Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry
© The Author(s) 2010
Received: 4 June 2010
Accepted: 5 October 2010
Published: 5 October 2010
Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.
Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin® or Prolastin®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.
Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.
The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.
The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.
In subjects with a hereditary deficiency of alpha-1 antitrypsin (AAT), the pathophysiology of emphysema is believed to be a direct consequence of tissue damage caused by a reduced ability of AAT to inactivate neutrophil elastase, which is released by migrating neutrophils in response to inflammatory stimuli . It is logical that augmentation of the circulating levels (and hence lung levels) of AAT would confer normal protection by restoring the inhibitory capacity of AAT in the lungs. The net result is argued to be retardation of the destructive process and, therefore, the progressive decline in lung physiology . A strategy of weekly augmentation with AAT was thus introduced in the 1980s, confirming that the attainment of a putative protective level was possible with weekly infusions of AAT at a dose of 60 mg•kg-1 body weight .
Because the numbers required to perform a controlled clinical trial using forced expiratory volume in 1 second (FEV1) are thought to be prohibitive (requiring inclusion of a large number of individuals with a rare disease over many years [4, 5]), no such study has been undertaken. Despite this, augmentation therapy is widely prescribed using varying treatment intervals and doses of plasma-derived AAT .
In the past, the mainstay of clinical assessment of emphysema was lung function and especially gas transfer measurements, although recent data have indicated that there is differential progression depending on disease severity . Computed tomography (CT) densitometry is a validated and more direct measure of pathological emphysema [8–10] that relates well to physiological and clinical features of disease [11, 12], progresses uniformly across disease severity  and has specifically been shown to be the best independent predictor of mortality .
In 1999, Dirksen, et al reported a 3-year Danish-Dutch controlled study of intravenous (IV) AAT augmentation therapy, with loss of lung tissue measured by CT densitometry as a secondary outcome parameter in 56 patients . The study suggested a reduction in emphysema progression with AAT augmentation therapy measured by CT, although the p value for the treatment difference obtained (p = 0.07) failed to achieve the conventional level of significance, which may reflect the number of subjects in the trial.
More recently, the EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (77 patients studied over 24-30 months), using a similar placebo-controlled trial design of IV AAT, explored CT densitometry as the primary outcome . Lung density was analysed using 4 different methods of adjustment that corrected for variation in inspiratory levels between scans, and all showed a trend towards efficacy. However, endpoint analysis using a statistical correction for lung volume not only proved to be the most sensitive method of analysis (based on monitoring progression in the placebo group), but also achieved a conventional level of statistical significance with regard to lung tissue loss between both treatment groups. Interestingly, in both the Danish-Dutch and EXACTLE studies, there was little difference in density loss between the AAT and placebo groups within the first year while, subsequently, the difference between the groups increased with time. Furthermore, the effect of therapy in clinical trials is usually determined by endpoint analysis. For these reasons, we chose to re-analyse the Danish-Dutch study using an endpoint analysis, utilising only the first and last available measurement.
In addition, because of the similar study design and method of CT densitometry, we combined the raw data from both studies to increase the statistical power as suggested in the previous Danish-Dutch study .
