite comparison with augmentation therapy recipients in a German registry in which criteria for treatment were as follows: confirmed serum level < 80 mg/dL, age > 18 years, demonstrated FEV1 < 65% predicted, and/or measured FEV1 decline < 120 mL per year, and confirmed nonsmoking status for 3 months before the first infusion.24
Compared with the German cohort of 443 subjects, NHLBI Registry augmentation therapy recipients were slightly younger (mean age, 46 years vs 48 years) and had less impaired lung function (mean FEV1 47% vs 37% predicted). However, in the absence of information about German 1-antitrypsin-deficient individuals for whom augmentation therapy was not prescribed, it is difficult to draw firm conclusions about differences in prescribing behavior in these two cohorts.
In the NHLBI Registry, prescribing behavior also deviated from recommended guidelines regarding the frequency of administering augmentation therapy. Although once-weekly dosing is currently the only FDA-approved regimen, other dosing frequencies were commonly reported by enrollees at baseline (49%). Furthermore, among those 633 subjects for whom serial reports of dosing frequency were available, subjects frequently shifted from weekly therapy to less frequent infusions. Specifically, only 33% of subjects reported remaining on weekly augmentation therapy vs 51% who were receiving weekly therapy at Registry baseline. Although reasons for altering the dosing frequency were not ascertained, it is likely that the shift toward less frequent dosing reflected subjects’ desires to simplify therapy and/or to receive less frequent infusions. Less frequent dosing may also incur lower administration costs.25
The NHLBI Registry has also afforded the opportunity to examine the frequency and spectrum of adverse events to augmentation therapy in the largest single cohort assembled to date. As with patterns of augmentation therapy use, these data are of interest in comparison with the German Registry,24 in which 443 subjects reported 124 adverse events. With regard to the types of events in these two registries, several event types accounted for greater proportions of events in German vs NHLBI Registry subjects. For example, dyspnea accounted for 14% of all events in the German Registry vs 9% in the current series. A total of 14% of all events in the German series were characterized as urticaria vs 3% of events in the current series, and 17% of events in the German series included emesis vs 2% in the NHLBI series. In contrast, comparing the frequencies of events that led to such actions as acute hospitalization, emergency department or physician visits, new medication prescriptions, or discontinuation of augmentation therapy, the rate was lower in the German study (1%) than in the NHLBI study (6%). Also, although events eliciting significant responses such as those above were uncommon in both registries, the nature of these events differed. For example, anaphylaxis accounted for four of the five severe events noted in the German Registry, but was not observed in the NHLBI Registry. Although hypotension was reported in two NHLBI Registry participants, this was not deemed part of an acute anaphylactic or anaphylactoid event. Also, fewer events caused permanent discontinuation of augmentation therapy in the German (0.4%) than in the NHLBI Registry (1.1%).
With regard to possible explanations for these discordant rates between the two registries, use of the same drug in both registries requires implicating other factors. Possibilities include recall bias, effects of different lots or batches of medication, differences in the two study populations, and center variation. With regard to possible recall bias, adverse events in both registries were recorded during interval visits to the participating study centers (ie, every 6 to 12 months), so that differences in recall or subjects’ threshold for reporting symptoms may vary. Variation in adverse event reporting rates were apparent between centers in the NHLBI Registry, though this variability did not confound interpretation of risk factors for adverse events as noted. Nevertheless, the possibility of center variation may also contribute to discordant adverse event rates. With regard to "batch" or "lot" effects, although the rate of adverse events was relatively consistent at 2 to 3% of subjects per quarter in the NHLBI Registry, two recalled lots of commercial 1-antiprotease (in 1989 and 1991) were associated with clusters of adverse events. Events related to the flawed lots, which were recalled (due to the sucrose component in one instance and presence of a pyrogen in the other), were excluded from the analysis of adverse events in the NHLBI Registry.
Notably, although the estimated adverse events rates were low in the Registry ( 0.030 events per patient-month) and the differences in absolute rates by augmentation therapy infusion frequency were even lower, our data do show a lower rate of adverse events in participants receiving augmentation therapy less frequently than weekly. At the same time, our analytic strategy addressed the overall risk over time of adverse events, and it is likely that the higher rate with weekly infusions reflects the higher infusion frequency than other (eg, monthly, biweekly, etc.) regimens. Notwithstanding the small differences in absolute rates by infusion frequency, it is possible that the lower rate of adverse events, along with lower administration costs and greater convenience, contributed to the observed trends toward use of lower infusion frequencies over the Registry. Given the lower rate with which infusion frequencies other than weekly ensured maintenance of serum levels above the protective threshold,18
19
the clinicians’ decision about whether to prescribe augmentation therapy weekly or less often seems to involve weighing pharmacokinetics vs adverse event profiles. The observation that 34% of Registry participants experienced a lengthened interinfusion interval over the course of the Registry suggests that clinicians were swayed more by issues of convenience, cost, and possibly adverse event frequency than by adherence to the recommendation of weekly therapy.
In summary, this analysis of patterns of prescribing augmentation from the NHLBI Registry suggests that the managing physicians generally complied with ATS guidelines in recommending augmentation therapy for most 1-antitrypsin-deficient participants with established airflow obstruction. In instances where augmentation therapy was not prescribed despite the participants’ having an FEV1 < 80% predicted, financial constraints were the most commonly cited single reason. Variance from ATS guidelines was also observed because some participants were prescribed to receive augmentation despite normal airflow and because the dosing frequency often varied from the FDA-approved once-weekly regimen. Finally, analysis of adverse events suggests that severe events were uncommon and infrequently led to discontinuation of therapy.
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Footnotes |
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The opinions expressed are the private views of the authors and should not be construed to represent the official opinion of the US Department of the Navy or the Department of Defense.
Research conducted with the support of the National Heart, Lung, and Blood Institute of the National Institutes of Health, contract NO1-HR-86036.
Received for publication January 14, 2002. Accepted for publication December 19, 2002.
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1-antitrypsin deficiency. Chest 2001;119,745-752This article has been cited by other articles:
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  R. A. Sandhaus, G. Turino, J. Stocks, C. Strange, B. C. Trapnell, E. K. Silverman, S. E. Everett, J. K. Stoller, and for the Medical and Scientific Advisory Committee {alpha}1-Antitrypsin Augmentation Therapy for PI*MZ Heterozygotes: A Cautionary Note Chest, October 1, 2008; 134(4): 831 - 834. [Abstract] [Full Text] [PDF]
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J. K. Stoller, J. Tomashefski Jr, R. G. Crystal, A. Arroliga, C. Strange, D. N. Killian, M. D. Schluchter, H. P. Wiedemann, and for the {alpha}1-Antitrypsin Deficiency Registry S Mortality in Individuals With Severe Deficiency of {alpha}1-Antitrypsin: Findings From the National Heart, Lung, and Blood Institute Registry Chest, April 1, 2005; 127(4): 1196 - 1204. [Abstract] [Full Text] [PDF]
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 J K Stoller and L S Aboussouan {alpha}1-Antitrypsin deficiency {middle dot} 5: Intravenous augmentation therapy: current understanding Thorax, August 1, 2004; 59(8): 708 - 712. [Abstract] [Full Text] [PDF]
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