Bronchodilator Reversibility in COPD

CHEST Special Features Bronchodilator Reversibility in COPD Nicola A. Hanania, MD, FCCP ; Bartolome R. Celli, MD, FCCP ; James F. Donohue, MD, FCCP ; and Ubaldo J. Martin, MD, FCCP COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The diagnosis of COPD is based on spirometric evidence of airways obstruction following bronchodilator administration. Although it used to be commonly believed that patients with COPD have largely irreversible airflow obstruction, evidence now suggests that a considerable proportion of patients exhibit clinically significant bronchodilator reversibility. The complexity and inherent variability of a patient s acute response to a bronchodilator and the lack of a standardized procedure for assessing bronchodilator reversibility have led to significant confusion surrounding this concept. Although bronchodilator reversibility commonly is defined based on thresholds for improvement in, lung volume-based measures of pulmonary function may be of particular importance in patients with severe COPD. The usefulness of acute reversibility to short-acting bronchodilators in predicting a patient s long-term response to bronchodilator maintenance therapy is also unclear, although most studies suggest that a lack of acute response to short-acting bronchodilators does not preclude a beneficial long-term response to maintenance bronchodilator treatment. This review outlines recent findings about the prevalence and usefulness of bronchodilator reversibility in patients with COPD based on the available literature and proposes areas of future research. CHEST 2011; 140(4):1055 1063 Abbreviations: ACCP 5 American College of Chest Physicians; ATS 5 American Thoracic Society; DPI 5 dry powder inhaler; ERS 5 European Respiratory Society; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; IC 5 inspiratory capacity; MCID 5 minimal clinically important difference; MDI 5 metered-dose inhaler; pmdi 5 pressurized metered-dose inhaler; UPLIFT 5 Understanding Potential Long-term Impacts on Function with Tiotropium The American Thoracic Society (ATS)/European Respiratory Society (ERS) and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines define COPD as a preventable and treatable disease characterized by airflow limitation that is not Manuscript received November 18, 2010; revision accepted April 3, 2011. Affiliations: From the Section of Pulmonary and Critical Care Medicine, Asthma Clinical Research Center (Dr Hanania), Baylor College of Medicine, Houston, TX; Division of Pulmonary and Critical Care Medicine (Dr Celli), Brigham and Women s Hospital, Harvard University, Boston, MA; Division of Pulmonary Disease and Critical Care Medicine (Dr Donohue), University of North Carolina at Chapel Hill, Chapel Hill, NC; and Clinical Research, Respiratory and Inflammation Therapeutic Area (Dr Martin), AstraZeneca LP, Wilmington, DE. Funding/Support: This work was funded by AstraZeneca LP. Correspondence to: Nicola A. Hanania, MD, FCCP, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030; e-mail: hanania@bcm.tmc.edu. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/ site/misc/reprints.xhtml ). DOI: 10.1378/chest.10-2974 fully reversible. 1,2 Airflow limitation in COPD, defined as a postbronchodilator /FVC of, 0.70, is recommended by the GOLD guidelines for use in diagnosis, staging, and monitoring progression of COPD. 2 However, it should be noted that this spirometric cut-point has not been clinically validated and its use may result in overdiagnosis of COPD in older adults and underdiagnosis in younger adults. 2-4 Defining COPD based on an /FVC ratio less than the lower limit of normal may minimize misdiagnosis; however, widespread use of this criterion is hindered by the limited availability of postbronchodilator reference values. 2 The extent to which airflow obstruction is reversible following the acute administration of an inhaled short-acting bronchodilator is unclear in patients with COPD.5 Moreover, a standard definition of clinically relevant bronchodilator reversibility has not been established, and confusion exists surrounding its usefulness in confirming the diagnosis of COPD and its predictive value in determining long-term response www.chestpubs.org CHEST / 140 / 4 / OCTOBER, 2011 1055

