We thank Drs. McCarthy and Dimitrov for their thoughtful criticisms and insightful questions. Responding to their concerns gives us the opportunity to further clarify the results of our recently published meta-analysis of augmentation therapy in alpha1 antitrypsin deficiency emphysema (Citation1).
We agree with Drs. McCarthy and Dimitrov that the meta-analysis data leans heavily upon the findings of the NHLBI registry (Citation2). However, for several reasons, we do not feel that this should call into question our conclusions. First, the findings of the NHLBI registry were consistent with and of a similar order of magnitude to findings gathered in other countries, by other means and at other times both preceding and following the analysis of American data (Citation3–5).
Second, the finding of preserved lung function by restoration of serum levels is biologically plausible and consistent with what is understood of emphysema pathogenesis in alpha1 antitrypsin deficiency emphysema (Citation6). Finally, these spirometric results are consistent with lung protection demonstrated more directly by both previously and more recently published results showing preservation of lung density as measured by CT scan in patients receiving augmentation therapy (Citation4,Citation7). In short, although the NHLBI data is predominant in the analysis, it is entirely congruent with other data and is not an outlier that skewed the conclusions.
We agree that the pre-post nature of the Wencker study design is limited but opted to include it in our metaanalysis to ensure completeness of all available published data (Citation5). We are not sure what McCarthy and Dimitrov mean by “eventual physiological decline” but suspect that they mean that rates of lung function decline are not constant over a lifetime and hence may slow in subsequent follow-up, irrespective of therapy.
However, we do not think that the changes in rates of decline are entirely predictable and are necessarily expected to slow in patients with COPD and indeed where this occurs (especially in end-stage disease) this more likely represents a survivor effect (Citation8). Although rates of lung function decline may slow with various non-specific therapies, they may accelerate with increasing numbers of exacerbations in patients with increasingly severe airflow limitation (Citation9). Further, we suspect that the relatively short time frames described in the Wencker data are unlikely to be skewed by changes in the natural history of rate of decline. In any event, the metaanalysis, consistent with practice in this area, stratified outcomes by baseline FEV1, a variable related to subsequent rate of decline.
Drs. McCarthy and Dimitrov raise an interesting issue about the number of data points needed to establish an accurate rate of FEV1 decline. We believe that this is an area where further research is needed. In a recent analysis of Canadian Alpha1 Antitrypsin Registry data, we found, contrary to the statements of McCarthy and Dimitrov, that greater sensitivity and specificity for detection of rapid decline was seen when we used first and last data points rather than all available data points in our analysis of patients followed longitudinally.
Statistically, because of the inherent variability of the test the number of points needed to define slope depends on the number of subjects and the length of time being monitored, thus 2 points 5 years apart are better than 3 over 2 years These preliminary findings are concordant with the densitometry results of the recent EXACTLE trial (Citation7). When several methods of analysing lung density changes over time were compared, use of the first and last measurements was a more robust means of detecting differences than using first, middle and last data points.
We must agree with McCarthy and Dimitrov that changes in medical practices over time could alter rates FEV1 decline independently of augmentation therapy infused. We would, however, question the example of tiotropium. In the recently published UPLIFT trial there was no evidence that long-term use of this anticholinergic bronchodilator altered rates of FEV1 decline despite a reduction in the number of exacerbations (Citation10). More plausibly, the use of ICS/LABA combinations may alter the rate of lung function decline as suggested by a recent post hoc analysis of the TORCH trial (Citation11, 12). Nonetheless, any impact of non-specific therapy seems an unlikely confounder for our results. In almost all of the data gathered, patients in augmented and comparator groups were assessed concurrently and were likely to have received the same concomitant therapy. The small amount of data provided by the Wencker study may be an exception but in that instance tiotropium was unavailable and ICS/LABA combinations were not in widespread use in the treatment of COPD.
McCarthy and Dimitrov suggest that slowing the rate of FEV1 decline of 18ml/yr “seems negligible”. Certainly, from the standpoint of a clinician assessing an individual patient on two occasions this degree of FEV1 change is so small as to be overlooked in the usual clinical setting. However, in the context of rate of decline over years we are not sure that the term negligible should be used. The MCID for rate of FEV1 decline is not well established. However, the benchmark of 15ml/yr was used as the target for the UPLIFT trial (Citation13). The previously reported slowing of FEV1 decline associated with reduced mortality in the TORCH study was 17 ml/yr (Citation12). Against these benchmarks and the benchmark of normal rate of decline approximating 30 ml/yr in the healthy individual, we believe that the preservation of 18 ml/yr is substantial.
Drs. McCarthy and Dimitrov raise the challenging issue of cost and we note that assessment of cost effectiveness was beyond the scope of our analysis. We agree that by any standard, augmentation therapy is expensive and that further research should be directed at lowering its cost to make it more widely available. We disagree, however, about the need for a single randomized control trial based on FEV1 endpoints (which is not likely to be feasible) given that the available data as per our metaanalysis is consistent with the expected biological mechanism of augmenting alpha1 antitrypsin serum levels and with other more sensitive and specific endpoints such as preservation of CT scan lung density.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES
- Chapman KR, Stockley RA, Dawkins C, Wilkes MM, Navickis RJ, Navickis RJ. Augmentation therapy for a1 antitrypsin deficiency: A meta-analysis. COPD: J Chron Obstruct Pulmon Dis 2009; 6(3):177–184.
- Vreim CE, Wu M, Crystal RG, Buist AS, Burrows B, Cohen AB, Survival and FEV1 decline in individuals with severe deficiency of a1-antitrypsin. Am J Respir Crit Care Med 1998; 158(1):49–59.
- Seersholm N, Wencker M, Banik N, Viskum K, Dirksen A, Kok-Jensen A, Does alpha12-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Eur Respir J 1997; 10:2260–2263.
- Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DCS, Ulrik CS, A randomized clinical trial of a1-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999; 160(5):1468–1472.
- Wencker M, Fuhrmann B, Banik N, Konietzko N, Wissenschaftliche A. Longitudinal follow-up of patients with a1-protease inhibitor deficiency before and during therapy with IV a1-protease inhibitor. Chest 2001; 119(3):737–744.
- Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316:1055–1062.
- Dirksen A, Piitulainen E, Parr DG, Deng C, Wencker M, Shaker SB, Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J 2009; 33(6):1345–1353.
- Soriano JB, Miravitlles M. Your racing horses will help you to quit: a lesson for COPD and alpha1-antitrypsin deficiency research. Eur Respir J 2009; 33(6):1244–1246.
- Wencker M, Banik N, Buhl R, Seidel R, Konietzko N. Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1- AT-study group. Eur Respir J 1998; 11(2):428–433.
- Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359(15):1543–1554.
- Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356(8):775–789.
- Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: Results from the TORCH study. Am J Respir Crit Care Med 2008; 178(4):332–338.
- Decramer M, Celli B, Tashkin DP, Pauwels RA, Burkhart D, Cassino C, Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: The UPLIFT trial. COPD 2004; 1(2):303–312.