Materials and methods
Comparison of study characteristics
PiZZ on IEF
PiZZ or severe deficiency with AAT concentrations <11 μM
Lung function, FEV1
25-80% and FEV1/VC ≤70% or
≤80% if spirometry normal
≥1 exacerbation in the past 2 years
Never or ex-smokers for >6 months Cotinine checked every 4 weeks
Never or ex-smokers for >6 months Cotinine checked at 1, 6, 24 and 30 months
Previous augmentation therapy
Never or ≤1 month in past 2 years
Randomised, double-blind, placebo-controlled
Randomised, double-blind, placebo-controlled
250 mg•kg-1 body weight AAT
60 mg•kg-1 body weight AAT
Every 4 weeks
625 mg•kg-1 body weight albumin
2 (Copenhagen, Leiden)
3 (Copenhagen, Birmingham, Malmö)
Duration of study
Minimum 3 years
24 months (optional 6-months extension)
January 1991 to August 1997
November 2003 to December 2006
FEV1 measured by home spirometry twice daily
Change in PD15 measured by CT
Change in PD15 measured by CT
Lung function (FEV1, KCO)
Quality of life (SGRQ)
Patient baseline demographic characteristics*
(n = 27)
(n = 27)
(n = 38)
(n = 39)
(n = 60)
(n = 59)
48.0 ± 7.99
47.5 ± 7.29
54.7 ± 8.4
55.3 ± 9.8
51.6 ± 9.03
51.8 ± 9.73
Sex (n) male/female
Smoking status (n, ex/never)
Body mass index (kg•m2)
23.3 ± 3.15
24.4 ± 2.70
24.3 ± 3.3
24.3 ± 3.5
24.0 ± 3.3
24.5 ± 3.2
FEV1 (L), median
1.63 ± 0.49
1.72 ± 0.53
1.44 ± 0.60
1.35 ± 0.62
1.55 ± 0.56
1.48 ± 0.63
FEV1% predicted, median
47.3 ± 11.4
51.2 ± 14.5
46.3 ± 19.6
46.6 ± 21.0
48.0 ± 16.4
47.9 ± 18.6
AAT (n = 27)
Placebo (n = 27)
AAT (n = 38)
Placebo (n = 39)
AAT (n = 60)
Placebo (n = 59)
VC % predicted
114 ± 14.7
117 ± 16.4
94 ± 21.8
98 ± 23.2
103.1 ± 21.8
104.7 ± 23.9
DLCO% predicted Median
59.7 ± 16.0
60.1 ± 16.3
50.7 ± 19.5
52.2 ± 15.2
56.3 ± 17.3
55.7 ± 15.9
KCO % predicted
62.2 ± 17.62
59.9 ± 16.9
55.3 ± 21.0
56.5 ± 14.8
60.0 ± 18.9
58.6 ± 15.5
Unadjusted PD15 (g•L -1 )
71.41 ± 20.87
75.56 ± 25.53
47.98 ± 19.07
45.48 ± 16.95
58.88 ± 23.03
59.79 ± 25.83
TLC-adjusted PD15† (g•L -1 )
59.9 ± 11.03
62.98 ± 13.49
54.6 ± 17.4
53.9 ± 16.0
57.1 ± 15.2
58.2 ± 15.7
Lung volume (L)
5.71 ± 1.27
5.52 ± 1.34
7.46 ± 1.60
7.27 ± 1.78
6.61 ± 1.67
6.35 ± 1.69
Both studies were randomised, placebo-controlled, double-blind, parallel-group trials [14, 15]. Patients in the Danish-Dutch study were randomised to receive infusions of either AAT (Alfalastin®; Laboratoire Français du Fractionnement et des Biotechnologies, 3 avenue des Tropiques, BP 305, Les Ulis, 91958 Courtaboeuf Cedex, France; 250 mg•kg-1 body weight) or placebo (human albumin solution; 625 mg•kg-1 body weight) every 4 weeks for ≥3 years . Patients in the EXACTLE study were randomised to weekly infusions of AAT (Prolastin®; Talecris Biotherapeutics, Inc., Research Triangle Park, NC, USA; 60 mg•kg-1 body weight) or placebo (2% albumin) for 24 months, with an optional extension to 30 months in subjects who agreed to continue in the study .
Data analysis and CT densitometry
CT scans were performed at baseline and annually thereafter. In the EXACTLE study, there was an option for additional scans at 30 months in those subjects who had their participation prolonged from 24 months . CT scans were obtained during both trials using different scanner protocols. For the Danish-Dutch study, scans were acquired during a breath hold (Dutch patients) or during quiet tidal breathing (Danish patients). The EXACTLE trial acquired scans during a breath hold at maximum inspiration as summarised in the online supplement for Dirksen et al . In both trials, CT scanners were carefully calibrated and all scan data were centrally analysed by BioImaging Technologies, Inc. (Leiden, The Netherlands) using PulmoCMS® (Medis Specials, Leiden, The Netherlands) for the EXACTLE study, and by Leiden University Medical Centre for the Danish-Dutch study.
Data analysis and FEV1
We also took the opportunity to review the FEV1 decline from both studies using all available data and a slope analysis for the patients included in the integrated analysis. From the original Danish-Dutch study we were, however, unable to retrieve spirometry from 4 of the subjects.