to treatment. Some factors contributing to this confusion include the following: (1) potential misdiagnosis of COPD when using an /FVC ratio of, 0.70 as the only spirometric criterion, (2) the use of different definitions for a clinically relevant response to bronchodilation and different methodologies for determining reversibility in clinical studies, (3) the inherent within-subject variability in response to bronchodilator treatment, (4) the lack of understanding of the effect of COPD severity on treatment response, and (5) the lack of standardization surrounding lung function measures other than (eg, lung volume-based measures) in assessing bronchodilator reversibility. In this review, we outline recent findings surrounding the measurement and usefulness of acute bronchodilator reversibility in patients with COPD based on the available evidence in the current literature. Future areas of research that may contribute to a better understanding of the concept of reversibility in patients with COPD are also discussed. Determination of Bronchodilator Reversibility Although no standard definition of acute bronchodilator reversibility exists, available definitions are based on the absolute or percentage improvements in, FVC, or both from baseline following bronchodilator administration ( Table 1 ). 2,6-9 In addition, the definitions for a clinically meaningful improvement in after long-term treatment may differ from the criteria used to determine acute bronchodilator reversibility. Although a minimal clinically important difference (MCID) for has not been established, evidence suggests that a change in trough of 100 ml can be perceived as significant by most patients with COPD. 10 The ATS/ERS Task Force suggests a range of values for the MCID from baseline in (100-140 ml) and considers a change of 5% to 10% from baseline to be clinically important. 11 Currently there is no clear consensus as to which definition of acute bronchodilator reversibility should be universally adopted because several factors may influence the determination of bronchodilator reversibility ( Table 2 ). 2,9 Compared with patients with less severe COPD, patients with more severe COPD tend to have lower baseline values and may, therefore, have greater percentage changes from baseline in pulmonary function measures but smaller absolute improvements from baseline. 11 Thus, the use of the combined 12% and 200 ml criteria recommended by ATS/ERS guidelines, which incorporate a measure of absolute pulmonary function improvement, may provide a more comprehensive approach. 9 Furthermore, there is no agreement regarding the specific bronchodilator, dose, or method of bronchodilator administration that should be used to determine reversibility. 9 The ATS/ERS Task Force recommends using a short-acting b 2 -adrenoceptor agonist, such as albuterol, or an anticholinergic, such as ipratropium bromide, for reversibility testing. 9,12 The drug should be administered as four separate doses (100 mg/dose for albuterol or 40 m g/dose for ipratropium bromide) using a spacer device. 9,12 In addition, it is recommended that spirometry be performed 15 min following albuterol administration or 30 min following ipratropium bromide administration. 9,12 When determining acute bronchodilator reversibility to a specific study drug, the timing of spirometric testing following drug administration should be based on the reported time to onset for the drug used. 9 GOLD guidelines recommend using an adequate dose of bronchodilator (eg, 400 m g albuterol) to minimize variability. 2 Published clinical studies have used differing methodologies to determine acute bronchodilator reversibility, including different definitions of reversibility and different types and doses of drugs. In two studies including 726 and 411 patients with COPD, Bleecker et al 13 and Mahler et al, 14 respectively, defined bronchodilator reversibility based on an increase from baseline in of 12% and 200 ml (ATS criteria) 30 min after treatment with 180 m g of albuterol. In contrast, in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial (N 5 5,993), reversibility was determined at baseline by assessing bronchodilation 30 min after administration of short-acting bronchodilators that would produce near-maximal bronchodilation: ipratropium metered-dose inhaler (MDI) 80 m g followed 60 min later by albuterol MDI 400 m g. 15 In that analysis, reversibility was assessed using three reported definitions for improvement in : (1) 12% and 200 ml increase from baseline (ATS), (2) 15% increase from baseline (American College of Chest Physicians [ACCP]), and (3) 10% increase in percentage predicted (ERS). 15 That analysis also assessed reversibility based on responsiveness in alone, FVC alone, and either or FVC using ATS criteria. 15 In a more recent post hoc analysis of data pooled from common treatment arms in two other clinical studies in patients with moderate to very severe COPD, 16,17 reversibility was assessed 15 to 30 min after the administration of albuterol at screening and within 30 or 60 min after administration of the study drug (one of the following: budesonide/formoterol pressurized metered-dose inhaler [pmdi] 160/4.5 mg 3 2 inhalations [320/9 mg], budesonide/formoterol pmdi 80/4.5 mg 3 2 inhalations [160/9 m g], or formoterol dry powder inhaler [DPI] 4.5 m g 3 2 inhalations [9 m g]) on the day of randomization. 18 In that analysis, reversibility was also determined based on improvements in FVC or 1056 Special Features

