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The effects of long-acting bronchodilators on total mortality in patients with stable chronic obstructive… Kliber, Agnes; Lynd, Larry D; Sin, Don D May 11, 2010

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Kliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Open AccessR E V I E WReviewThe effects of long-acting bronchodilators on total mortality in patients with stable chronic obstructive pulmonary diseaseAgnes Kliber1, Larry D Lynd2,3 and Don D Sin*1,3,4AbstractBackground: Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of mortality worldwide. Long-acting bronchodilators are considered first line therapies for patients with COPD but their effects on mortality are not well known. We performed a comprehensive systematic review and meta-analysis to evaluate the effects of long-acting bronchodilators on total mortality in stable COPD.Methods: Using MEDLINE, EMBASE and Cochrane Systematic Review databases, we identified high quality randomized controlled trials of tiotropium, formoterol, salmeterol, formoterol/budesonide or salmeterol/fluticasone in COPD that had a follow-up of 6 months or longer and reported on total mortality. Two reviewers independently abstracted data from the original trials and disagreements were resolved by iteration and consensus.Results: Twenty-seven trials that included 30,495 patients were included in the review. Relative risk (RR) for total mortality was calculated for each of the study and pooled together using a random-effects model. The combination of inhaled corticosteroid (ICS) and long-acting beta-2 agonist (LABA) therapy was associated with reduced total mortality compared with placebo (RR, 0.80; p = 0.005). Neither tiotropium (RR, 1.08; p = 0.61) nor LABA by itself (RR, 0.90; p = 0.21) was associated with mortality.Conclusions: A combination of ICS and LABA reduced mortality by approximately 20%. Neither tiotropium nor LABA by itself modifies all-cause mortality in COPD.IntroductionChronic obstructive pulmonary disease (COPD) affectsmore than 300 million people worldwide [1]. It is cur-rently the 4th leading cause of mortality accounting fornearly 3 million deaths annually and is the only majorcause of mortality that is increasing in both the developedand developing countries [2]. By 2020, it will become the3rd leading cause of death (accounting for 5 million deathsper year) and the 5th leading causing of disability world-wide [2]. Expert guidelines recommend the use of long-acting bronchodilators as first-line therapies for patientswith persistent symptoms [3,4]. However, their effect onmortality remains controversial. A previous meta-analy-sis suggested that inhaled long-acting anticholinergicbronchodilators had no effect on total mortality [5]. Onthe other hand, a secondary analysis of the UPLIFT trialsuggested a mortality benefit [6]. Similarly, although theTORCH trial suggested a modest mortality benefit withinhaled corticosteroid/long-acting beta-2 agonist combi-nation (ICS/LABA), meta-analyses suggested that theymay only reduce mortality when compared to placebo [7]or ICS alone [8] but not to LABA alone [7]. However,there were several limitations to the prior meta-analyses,which may have led to some of the discordant findings.First, the prior meta-analysis on tiotropium did notinclude data from the recently completed UPLIFT trial.Second, prior meta-analyses did not address the effect ofLABA on total mortality, making it difficult to assesswhether or not LABA can be used as a reasonable com-parator for ICS/LABA. Third, the findings from the ICS/LABA on mortality are dominated by data from one trial(i.e. TORCH), raising doubts about the robustness of the* Correspondence: don.sin@hli.ubc.ca1BioMed Central© 2010 Kliber et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.results from previous meta-analyses. Fourth, and most Department of Medicine (Respiratory Division), University of British Columbia, 6040 Iona Drive, Vancouver, V6T 