Volume correction of CT Scans
The level of inspiration during scan acquisition is recognised to influence lung density and reduce the reproducibility of CT. In the chosen method (statistical/endpoint analysis method), volume correction was made by including the change in log-transformed total lung volume (TLV) as a covariate in the statistical model as described . This method corrects for intra-patient differences in inspiration between scans as well as inter-patient differences in technique between centres.
The raw data from the Danish-Dutch and EXACTLE studies were retrieved and combined. A study ID variable was included in the integrated analysis database to identify the records in the Danish-Dutch or EXACTLE studies.
All CT scan analyses were based on the modified intent-to-treat (ITT) population, which included (in common with the ITT) all randomised subjects who received the study therapy. However, those subjects in the modified ITT population also had to have one valid CT scan measurement at baseline and at least one valid CT scan assessment at the Month 12 visit or after.
For the Danish-Dutch and EXACTLE studies, PD15 was analysed using an analysis of covariance (ANCOVA) model with change from baseline to the last CT scan measurement in PD15 as the dependent variable, treatment and centre as fixed factors, and change in logarithm of CT-measured TLV and baseline measurement as covariates (statistical/endpoint analysis method).
For the combined data of the integrated analysis, the study ID was added to the model as a fixed effect. The ANCOVA model included the change from baseline to the last CT scan as the dependent variable; study (EXACTLE versus Danish-Dutch), treatment, centre and change in logarithm of lung volume as fixed factors, and baseline measurement as covariate.
Patient disposition and baseline characteristics
CT densitometric measurements from a total of 119 patients were analysed (AAT, n = 60; placebo, n = 59). In the Danish-Dutch study, CT data were obtained from 54 patients, comprising 26 patients from Denmark and 28 patients from The Netherlands. In the EXACTLE study, 65 patients provided data, 27 from Denmark, 23 from the United Kingdom and 15 from Sweden. The patient disposition by treatment is shown in Figure 1.
In the Danish-Dutch study, the mean (range) length of exposure was 2.52 (0.9-4.2) years to AAT, and 2.55 (0.9-3.9) years to placebo. The corresponding values in the EXACTLE study were 2.23 (1.1-2.6) and 2.18 (0.8-2.6) years, respectively. For the combined data from both studies, the mean (range) length of exposure to AAT was 2.36 (0.9-4.2) years and to placebo, 2.33 (0.9-3.9) years.
The characteristics for patients at baseline are summarised in Table 2. Baseline demographics for patients enrolled into the Danish-Dutch and EXACTLE studies were comparable, although patients in the EXACTLE study were slightly older and had a lower FEV1% predicted. For the combined data, there were no statistically significant differences between the group receiving AAT or placebo with respect to age or body mass index. There were some gender differences between the treatment groups, with more male subjects in the active treatment group, although this was not statistically significant (p = 0.093).
All patients fulfilled the physiological inclusion criteria shown in Table 1. There were no statistically significant differences at baseline between the treatment groups with regard to these parameters. There was also no significant difference in total lung capacity-adjusted PD15 between the 2 groups at baseline (p = 0.691).
CT densitometric progression
Changes in unadjusted 15th percentile lung density (g•L- 1) using endpoint analysis
(n = 27)
(n = 27)
(n = 36)
(n = 35)
(n = 60)
(n = 59)
Change from baseline to last CT scan, LS mean
Estimated treatment difference between changes from baseline, 95% CI†
p value for treatment difference
The FEV1 declined significantly in both the combined treated and placebo groups. The average annualised difference in FEV1 loss was 13 mL•yr -1 greater in the treated group although this is within the error of measurement (95% CI, -38 to 13; p = 0.321).
Until now, a suitably powered double-blind randomised trial of the clinical effectiveness of AAT augmentation therapy has been lacking. The individual and combined analysis of the Danish-Dutch and EXACTLE trials confirms that AAT augmentation therapy has a beneficial effect on the decline in lung density, which is a measure of the progression of emphysema.