Table 1 Common Criteria Used to Assess Acute Bronchodilator Reversibility Guideline Criteria ATS 6 FEV 1 or FVC improvement from predose value by 12% and 200 ml GOLD 2 improvement from predose value by. 12% and. 200 ml ERS7 Percentage predicted improvement from predose value by 10% ACCP8 improvement from predose value by 15% ATS/ERS9 FEV 1 and/or FVC improvement from predose value by. 12% and. 200 ml Data from References 2, 6-9. ACCP 5 American College of Chest Physicians; ATS 5 American Thoracic Society; ERS 5 European Respiratory Society; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease. inspiratory capacity (IC) of 12% and 200 ml 1 h after administration of the study drug. 18 The lack of a standard criterion for defining and determining reversibility leads to difficulties in interpreting and comparing the results of acute reversibility tests across studies because reversibility status is affected by the improvement threshold 19 and the specific bronchodilator used. 20 In a study by Calverley et al, 19 42% of patients with COPD (n 5 660) showed reversibility to albuterol 400 m g followed 30 min later by ipratropium 80 m g administered via a spacer based on the combined ATS threshold ( 12% and 200 ml improvement in ). However, based on the ERS criterion ( 10% improvement in predicted ), only 23% of the patients exhibited reversibility. 19 Another study (n 5 813) evaluating reversibility in patients with COPD showed differences in the percentage of patients exhibiting reversibility based on an improvement in of 12% or 200 ml when different bronchodilators were used: 11% with ipratropium, 27% with albuterol, and 35% with ipratropium and albuterol. 20 Within-Subject Variability in Bronchodilator Reversibility The interpretation of acute reversibility findings is also complicated by the inherent variability in patient-level factors. Considerable variation exists in bronchodilator response over time. 21 In a study by Calverley et al, 19 reversibility status changed with subsequent study visits in 52% and 38% of patients based on the ATS threshold and the ERS criterion, respectively. Anthonisen and Wright 21 reported withinand between-subject variability in the annual percentage change in of 11.1% and 11.0%, respectively, after 250 m g of isoproterenol over 2.5 to 3 years. In that study, a correlation between variability in bronchodilator response and the patient s baseline value was reported. 21 In patients with lower baseline values, variability in response tended to be greater when expressed as a percentage change from prebronchodilator levels but smaller when expressed as a volume difference between prebronchodilator and postbronchodilator values. 21 Meanwhile, overall variability in response tended to be greater in patients with higher baseline values. 21 Changes in reversibility status using the ATS or ERS criteria after treatment with albuterol 400 mg followed 30 min later by ipratropium 80 m g also have been observed with repeated testing over time and were reported to be associated with changes in the prebronchodilator value. 19 Evidence also suggests that within-subject daily variation in the change in occurs in response to the same bronchodilator. 22 The extent of bronchodilator reversibility may also be affected by other medications taken before reversibility testing and the duration for which they were withheld. It is generally recommended that patients abstain from taking short-acting bronchodilators and caffeine-containing products for at least 6 h before bronchodilator reversibility testing. 2,21 Long-acting bronchodilators should be withheld for a longer period (12 to 24 h). 2,21 Finally, reversibility determination based only on improvements in may result in an underestimate of bronchodilator responsiveness. The inclusion of lung volume-based measures (eg, IC) may be more sensitive and may provide a more comprehensive assessment of reversibility in patients with COPD, particularly those with severe disease, as outlined following. 23 Bronchodilator Reversibility in COPD FEV 1 It is believed that patients with COPD have considerably less reversible airflow obstruction than patients with asthma, and this concept was, for a long time, inappropriately used to differentiate one disease from the other. 5 Evidence now suggests that patients with COPD indeed can also show significant reversibility following acute bronchodilator administration 13-15,18,24 and that reversibility testing may not be sensitive Table 2 Factors That May Influence the Determination of Acute Bronchodilator Reversibility in Patients With COPD Criterion used to define reversibility Baseline Dose and type of bronchodilator used to assess reversibility Prior use of bronchodilator(s) Timing of reversibility testing following bronchodilator administration Delivery technique Data from References 2, 9. www.chestpubs.org CHEST / 140 / 4 / OCTOBER, 2011 1057