2E8, CanadaFull list of author information is available at the end of the articleKliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 2 of 13importantly, many of the previous trials of ICS/LABAused a factorial design. However, none of these studieshad sufficient power to assess interactions between treat-ments or to adjust for multiple comparisons. From amethodological perspective, it is essential that the activetreatment drugs be compared against one (primary) ref-erence group (and not to each other) unless adjustmentsare made for multiple comparisons [9]. To address theselimitations and to determine the effects of these drugs ontotal mortality in COPD, we performed a systematicreview and meta-analysis with and without TORCH forICS/LABA and inclusive of UPLIFT for tiotropium.Importantly, to maintain statistical integrity, for trialsthat used a factorial design, we determined survivaleffects of the primary active treatment drug against theprincipal comparator group identified a priori in each ofthe individual studies.MethodsData Sources and SearchesWe examined the relationship of tiotropium, a long-act-ing anticholinergic, as well as formoterol and salmeterol,which are long-acting beta-2 agonists, by themselves or incombination with an inhaled corticosteroid to all-causemortality. Using MEDLINE, EMBASE and Cochrane Sys-tematic Review databases, we conducted a detailed litera-ture search to identify high-quality randomizedcontrolled trials of tiotropium, formoterol, salmeterol,formoterol/budesonide or salmeterol/fluticasone inpatients with stable COPD in which total mortality wasreported. We supplemented the electronic search byreviewing the bibliographies of selected articles, examin-ing review articles on this topic and contacting experts inthe field. Studies in abstract form were included only ifthe methods and results could be adequately analyzed.Study SelectionWe restricted the search to studies that were conductedin adults (>19 years of age), had follow-up of 6 months orgreater, and were published in the English language witha Jadad score of 3 or greater [10]. We restricted the dura-tion to 6 months to ensure that patients had a reasonablewindow of exposure to the drugs. We excluded trials inwhich there were no deaths. The details of the search areprovided in Additional File 1.Data Extraction and Quality AssessmentData were abstracted from each trial by 2 authors (A.K,D.D.S) independently using a standardized data abstrac-tion form. Any discrepancies were resolved by iterationand consensus. The primary endpoint was total mortalitywere stratified according to the study drug and to themain comparator group. For analytic purposes, the activetreatment compound (i.e. tiotropium, formoterol, salme-terol or formoterol/budesonide or salmeterol/flutica-sone) was compared against the main reference group. Inmost cases, the main reference group was placebo; how-ever, we also included studies in which the main compar-ator was another active drug (e.g. tiotropium orsalmeterol). Quality of the trials was assessed using theQUOROM guidelines as well as using the Jadad scale[10].Data Synthesis and AnalysisThe results were analyzed by intention-to-treat wheneverpossible. To maintain the statistical integrity of the origi-nal trial, for studies that used a factorial design, we deter-mined the mortality rate of the active treatment drugsagainst one (primary) reference group (e.g. placebo) thatwere identified a priori. This mitigated the possibility ofpost hoc analyses. To be conservative, a DerSimonian andLaird random-effects model was used to pool the resultsof individual trials together. The results are reported asrelative risks (RR) and 95% confidence intervals (CI). Het-erogeneity of results across individual studies was exam-ined using a chi-square test. All analyses were conductedusing RevMan version 5.0 (the Cochrane Collaboration,Oxford, England).ResultsThe search results are shown in figure 1. The baselinepatient characteristics of the selected