AAT augmentation therapy is an accepted therapeutic regimen , and an earlier observational study showed better overall survival and reduced FEV1 decline (albeit in a subset with moderate airflow obstruction) for patients receiving therapy with varying regimens . Whereas the recommended regimen is 60 mg•kg-1 body weight per week, other adopted approaches are likely to be as effective if the nadir AAT level is mostly above the putative protective threshold of 11 μM.
Preservation of normal lung structure has been the long-term aim of preventive therapy in chronic obstructive pulmonary disease (COPD). However, studies of this concept have used FEV1 as the endpoint, since it is not only a defining feature of COPD but also reflects patients with a variety of phenotypes, including those with small airways disease and emphysema. Moreover, FEV1 is a reasonable marker of a patient's health status and exercise capacity , and has previously been considered to be the best predictor of respiratory and all-cause mortality . This has led to the tenet that the maintenance of FEV1 reflects disease stability or a consequent reduction in mortality. Nevertheless, FEV1 is a poor surrogate measure for the presence and severity of emphysema and its progression. For instance, it has been demonstrated that patients with apical emphysema may have a preserved FEV1 in both AAT deficiency [8, 19] and usual COPD .
The FEV1 data from this combined study confirm that even doubling the number of subjects is inadequate to verify whether augmentation therapy affects this non-specific and relatively insensitive outcome of emphysema. Much larger numbers of subjects studied over a longer period of time are required  in order to determine the response of therapy on FEV1, even though longitudinal CT data have confirmed that decline in FEV1 does generally relate to loss of lung density, but only if sufficient data are analysed . Extensive observational studies of lung density in AAT deficiency using CT scanning have demonstrated that this parameter not only relates to progressive reduction in FEV1 , health status and exercise capacity , but is indeed a better predictor of all-cause mortality than FEV1 . It is possible to extrapolate the findings of this combined analysis to conventional measures such as the FEV1 using previously published data . This indicates that the reduction in densitometry quantified here (1 HU/year) is equivalent to about a 38 ml difference in FEV1 decline in patients in GOLD stage 2.
However as indicated above the decline in FEV1 is not linear throughout the disease process. Therefore, for this and other reasons, stabilisation of emphysema progression, as indicated by CT densitometry, would be as important an aim, if not more so, than preserving FEV1. The current combined analysis of the only 2 controlled clinical trials completed to date has confirmed that AAT augmentation therapy significantly reduces the decline in lung density, and may thus reduce the future risk of mortality as well as the deterioration in health status.
With AAT augmentation therapy becoming widely accepted throughout the United States and Europe, the ability to deliver appropriately powered placebo-controlled clinical trials, particularly those requiring a physiological measurement outcome, has become difficult to justify ethically and even more difficult to deliver. The current analysis, however, provides evidence of augmentation therapy reducing the rate of progression of lung tissue loss. The data, therefore, permit future studies to be powered for comparison of different therapeutic regimens using CT scans rather than physiology (either FEV1 or gas transfer). However, it should also be noted that even CT scans, as well as accepted physiological measurements, are only surrogate measures of emphysema. Importantly, the change in physiological endpoints varies throughout the course of the disease, with FEV1 decline being greatest in subjects with moderate airflow obstruction (35-79% of predicted)  and gas transfer decline being greatest in those with most severe disease . On the other hand, loss of lung density as assessed by PD15 shows a more constant change across all stages of disease severity , suggesting that it is a better marker of the continuing disease process.
It is not always feasible to conduct powered clinical studies , and sometimes a combination of comparable studies is necessary. For example, meta-analysis of several studies has been used to support the use of antibiotics in acute exacerbations of COPD .
In clinical medicine, meta-analyses are accepted and useful tools that combine results from several studies to draw conclusions about clinical effectiveness. These can be either based on the analysis of published data (so-called 'aggregated analysis') or by pooling individual patient data (also termed 'integrated analysis') . Trials with different protocols, but with common characteristics, can be pooled for these analyses. An integrated analysis based on individual patient data offers numerous advantages over the use of aggregated data; it is more reliable than aggregate meta-analyses and may thus lead to different conclusions [23, 24]. This approach has been used more frequently in recent years  and also allows, as aggregate analyses similarly do, for the inclusion of different drug substances belonging to the same drug class, and different predefined clinical endpoints in the source studies [25, 26], provided that the studies have common characteristics to enable the pooling of data.