or specific enough to differentiate asthma from COPD. 25 In a post hoc analysis of two randomized, double-blind, parallel-group studies of patients aged 40 years with COPD and no prior history of asthma, Bleecker et al 13 assessed the efficacy of fluticasone/salmeterol 250/50 m g bid compared with four-times-daily treatment with ipratropium/albuterol 36/206 m g according to initial bronchodilator reversibility status at screening. Of the 726 patients, 44% exhibited reversibility based on ATS criteria.13 Likewise, Mahler et al 14 assessed the efficacy of salmeterol 42 m g bid compared with ipratropium 36 m g administered four times daily or placebo according to bronchodilator reversibility status in patients with COPD and no known history of asthma or other chronic respiratory disease other than COPD in a 12-week randomized, double-blind study. Of the 411 patients enrolled, approximately 65% showed reversibility based on ATS criteria. 14 The UPLIFT study measured bronchodilator reversibility following ipratropium and albuterol administration to produce near-maximal bronchodilation using the three criteria as discussed previously. 15 In that study, more than half of the patients exhibited bronchodilator reversibility in based on ATS and ACCP criteria, whereas 39% showed reversibility based on the ERS criterion ( Fig 1 ; criteria defined in Table 1 ). 15 As described earlier, bronchodilator reversibility was assessed recently in a post hoc analysis of data pooled from common treatment arms in a 6-month study 16 and a 12-month study 17 that included patients with moderate to very severe COPD. 18,24 At the screening visit, 34% to 39% of patients exhibited acute reversibility to albuterol based on ATS criteria, 18 whereas 51% to 54% of patients showed acute reversibility within 30 min to formoterol-containing treatment (budesonide/formoterol pmdi or formoterol DPI), 18 based on the same criteria on the day of randomization. When using the GOLD-recommended thresholds for classifying COPD severity (mild: 80% predicted ; moderate: 50% to, 80% predicted ; severe: 30% to, 50% predicted ; and very severe:, 30% predicted ), 2 bronchodilator reversibility (measured by changes in ) generally decreases as COPD severity increases. In the analysis reported by Bleecker et al, 13 the group of patients classified as nonreversible (n 5 399) at baseline comprised more patients who had GOLD stage III (severe; 45%) or IV (very severe; 12%) COPD compared with the group classified as reversible (n 5 320) (III, 40%; IV, 4%). Tashkin et al 15 reported a decrease in the percentage of patients who exhibited bronchodilator reversibility following ipratropium and albuterol administration with increasing COPD severity when using ATS criteria, but a similar percentage of patients Figure 1. Percentage of patients exhibiting reversibility to different thresholds for improvements in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study at baseline. ACCP 5 American College of Chest Physicians; ATS 5 American Thoracic Society; ERS 5 European Respiratory Society. (Reprinted with permission from Tashkin et al. 15 ) exhibited bronchodilator reversibility across COPD severity categories when using the ACCP criterion ( Fig 2 ). Similar observations were noted following formoterol-containing treatment in the previously mentioned post hoc analyses of the 6-month and 12-month studies. 24 However, a considerable percentage of patients with GOLD stage IV COPD still met ATS criteria for bronchodilator reversibility following ipratropium and albuterol treatment (approximately 20%; Fig 2 ) 15 or formoterol-containing treatment (31%-41%). 18 It should be noted that the GOLDrecommended threshold values for COPD severity are not clinically validated, 2 and some overlap may exist between severity categories due to intraindividual and interindividual variation in percent predicted values. Further to this point, Weatherall et al 26 proposed using cut-off values of 80%, 60%, and 40% (instead of the GOLD-recommended thresholds of 80%, 50%, and 30%) based on similar magnitudes of change in St. George Respiratory Questionnaire scores between severity categories. The uncertainty surrounding the criteria that should be used for COPD severity classification hinders a definitive assessment of reversibility status by COPD severity category. Notably, improvements in pulmonary function following bronchodilator administration have also been demonstrated in healthy subjects, 27 and this bronchodilator responsiveness has been shown to decrease with age in healthy subjects. 27 Johannessen et al 27 reported mean changes in of 115 to 145 ml, 56 to 78 ml, and 34 to 46 ml 15 min after administration of 0.3 mg of albuterol DPI in healthy subjects aged 37 to 39, 40 to 59, and 60 to 82 years, respectively. Therefore, one limitation of most of the analyses described earlier is that they did not use postbronchodilator reference values or lower limit of normal when diagnosing COPD or adjust for patient age when assessing bronchodilator reversibility. 13-15,18,24 Data from 1058 Special Features