studies are summa-rized in Table 1. We identified 6 trials that compared sal-meterol/fluticasone combination against placebo (n =2781 in active treatment vs 2487 in placebo), 4 trials thatcompared formoterol/budesonide against placebo (n =1233 vs n = 1242), 1 trial that compared salmeterol/fluti-casone against tiotropium (n = 658 vs 665) and 6 trialsthat compared salmeterol/fluticasone against salmeterolby itself (n = 2094 vs n = 2088). One trial was excluded astreatment with salmeterol/fluticasone or salmeterol alonewas in addition to tiotropium, which could have led tosignificant drug to drug interactions [12]. The collectiveresults of inhaled corticosteroid/long-acting beta-2 ago-nist combination are summarized in figure 2. In total,there were 269 deaths in the inhaled corticosteroid (ICS)/long acting beta-2 agonist (LABA) arm (n = 6766) and333 deaths in the reference group (n = 6482) for a relativerisk of 0.80 (95% CI, 0.69 to 0.94; p = 0.005) in favor of theactive treatment group. The results were largely driven bydata from Calverley et al, which accounted for 74% of thetotal weight [13]. The data, however, were robust to the(regardless of the cause). Disease specific mortality wasnot determined as assigning causality to deaths in COPDis problematic and fraught with errors [11]. The trialsexclusion of Calverley et al's study. Its exclusion resultedin a similar risk estimate in favor of ICS/LABA combina-tion (RR, 0.73; 95% CI, 0.54 to 0.99; p = 0.04) (figure 3).Kliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 3 of 13The comparison between ICS/LABA and placebo(excluding studies that did not use a placebo comparator)was also significant (RR, 0.83; 95% CI, 0.70 to 0.98; p =0.03; see figure 4).We identified 5 trials that compared salmeterol against(figure 5). There were 4 trials that compared formoterolagainst placebo. In these studies, there were 24 deaths inthe formoterol group (n = 1235) and 19 deaths in the pla-cebo group (n = 1242) for a relative risk of 1.23 (95% CI,0.61 to 2.46; p = 0.57). In total, the long-acting beta-2Figure 1 Flow Diagram Outlining the Search Strategy.placebo. There were 222 deaths in the salmeterol group(n = 2795) and 254 deaths in the placebo group (n = 2805)for a relative risk of 0.88 (95% CI, 0.75 to 1.04; p = 0.13)agonists by themselves did not significantly alter totalmortality in COPD (RR, 0.90; 95% CI, 0.77 to 1.06; p =0.21).e 4 of 13Table 1: Summary Of Clinical Trials That Were Included In This Analysis% Current SmokersJadad ScoreProhibited COPD DrugsNA 3 LABA/other anticholinergics32 3 other anticholinergics, oral beta agonists30 3 other anticholinergics; oral CS >20 mg/d29 4 other anticholinergics75 4 other anticholinergicsNA 3 LABAs, other anticholinergicsNA 3 Insufficient details providedNA 3 Insufficient details provided41 4 All prohibited except salbutamol35 3 Only study drugs allowed34 3 ICS, all bronchodilators except terbutaline, leukotriene modifiers,42 3 All drugs except salbutamol40 3 ICS, LABA, TI42 3 regular oral CS, LABA and TI38 4 All drugs except salbutamolKliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Pag Author N Drug 1 Drug 2 Comparator Follow-up Mean Age (SD) % Men Mean FEV1 (SD)Casaburi 2002[39] 921 TI (18 ug OD) None PL 49 weeks 64 (9) 76 1.02 (0.44)Chan 2007[40] 913 TI (18 ug OD) None PL 48 weeks 66 (9) 60 0.97 (0.38)Niewoehner 2005[41] 1829 TI (18 ug OD) None PL 6 months 68 (10) 99 1.04 (0.4)Tashkin 2008[35] 5993 TI (18 ug OD) None PL 9 months 65 (8) 75 1.10 (0.4)Tonnel 2008[42] 554 TI (18 ug OD) None PL 6 months 64 (10) 86 1.36 (0.46)Vincken 2002[14] 535 TI (18 ug OD) None IP (40 ug QID) 6 months 64 (8) 85 1.22 (0.43)Brusasco 2003[43] 1207 TI (18 ug OD) SALM (50 ug BID) PL 6 months 64 (9) 76 1.10 (0.39)Vogelmeier 2008[44] 640 TI (18 ug OD) FORM (10 ug BID) PL 24 weeks 63 (9) 78 1.52 (0.39)Tashkin 2008[20] 1148 BUD/FORM (320 ug/9 ug BID)FORM (9 ug BID) PL 6 months 63 (10) 67 1.04 (0.41)Szafranski 2003[45] 614 BUD/FORM (320 ug/9 ug BID)FORM (9 ug BID) PL 12 months 64 (NA) 