Although there were some differences in study characteristics, the EXACTLE and Danish-Dutch trials both had a randomised, placebo-controlled, blinded, parallel design and had a similar CT scan protocol. The 2 studies were comparable with regard to treatment drug, treatment duration and patient characteristics. There is a general belief that maintaining AAT above a protective level of 11 μM is the key to a successful therapeutic outcome, and both studies had treatment regimens that are able to maintain protective levels of AAT, either consistently, or for at least 3 out of the 4 weeks in the monthly regimen used in the Danish-Dutch trial .
The Jadad scale is widely used to assess the methodological quality of clinical trials [27, 28]. When evaluated on this scale, the design of the 2 studies met the standards required for their results to be included in a meta- or integrated analysis. Although the principle of meta- or integrated analyses is based on the inclusion of several studies, p values are reported without statistical adjustment of the alpha level.
Integrating the data from the 2 studies increased the numbers and hence the power of the observations. By using the most sensitive method for assessing emphysema progression (as measured by tissue loss) with endpoint analysis of PD15, the mean data demonstrate a deceleration of lung tissue loss with AAT augmentation therapy with a high degree of statistical significance. It is, however, recognised that progression even in CT densitometry varies between individuals. Thus adequate historical data will remain a prerequisite to therapeutic decision making. Furthermore, it should be noted that the treatment effect may not be demonstrable for the first 12 months of therapy [14, 15]. The exact reasons remain unknown but it is possible that a period of time is required to reverse the established, destructive inflammatory process. This observation clearly has potential impact on the design of future phase 2 and 3 studies in AAT deficiency and support an end point analysis as the best primary outcome.
In conclusion, the overall results are supportive of the efficacy of AAT augmentation therapy and, importantly, provide confirmatory data to power and analyse future alternative strategies for which long-term IV placebo arms cannot be justified ethically.
Disclosure of prior abstract publications
Abstracts of this study have been published by the American Thoracic Society (Am J Respir Crit Care Med, Apr 2008;177), and by the European Respiratory Society (Eur Respir J, Oct 2008;32(Supplement 52):738s).
This study was sponsored by Talecris Biotherapeutics, Inc. (Research Triangle Park, NC 27709, USA).
Technical editorial assistance was provided under the direction of the authors by M Kenig at PAREXEL (Worthing, UK) and was supported by Talecris Biotherapeutics, Inc.
- Snider GL, Lucey EC, Christensen TG, Stone PJ, Calore JD, Catanese A, Franzblau C: Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. Am Rev Respir Dis 1984, 129:155–160.PubMedGoogle Scholar
- Seersholm N, Wencker M, Banik N, Viskum K, Dirksen A, Kok-Jensen A, Konietzko N: Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Eur Respir J 1997, 10:2260–2263.View ArticlePubMedGoogle Scholar
- Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, Crystal RG: Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987, 316:1055–1062.View ArticlePubMedGoogle Scholar
- Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, Fallat RJ, Turino GM, Vreim CE, Wu MC: Feasibility of a clinical trial of augmentation therapy for alpha(1)-antitrypsin deficiency. The Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000,161(3 pt 1):796–801.View ArticlePubMedGoogle Scholar
- Burrows B: A clinical trial of efficacy of antiproteolytic therapy: can it be done? Am Rev Respir Dis 1983, 127:S42-S43.View ArticlePubMedGoogle Scholar
- American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency Am J Respir Crit Care Med 2003, 168:818–900.Google Scholar
- Dawkins PA, Dawkins CL, Wood AM, Nightingale PG, Stockley JA, Stockley RA: Rate of progression of lung function impairment in alpha-1-antitrypsin deficiency. Eur Respir J 2009, 33:1338–1344.View ArticlePubMedGoogle Scholar