Figure 2. Percentage of patients demonstrating reversibility based on improvements in by COPD severity with ipratropium 80 m g and albuterol 400 m g in the UPLIFT study using the ATS or ACCP criteria. GOLD 5 Global Initiative for Chronic Obstructive Lung Disease. See Figure 1 legend for expansion of the other abbreviations. (Reprinted with permission from Tashkin et al. 15 ) a post hoc analysis of the UPLIFT trial in patients with COPD showed a significant ( P,.0001) difference in age between poorly responsive (65.1 years) and responsive patients (64.0 years) when using the combined ATS criteria for reversibility; however, differences between the two groups were not significant when using criteria of 15% for or 10% predicted. 15 Further research is warranted to assess the effects of age on reversibility in patients with and without COPD; however, available data generally suggest that patients with COPD can demonstrate significant acute bronchodilator reversibility. 13-15,18,24 Lung Volumes Lung volume-based measures of pulmonary function contribute important information about a patient s responsiveness to bronchodilator treatment. Findings have shown that patients who do not meet the threshold for reversibility based on may show considerable improvements in lung volume measurements, 15,23,28 with this effect being more pronounced with increasing COPD severity. 15 Moreover, improvements in IC correlate with improvements in exercise tolerance and endurance, 29,30 which are recognized as important goals of disease management. 2 A retrospective analysis of 957 patients aged 55 years with moderate or severe hyperinflation showed that in patients with severe hyperinflation (n 5 281; total lung capacity. 133% predicted and /FVC ratio, 85% predicted), only 11% showed reversibility to albuterol based on ATS criteria, whereas 26% exhibited reversibility based on IC (improvement of 10% predicted and 200 ml) and 53% based on FVC (ATS criteria). 28 Similarly, results from a study of 168 men with COPD showed that 34% of patients who did not exhibit bronchodilator reversibility in had reversibility in FVC after albuterol administration based on ATS criteria. 23 Additionally, Tashkin et al 15 reported that 49% of patients with GOLD stage IV (very severe) COPD exhibited a significant FVC response to ipratropium and albuterol treatment without showing a significant response based on ATS criteria; this percentage was only 5% in patients with GOLD stage II (moderate) COPD. Hence, assessing bronchodilator reversibility based on lung volume-based measures of pulmonary function in addition to may be important, particularly in patients with more severe COPD. The magnitude of observed improvements in FVC or IC after bronchodilator treatment also suggests that patients with COPD experience a clinically relevant bronchodilator response. In a post hoc analysis of data from the UPLIFT study, an increase in FVC from baseline of 471 ml (20.1%) was observed after ipratropium and albuterol treatment on the day of randomization. 15 In a 4-week randomized, double-blind, placebo-controlled study of 81 patients with COPD, treatment with tiotropium 18 m g daily resulted in significant ( P,.01) differences from placebo in peak FVC (480 ml) and IC (350 ml) after 4 weeks of treatment. 31 In addition, greater improvements in FVC and IC were observed after formoterol-containing treatments (budesonide/formoterol pmdi 320/9 mg, budesonide/formoterol pmdi 160/9 m g, and formoterol DPI 9 m g) compared with placebo (FVC 350-410 ml vs 100 ml, respectively; IC 250-330 ml vs 100 ml, respectively) on the day of randomization. 18 Overall, these findings show that patients with COPD exhibit considerable improvements in lung volume-based measures of pulmonary function after bronchodilator treatment. However, despite the importance of lung volume-based measures of pulmonary function, the US Food and Drug Administration recommends using as the primary efficacy end point in clinical studies assessing COPD medications and does not recommend lung volume-based measures as a primary measure of efficacy. 32 This preference for assessment of rather than FVC or IC in clinical trials include the following: (1) greater variability with lung volume-based measures compared with, 33 (2) lack of established MCID values for lung volume-based measures, 11 (3) lack of standardized testing procedures across study centers, (4) lack of established reference values for lung volume-based measures, (5) insufficient experience with lung volumebased measures in large clinical trials to enable large data sets to be scrutinized, and (6) increased effort to obtain lung volume-based measures as they may www.chestpubs.org CHEST / 140 / 4 / OCTOBER, 2011 1059