80 0.98 (NA)Calverley 2003[46] 765 BUD/FORM (320 ug/9 ug BID)FORM (9 ug BID) PL 12 months 64 (NA) 76 0.99 (0.33)Rennard 2009[21] 1470 BUD/FORM (320 ug/9 ug BID)FORM (9 ug BID) PL 12 months 63 (9) 64 1.01 (0.43)Ferguson 2008[47] 782 SALM/FLU (50 ug/250 ug BID)None SALM (50 ug BID)12 months 65 (9) 56 0.94 (0.36)Kardos 2007[48] 998 SALM/FLU (50 ug/500 ug BID)None SALM (50 ug BID)44 weeks 63 (8) 76 1.13 (0.41)Wedzicha 2008[15] 1323 SALM/FLU (50 ug/500 ug BID)None TI 18 ug OD 24 months 64 (NA) 83 1.12 (NA)e 5 of 13Calverley 2003[49] 1091 SALM/FLU (50 SALM (50 ug BID) PL 12 months 64 (NA) 73 1.26 (0.48) 52 5 Oral or inhaled CS or LABAsNA 3 Not specifiedNA 3 Not specified50 3 Bronchodilators except salbutamol, oral CS43 4 CS, LABA22 4 ICS, LABA40 4 TI or LABANA 3 Not specifiedNA 3 Not specified42 4 All prohibited except salbutamol and ipratropiumNA 3 Not specified37 4 All prohibited except salbutamol, ipratropium and xanthinespium bromide; LABA, long acting bronchodilators, N = total sample Table 1: Summary Of Clinical Trials That Were Included In This Analysis (Continued)Kliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Pag ug/500 ug BID)SCO30002 2008 [50] 387 SALM/FLU (25 ug/250 ug BID)FP (250 ug BID) PL 12 months 65 (9) 82 1.54 (NA)SCO100540 2006[51] 445 SALM/FLU (50 ug/500 ug BID)None PL 6 months 66 (8) 89 1.05 (0.37)Mahler 2002[52] 506 SALM/FLU (50 ug/500 ug BID)SALM (50 ug BID) PL 24 weeks 62 (NA) 64 1.27 (NA)Calverley 2007[13] 4633 SALM/FLU (50 ug/500 ug BID)SALM (50 ug BID) PL 36 months 65 (8) 76 1.12 (0.4)Zheng 2007[53] 445 SALM/FLU (50 ug/500 ug BID)NA PL 24 weeks 66 (8) 89 1.05 (NA)Stockley 2006[54] 634 SALM (50 ug BID) NA PL 12 months 62 (9) 77 1.30 (0.5)SCO30002 2008[55] 256 SALM/FLU (50 ug/500 ug BID)FLU (500 ug BID) PL 52 weeks 64 (NA) 82 1.50 (NA)SCO100470 2006 [56] 1050 SALM/FLU (50 ug/250 ug BID)None SALM (50 ug BID)6 months 64 (9) 78 1.67 (0.46)Anzueto 2009[57] 797 SALM/FLU (50 ug/250 ug BID)None SALM (50 ug BID)12 months 65 (NA) 54 1.17 (0.51)SCO40041 2008 [58] 186 SALM/FLU (50 ug/250 ug BID)None SALM (50 ug BID)3 years 66 (9) 61 NAWouters 2005 [59] 373 SALM/FLU (50 ug/500 ug BID)None SALM (50 ug BID)12 months 64 (8) 74 1.41 (0.48)Abbreviations:BID, twice daily; CS, corticosteroids; FEV1, forced expiratory volume in one second; FLU, fluticasone; FORM, formoterol; ICS, inhaled corticosteroids; IP, ipratrosize; NA, not available; OD, once daily; PL, placebo; SALM, salmeterol; SD, standard deviation; TI, tiotropiumKliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 6 of 13We identified 9 clinical trials that compared tiotropiumagainst placebo but one study reported no deaths anddata from one of the studies overlapped substantially withanother, leaving 7 clinical trials for analysis (figure 6). Inall, there were 431 deaths in the tiotropium group and453 deaths in the placebo group for a relative risk of 0.94(95% CI, 0.80 to 1.11; p = 0.46). There was one study thatcompared tiotropium against ipratropium (RR, 1.51; 95%CI, 0.41 to 5.50; p = 0.53) [14] and one that comparedtiotropium against salmeterol/fluticasone combinationsis, we excluded studies that compared tiotropiumagainst a comparator other than placebo or ipratropiumbromide and repeated the analysis. This made no mate-rial impact on the results (figure 7). Tiotropium was notassociated with total mortality (RR, 0.94; 95% CI, 0.83 to1.06; p = 0.33).DiscussionThe most important findings from the present meta-analysis were that 1) inhaled corticosteroids (ICS) inFigure 2 The Effects of Inhaled Corticosteroid/Long-Acting Beta-2 Agonist Combination on Total Mortality. Abbreviations: BUD/F, budes-onide/formoterol combination; CI, confidence interval; ICS/LABA, inhaled corticosteroids/long-acting beta-2 agonist combination; M-H, Mantel-Han-zel; SALM, salmeterol; SFC, salmeterol/fluticasone combinationSC030002 2008SCO100540 2006Zheng 2007Mahler2002Calverley 2003Calverley 2007Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 4.32, df = 5 (P = 0.50); I² = 0%Test for overall