- Parr DG, Stoel BC, Stolk J, Stockley RA: Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am J Respir Crit Care Med 2004, 170:1172–1178.View ArticlePubMedGoogle Scholar
- Dirksen A, Friis M, Olesen KP, Skovgaard LT, Sørensen K: Progress of emphysema in severe alpha 1-antitrypsin deficiency as assessed by annual CT. Acta Radiol 1997, 38:826–832.View ArticlePubMedGoogle Scholar
- Parr DG, Stoel BC, Stolk J, Stockley RA: Validation of computed tomographic lung densitometry for monitoring emphysema in alpha1-antitrypsin deficiency. Thorax 2006, 61:485–490.View ArticlePubMedPubMed CentralGoogle Scholar
- Dowson LJ, Newall C, Guest PJ, Hill SL, Stockley RA: Exercise capacity predicts health status in alpha(1)-antitrypsin deficiency. Am J Respir Crit Care Med 2001, 163:936–941.View ArticlePubMedGoogle Scholar
- Dowson LJ, Guest PJ, Hill SL, Holder RL, Stockley RA: High-resolution computed tomography scanning in α1-antitrypsin deficiency: relationship to lung function and health status. Eur Respir J 2001, 17:1097–1104.View ArticlePubMedGoogle Scholar
- Dawkins PA, Dowson LJ, Guest PJ, Stockley RA: Predictors of mortality in alpha 1-antitrypsin deficiency. Thorax 2003, 58:1020–1026.View ArticlePubMedPubMed CentralGoogle Scholar
- Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DC, Ulrik CS, Skovgaard LT, Kok-Jensen A, Rudolphus A, Seersholm N, Vrooman HA, Reiber JH, Hansen NC, Heckscher T, Viskum K, Stolk J: A randomized clinical trial of alpha 1-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999, 160:1468–1472.View ArticlePubMedGoogle Scholar
- Dirksen A, Piitulainen E, Parr DG, Deng C, Wencker M, Shaker SB, Stockley RA: Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha-1 antitrypsin deficiency. Eur Respir J 2009, 33:1345–1353.View ArticlePubMedGoogle Scholar
- The Alpha-1-Antitrypsin Deficiency Registry Study Group: Survival and FEV 1 decline in individuals with severe deficiency of alpha 1-antitrypsin. Am J Respir Crit Care Med 1998, 158:49–59.View ArticleGoogle Scholar
- Ketelaars CA, Schlosser MA, Mostert R, Huyer Abu-Saad H, Halfens RJ, Wouters EF: Determinants of health-related quality of life in patients with chronic obstructive pulmonary disease. Thorax 1996, 51:39–43.View ArticlePubMedPubMed CentralGoogle Scholar
- Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM: Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996, 313:711–715.View ArticlePubMedPubMed CentralGoogle Scholar
- Holmes J, Stockley RA: Radiologic and clinical features of COPD patients with discordant pulmonary physiology: lessons from a-1-antitrypsin deficiency. Chest 2007, 132:909–915.View ArticleGoogle Scholar
- Klein JS, Gamsu G, Webb WR, Golden JA, Müller NL: High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology 1992, 182:817–821.View ArticlePubMedGoogle Scholar
- Drummond MF, Wilson DA, Kanavos P, Ubel P, Rovira J: Assessing the economic challenges posed by orphan drugs. Int J Technol Assess Health Care 2007, 23:36–42.View ArticlePubMedGoogle Scholar
- Saint SK, Bent S, Vittinghoff E, Grady D: Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis. JAMA 1995, 273:957–960.View ArticlePubMedGoogle Scholar
- Stewart LA, Parmar MK: Meta-analysis of the literature or of individual patient data: is there a difference? Lancet 1993, 341:418–422.View ArticlePubMedGoogle Scholar
- Riley RD, Lambert PC, bo-Zaid G: Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 2010, 340:c221.View ArticlePubMedGoogle Scholar
- Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C: Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet 2006, 367:1412–1420.View ArticlePubMedGoogle Scholar
- Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM, Connett JE, Lindmark B, Pauwels RA, Postma DS, Soriano JB, Szafranski W, Vestbo J: Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005, 60:992–997.View ArticlePubMedPubMed CentralGoogle Scholar
- Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996, 17:1–12.View ArticlePubMedGoogle Scholar
- Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ: Scales to assess the quality of randomized controlled trials: a systematic review. Phys Ther 2008, 88:156–175. Epub 2007 Dec 11View ArticlePubMedGoogle Scholar
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