require referral to a pulmonary function laboratory.11 Therefore, although lung volume-based measures provide important information about pulmonary function, these measures should be performed in conjunction with measurement. Therapeutic Implications of Bronchodilator Reversibility Another misconception about the usefulness of the acute bronchodilator reversibility is that patients with COPD who exhibit poor or no acute bronchodilator reversibility are not good candidates for long-term treatment with bronchodilators. This has been shown repeatedly to be inaccurate, although patients who exhibit acute reversibility to study medication or shortacting bronchodilators at baseline usually exhibit greater long-term improvements in pulmonary function than those classified as nonresponders. 14,34 Several studies have now shown that lack of an initial response to a short- or long-acting bronchodilator does not preclude subsequent benefit from maintenance bronchodilator therapy. 14,34 Thus, current guidelines no longer recommend using reversibility testing with a short-acting bronchodilator to predict longterm response to treatment. 2,9 In a post hoc analysis reported by Bleecker et al, 13 improvements in pulmonary function were observed with fluticasone/salmeterol 250/50 m g bid or ipratropium/albuterol 36/206 m g four times daily at baseline and week 8 in both reversible and nonreversible patients ( Fig 3 ). Although pulmonary function improvements were greater in reversible than nonreversible patients, improvements in dyspnea and COPD symptom scores generally were similar in both groups. 13 Similarly, Mahler et al 14 reported improvements in pulmonary function with both salmeterol administered bid and ipratropium administered four times daily in reversible and nonreversible patients ( Fig 4 ). Salmeterol treatment showed more sustained bronchodilation over 12 h compared with ipratropium treatment, with the decline in pulmonary function before the administration of the next dose of ipratropium (at 6 h) suggesting that ipratropium has a shorter duration of action. 14 The magnitude of bronchodilator response to salmeterol or ipratropium treatment over 12 h was greater in the reversible group compared with the nonreversible group at the end of 12 weeks. 14 However, nonreversible patients did show significantly greater improvements in pulmonary function with salmeterol or ipratropium treatment compared with placebo. 14 The magnitude of improvement in the UPLIFT analysis was greater in patients classified as responsive compared with those classified as poorly responsive, regardless of the criterion used. 15 Results Figure 3. Mean AUC on day 1 and after 8 weeks of treatment with FSC or IB/ALB by reversibility status at screening based on ATS criteria for improvement in. * P,.001 vs IB/ALB; P,.001 vs FSC; P.002 for week 8 vs day 1; ** P.01 for week 8 vs day 1. AUC 5 area under the curve; FSC 5 fluticasone/salmeterol combination; IB/ALB 5 ipratropium bromide/ albuterol. See Figure 1 legend for expansion of other abbreviation. (Reprinted with permission from Bleecker et al. 13 ) from a post hoc analysis of data from 5,783 patients in this study showed that both reversible and nonreversible patients experienced significant ( P,.005) improvements in postbronchodilator, FVC, and health-related quality of life (St. George Respiratory Questionnaire total score) and reductions in COPD exacerbations with tiotropium compared with placebo when using the ATS or ACCP criterion for reversibility. 35 Consistent with the data described previously, the ATS/ERS guidelines recommend that patients who do not demonstrate acute bronchodilator reversibility based on or FVC criteria should not be deprived of a 1- to 8-week trial on bronchodilator medication. 9 Future Needs Although current COPD guidelines recommend against using reversibility testing to predict a patient s long-term response to therapy, 2 these tests continue to be used in such capacities in clinical practice. Therefore, it is important to further explore the clinical implications of acute bronchodilator reversibility status in patients with COPD and to facilitate standardization of definitions and methods for reversibility testing. Current thresholds based on percentage improvements in can exaggerate the bronchodilator response in patients with a low baseline value. The ATS criterion, which includes an absolute improvement threshold of 200 ml in addition to the 12% threshold, may minimize this effect. 6 Future studies should explore associations between reversibility based on the ATS criteria and clinical benefits based on measures that are statistically derived (eg, improvements in symptom scores, COPD exacerbations, and pulmonary function). In addition, as 1060 Special Features

Figure 4. A, Change from baseline in over 12 h after 12 weeks of treatment with salmeterol, ipratropium, or placebo in patients classified as reversible. B, Change from baseline in over 12 h after 12 weeks of treatment with salmeterol, ipratropium, or placebo in patients classified as nonreversible. * P.026 vs placebo; 1 Significant differences between salmeterol and ipratropium. 14 (Reprinted with permission from Mahler et al. 14 ) greater focus is placed on patient-reported outcomes in COPD, associations between these measures and acute bronchodilator reversibility should be explored. The precise role of acute reversibility testing in the dose-finding phase of drug discovery, in particular with respect to bronchodilators, should also be explored. Although many patients with COPD demonstrate reversibility, approximately one-half fail to meet ATS criteria. 