effect: Z = 2.22 (P = 0.03)Tashkin 2009Rennard 2009Calverley2003Szafranski 2003Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 1.79, df = 3 (P = 0.62); I² = 0%Test for overall effect: Z = 0.07 (P = 0.94)Wedzicha 2008Test for overall effect: Z = 2.19 (P = 0.03)Wouters 2005SCO100470Ferguson 2008Anzueto 2009SCO40041 2008Kardos 2007Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 2.15, df = 5 (P = 0.83); I² = 0%Test for overall effect: Z = 0.70 (P = 0.49)Total (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 10.55, df = 16 (P = 0.84); I² = 0%Test for overall effect: Z = 2.81 (P = 0.005)1220419320235561921236457272691312972971653581533278127749425420812336581895183943949250720946766000310231244145919384336793233312514814818136115242487300481256205124266518453238840394487208864820.2%0.3%0.3%0.3%1.8%74.2%77.0%0.5%1.4%1.6%2.3%5.6%8.6%0.8%0.9%1.2%1.5%1.9%2.4%8.8%100.0%2.86 [0.12, 69.64]2.50 [0.12, 51.74]2.50 [0.12, 51.74]0.16 [0.01, 3.01]0.40 [0.13, 1.27]0.83 [0.70, 0.99]0.82 [0.69, 0.98]3.25 [0.34, 31.05]1.22 [0.33, 4.51]1.01 [0.30, 3.44]0.66 [0.24, 1.81]0.98 [0.51, 1.86]0.56 [0.33, 0.94]0.49 [0.09, 2.63]1.03 [0.21, 5.07]1.97 [0.50, 7.82]0.68 [0.19, 2.40]0.73 [0.24, 2.22]0.75 [0.28, 1.99]0.83 [0.50, 1.40]0.80 [0.69, 0.94]0.05 0.2 1 5 20Favours ICS/LABAl Favours controlStudySFC vs PlaceboDeaths Total Deaths Total Weight M-H, Random, 95% CIICS/LABA Controls Risk Ratio Risk RatioM-H, Random, 95% CIBUD/F vs PlaceboSFC vs TiotropiumSFC vs SALM(RR, 1.79; 95% CI, 1.06 to 3.02; p = 0.03) [15]. In sum,tiotropium was not associated with total mortality (RR,1.08; 95% CI, 0.79 to 1.48; p = 0.61). As a sensitivity analy-combination with a long-acting bronchodilator (LABA)were associated with a ~20% reduction in total mortality;whereas LABAs or long-acting anticholinergics by them-Kliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 7 of 13selves did not alter mortality; and 2) these data wererobust to the inclusion or exclusion of the TORCH andUPLIFT trials.These findings are largely in keeping with previousobservational studies, which have shown for the mostpart enhanced survival with the use of ICS/LABA combi-nations and a lack of survival benefits of short or long act-ing bronchodilators by themselves [16-18]. However, ourfindings appear discordant with a recent meta-analysispublished by Rodrigo and colleagues [19], which failed toLABA only (though the point estimate was 0.90 in favorof ICS/LABA). However, this study excluded trials thatdid not have a LABA arm and failed to capture morerecently published clinical trials (e.g. studies by Tashkinet al[20] and Rennard et al[21]). By adding these addi-tional studies, the present meta-analysis had greater sta-tistical power to determine the relationship of ICS/LABAcombination to total mortality. More importantly, in thepresent meta-analysis, we compared the active treatmentgroups (i.e. ICS/LABA or LABA or tiotropium) againstFigure 3 The Effects of Inhaled Corticosteroid/Long-Acting Beta-2 Agonist Combination on Total Mortality Excluding Calverley et al's Trial [13]. Abbreviations: BUD/F, budesonide/formoterol combination; CI, confidence interval; ICS/LABA, inhaled corticosteroids/long-acting beta-2 agonist combination; M-H, Mantel-Hanzel; SALM, salmeterol; SFC, salmeterol/fluticasone combinationSC030002 2008 [50]SCO100540 2006 [51]Zheng 2007 [53]Mahler2002 [52]Calverley 2003 [49]Subtotal (95% CI)Test for overall effect: Z = 1.07 (P = 0.28)Tashkin 2009 [20]Rennard 2009 [21]Calverley 2003 [46]Szafranski 2003 [45]Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 1.79, df = 3 (P = 0.62); I² = 0%Test for overall effect: Z = 0.07 (P = 0.94)Wedzicha 2008 [15] Test for overall effect: Z = 2.19 (P = 0.03)Wouters 2005 [59]SCO100470 [56]Ferguson 2008 [47]Anzueto 2009 [57]SCO40041 2008 [58]Kardos 2007 [48]Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 2.15, df = 5 (P = 0.83); I² = 0%Test for overall effect: Z = 0.70 (P = 0.49)Total (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 10.02, df = 15 (P = 0.82); I² = 0%Test for overall effect: Z = 2.05 (P = 0.04)122049355619212364572776131297297165358124827749425420812336581895183943949250720945233000310131459193843367932102125148148181361963300481256205124266518453238840394487208849580.9%1.0%1.0%1.0%6.9%10.8%1.8%5.3%6.0%8.8%21.9%33.3%3.2%3.6%4.8%5.7%7.3%9.4%34.1%100.0%2.86 [0.12, 69.64]2.50 [0.12, 51.74]2.50 [0.12, 51.74]0.16 [0.01, 3.01]0.40 [0.13, 1.27]0.61 [0.24, 1.52]3.25 [0.34, 31.05]1.22 [0.33, 4.51]1.01 [0.30, 3.44]0.66 [0.24, 1.81]0.98 [0.51, 1.86]0.56 [0.33, 0.94]0.49 [0.09, 2.63]1.03 [0.21, 5.07]1.97 [0.50, 7.82]0.68 [0.19, 2.40]0.73 [0.24, 2.22]0.75 [0.28, 1.99]0.83 [0.50, 1.40]0.73 [0.54, 0.99]0.05 0.2 1 5 20Favours ICS/LABA Favours controlStudy Deaths Total Deaths Total Weight M-H, Random, 95% CIICS/LABA Controls Risk Ratio Risk RatioM-H, Random, 95% CIHeterogeneity: Tau² = 0.00; Chi² = 3.88, df = 4 (P = 0.42); I² = 0%SFC vs PlaceboBUD/F vs PlaceboSFC vs TiotropiumSFC vs SALMfind a significant difference in total mortality betweenthose treated with ICS/LABA and those treated withthe primary reference group of the trial in order to pre-serve the integrity of the original trial design and avoidKliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 8 of 13the problem of multiple comparisons and post hoc analy-ses. Thus, for the trials that used a 2 × 2 factorial design,we compared the mortality effects of the active treatmentarm against the main reference group of the trial (whichin most cases was placebo) as the original trials did nothave sufficient power to assess interactions between thegroups or to correct for multiple comparisons [22].The mechanism by which ICS/LABA combinationreduces total mortality in COPD is uncertain. It is nowwell recognized that COPD is an inflammatory disorder,characterized by persistent lung and systemic inflamma-tion, which intensifies with disease progression and dur-ing clinical exacerbations [23,24]. Once COPD develops,the inflammatory response continues to persist manyyears after smoking cessation [25]. Although the inflam-matory process in COPD may be relatively insensitive toand in vivo [27,28]. For instance, Bourbeau and colleaguesfound that 3 months of therapy with salmeterol/flutica-sone combination attenuated lung inflammation, as char-acterized by a reduction in the number of CD8 positiveand CD68 positive cells in the airways of patients withsevere, stable COPD; whereas fluticasone by itself had noeffect [28]. Similarly, Barnes and colleagues observed asignificant reduction in the expression of inflammatorybiomarkers in the bronchial biopsies and sputum ofCOPD patients treated with salmeterol/fluticasone com-bination compared to those treated with placebo [27].These data have been replicated and extended by Lap-perre and colleagues, who showed that salmeterol/fluti-casone therapy for 30 months reduced lunginflammation, attenuated the rate of decline in lung func-tion, and improved bronchial responsiveness comparedFigure 4 The Effects of Inhaled Corticosteroid/Long-Acting Beta-2 Agonist Combination on Total Mortality Using Clinical Trials That Used Placebo-Treated Patients As The Main Comparator. Abbreviations: BUD/F, budesonide/formoterol combination; CI, confidence interval; ICS/LABA, inhaled corticosteroids/long-acting beta-2 agonist combination; M-H, Mantel-Hanzel; SALM, salmeterol; SFC, salmeterol/fluticasone combinationSC03002 2008 [50]SCO100540 2006 [51]Zheng 2007 [53]Mahler 2002 [52]Calverley 2003 [49]Calverley 2007 [13]Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 4.32, df = 5 (P = 0.50); I² = 0%Test for overall effect: Z = 2.22 (P = 0.03)Tashkin 2009 [20]Rennard 2009 [21]Calverley 2003 [46]Szafranski 2003 [45]Subtotal (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 1.79, df = 3 (P = 0.62); I² = 0%Test for overall effect: Z = 0.07 (P = 0.94)Total (95% CI)Heterogeneity: Tau² = 0.00; Chi² = 6.36, df = 9 (P = 0.70); I² = 0%Test for overall effect: Z = 2.16 (P = 0.03)12204193202355619221131297297165358153327812774942542081233401400031023124414591926312514814818136115242487300481256205124237290.3%0.3%0.3%0.3%2.1%89.8%93.2%0.6%1.7%1.9%2.7%6.8%100.0%2.86 [0.12, 69.64]2.50 [0.12, 51.74]2.50 [0.12, 51.74]0.16 [0.01, 3.01]0.40 [0.13, 1.27]0.83 [0.70, 0.99]0.82 [0.69, 0.98]3.25 [0.34, 31.05]1.22 [0.33, 4.51]1.01 [0.30, 3.44]0.66 [0.24, 1.81]0.98 [0.51, 1.86]0.83 [0.70, 0.98]0.05 0.2 1 5 20Favours ICS/LABA Favours placeboStudy Deaths Total Deaths Total Weight M-H, Random, 95% CIICS/LABA Placebo Risk Ratio Risk RatioM-H, Random, 95% CISFC vs PlaceboBUD/F vs Placebothe actions of glucocorticoids, the addition of a long-act-ing beta-2 agonist to an inhaled corticosteroid appears toamplify their anti-inflammatory effects both in vitro [26]to salmeterol alone or placebo[29]. Inhaled corticoster-oid/long acting beta-2 agonist combination may alsoattenuate the systemic inflammatory response in COPDKliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 9 of 13Figure 5 The Effects of Long-Acting Beta-2 Agonists on Total Mortality. Abbreviations: CI, confidence interval; FORM, formoterol; LABA; long-act-ing beta-2 agonists; M-H, Mantel-Hanzel; SALM, salmeterolStudySALM vs PlaceboTest for heterogeneity: P = 0.56FORM vs PlaceboTest for heterogeneity: P = 0.31Deaths Total Deaths Total Weight M-H, Random, 95% CILABA Placebo Risk Ratio Risk RatioM-H, Random, 95% CICalverley 2007 [13] 205 1542 231 1545 86.7% 0.89 [0.75, 1.06]Subtotal (95% CI) 222 2795 254 2805 93.2% 0.88 [0.75, 1.04]Subtotal (95% CI) 24 1235 19 1242 6.6% 1.23 [0.61, 2.46]Total (95% CI) 246 4030 273 4047 100.0% 0.90 [0.77, 1.06]0.05 0.2 1 5 20Favors LABA Favors PlaceboBrusasco 2003 [43] 6 405 5 400 1.9% 1.19 [0.36, 3.85]Stockley 2006 [54] 6 316 5 318 1.9% 1.21 [0.37, 3.92]Calverley 2003 [49] 5 372 10 361 2.3% 0.49 [0.17, 1.41]Tashkin 2008 [20] 1 284 1 300 0.3% 1.06 [0.07, 16.81]Rennard 2009 [21] 4 495 4 481 1.3% 0.97 [0.24, 3.86]Calverley 2003 [49] 13 255 5 256 2.5% 2.61 [0.94, 7.21]Mahler 2002 [52] 0 160 3 181 0.3% 0.16 [0.01, 3.10]Szafranski 2003 [45] 6 201 9 205 2.5% 0.68 [0.25, 1.88]Heterogeneity: Tau² = 0.00; Chi² = 7.59, df = 8 (P = 0.47); I² = 0%Test for overall effect: Z = 1.29 (P = 0.21)Figure 6 The Effects of Tiotropium on Total Mortality. Abbreviations: CI, confidence interval; ICS/LABA, inhaled corticosteroids/long-acting beta-2 agonist combination; M-H, Mantel-HanzelStudyTiotropium vs PlaceboTest for heterogeneity: P = 0.31Tiotropium vs IpratropiumTiotropium vs ICS/LABATotal (95% CI)Deaths478Total7469Deaths477Total6841Weight100.0%M-H, Random, 95% CI1.08 [0.79, 1.48]Tiotropium Controls Risk Ratio Risk RatioM-H, Random, 95% CITashkin 2008 [35] 381 2987 411 3006 38.0% 0.93 [0.82, 1.06]Subtotal (95% CI) 431 6448 453 6004 75.4% 0.94 [0.80, 1.11]0.1 0.2 0.5 1 2 5 10Favors tiotropium Favors controlVolgelmeier 2008 [44] 0 221 1 209 0.9% 0.32 [0.01, 7.70]Brusasco 2003 [43] 1 402 5 400 2.0% 0.20 [0.02, 1.70]Tonnel 2008 [42] 3 266 6 288 4.6% 0.54 [0.14, 2.14]Chan 2007 [40] 17 608 4 305 6.9% 2.13 [0.72, 6.28]Casaburi 2002 [39] 7 550 7 371 7.4% 0.67 [0.24, 1.91]Niewoehner 2005 [41] 22 914 19 915 16.0% 1.16 [0.63, 2.13]Vincken 2002 [14] 9 356 3 179 5.1% 1.51 [0.41, 5.50]Wedzicha 2008 [15] 38 665 21 658 19.0% 1.79 [1.06, 3.02]Heterogeneity: Tau² = 0.06; Chi² = 12.20, df = 8 (P = 0.14); I² = 34%Test for overall effect: Z = 0.51 (P = 0.61)Kliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 10 of 13[30], which is associated with morbidity and mortality[31,32].In addition to their anti-inflammatory effects, combi-nation therapy results in greater bronchodilation thanthat achieved by the individual mono-components [13].However, the combined bronchodilatory effects ofinhaled corticosteroid/beta-2 agonists is no better thanthat achieved with tiotropium alone in COPD [15].Despite this, the combination therapy results in superiorhealth status, and reduced mortality compared withtiotropium alone [15], suggesting that mechanisms otherthan bronchodilation and lung deflation are involved inthe mortality benefits