13-15 These findings may be relevant to population selection in dose-finding studies. Although high doses of the drug may be associated with greater adverse effects, the dose response may be shifted in less-reversible patients with COPD who may need higher doses to achieve clinical benefit. Evidence also suggests that results of reversibility testing may differ depending on the COPD severity category. Future studies should evaluate the clinical relevance of results of reversibility testing using the different available criteria with respect to other important measures, such as quality of life, exercise capacity, and symptoms, across all COPD severity categories. Future standardized methods for defining bronchodilator reversibility should also include guidance for selecting the drug, dose, and timing of reversibility testing after bronchodilator administration. Bronchodilator reversibility is commonly assessed based solely on criteria for improvements. 2,7,36 The ATS/ERS Task Force recommends the inclusion of FVC in assessing bronchodilator responsiveness. 9 Improvements in FVC may be clinically important, as they often correlate with improvements in exercise tolerance and endurance. 29,30 The need for the inclusion of IC in reversibility testing should also be explored because improvements in IC have been shown to correlate with improvements in dyspnea, 37 and the ratio of IC as a function of total lung capacity is an independent predictor of risk of death over time. 38 It is important to note that differences in the quality of patients spirometry technique may exist between clinical trials and real world clinical practice, with poorer technique leading to underestimation of, IC, and FVC. 39 Patients participating in clinical trials may undergo more extensive spirometry training and observation compared with patients in clinical practice, and clinical trials typically exclude patients who are unable to perform spirometry testing properly. These factors should be considered when interpreting reversibility data from clinical trials. Future research in patients with varying disease severity is warranted to further evaluate the clinical relevance and generalizability of these findings, and standardization of methods for measuring lung volumes and further research identifying MCIDs for lung volume-based measures are needed. Summary Patients with COPD were traditionally believed to have largely irreversible airway obstruction, and the acute reversibility status was often used to differentiate between COPD and asthma. However, recent studies demonstrate that many patients with COPD do indeed exhibit bronchodilator reversibility 13-15,18,24 and that reversibility testing is not a reliable measure to differentiate between asthma and COPD. 2,25 Several factors may influence bronchodilator reversibility, including disease severity, criteria used to define reversibility, and method and drug used for reversibility testing. Evidence also suggests that reversibility results can change with repeated testing in the same individual and do not predict a patient s longterm response to maintenance bronchodilator treatment. 14,34 Future research should explore the clinical relevance of the acute reversibility findings based on different criteria with respect to other important clinical outcomes, such as quality of life, exercise capacity, and dyspnea, in patients with COPD across a range of severity categories. www.chestpubs.org CHEST / 140 / 4 / OCTOBER, 2011 1061

Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hanania has received research grant support from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Novartis, and Pfizer and has served as a consultant for GlaxoSmithKline, Novartis, and Pfizer and on the Speakers Bureaus of GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca. Dr Celli has served as a consultant or on the advisory boards for AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline and has received industry-sponsored grants from AstraZeneca, Boehringer Ingelheim, and Pfizer. Dr Donohue has received grant monies from Boehringer Ingelheim, Novartis, Johnson & Johnson, National Institutes of Health, and Alpha-1 Foundation, has served as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Merck, and has participated in speaking activities for Boehringer Ingelheim, Pfizer, GlaxoSmithKline, and AstraZeneca. Dr Martin is an employee of and owns stock in AstraZeneca LP. Role of sponsors : AstraZeneca LP (Wilmington, Delaware) provided funding for writing assistance from Scientific Connexions (Newtown, Pennsylvania). Other contributions: We thank Anny Wu, PharmD, and Cynthia Gobbel, PhD, from Scientific Connexions (Newtown, Pennsylvania) for writing assistance funded by AstraZeneca LP (Wilmington, Delaware). References 1. Celli BR, MacNee W ; ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004 ; 23 ( 6 ): 932-946. 2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http:// www.goldcopd.com. Updated 2010. Accessed May 19, 2011. 3. Vollmer WM, Gíslason T, Burney P, et al. Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study. 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