of combination therapy.There were limitations to the present study. We did nothave access to individualized data; thus, we could notadjust for potential confounders. However, to mitigateconfounding, we chose large randomized controlled tri-als, which were of high quality (Jadad Score of 3 orgreater) and had a reasonable duration of follow-up (6months or greater), detailed accounting of all randomizedpatients in the study and reported excellence balance interms of patient characteristics and clinical statusbetween the active treatment and comparator arms. Sec-ondly, there was some heterogeneity in the doses anddrugs that were evaluated across the trials. We addressedthis issue by grouping the studies together, stratifiedaccording to the drug formulation and dose and used aconservative method of pooling the data (i.e. a randomeffects model). Thirdly, we assessed total but not diseasespecific mortality. We did not evaluate disease specificmortality because assigning causality to deaths in COPDis problematic [11]. Moreover, certain drugs have beencific mortality alone. Fourthly, we did not evaluate theeffects of inhaled corticosteroids on total mortalitybecause recent studies have established that these drugsdo not impact on overall mortality and expert guidelinesin general do not recommend inhaled corticosteroids asstandalone therapies for COPD [13,33]. Fifthly, somerecent trials were performed on the background of bron-chodilators, inhaled corticosteroids or both, which mayhave diluted the possible mortality benefits of the drug inquestion. This may be of particular concern in the mostrecent tiotropium trial in which a majority of studypatients were taking ICS, LABA or both at the time ofrecruitment [35]. Additionally, none of the studiesincluded in this meta-analysis except for Calverley et al.' sstudy [13] was powered on mortality. As such, patientswith complex or life-threatening co-morbidities weregenerally excluded from these trials, which likely reducedthe statistical power of the present study and limited thegeneralizability of the findings to patients with multipleco-morbidities. Another important consideration was thedifferential drop-out rate between the active treatmentand the comparator arms of the study. Collectively, thepatients in the comparator arm were more likely to drop-out of the trials compared with those who were assignedto active treatment arm (38% versus 30%; p < .0001).Although the precise effects of differential drop-out rateare not fully known, it may have biased the results infavor of the comparator arm, as patients who drop out aregenerally sicker, less motivated and have poorer progno-sis than those who remain in the study [36].COPD is a worldwide epidemic affecting ~10% ofadults 40 years of age and older and accounting for moreFigure 7 The Effects of Tiotropium on Total Mortality Using Clinical Trials That Used Placebo or Ipratropium Bromide As The Main Compar-ator. Abbreviations: CI, confidence interval; ICS/LABA, inhaled corticosteroids/long-acting beta-2 agonist combination; M-H, Mantel-HanzelStudy Deaths Total Deaths Total Weight M-H, Random, 95% CITiotropium Placebo or Ipratropium Risk Ratio Risk RatioM-H, Random, 95% CIVolgelmeier 2008 [44] 0 221 1 209 0.2% 0.32 [0.01, 7.70]Brusasco 2003 [43] 1 402 5 400 0.3% 0.20 [0.02, 1.70]Tonnel 2008 [42] 3 266 6 288 0.8% 0.54 [0.14, 2.14]Vincken 2002 [14] 9 356 3 179 0.9% 1.51 [0.41, 5.50]Chan 2007 [40] 17 608 4 305 1.3% 2.13 [0.72, 6.28]Tashkin 2008 [35] 381 2987 411 3006 90.9% 0.93 [0.82, 1.06]Total (95% CI) 440 6804 456 6183 100.0% 0.94 [0.83, 1.06]0.1 0.2 0.5 1 2 5 10Favors tiotropium Favors controlCasaburi 2002 [39] 7 550 7 371 1.4% 0.67 [0.24, 1.91]Niewoehner 2005 [41] 22 914 19 915 4.2% 1.16 [0.63, 2.13]Heterogeneity: Tau² = 0.00; Chi² = 6.67, df = 7 (P = 0.46); I² = 0%Test for overall effect: Z = 0.97 (P = 0.33)associated with increased risk of non-COPD relatedhealth events such as pneumonia [33] and stroke [34],which could have been missed by focusing on COPD-spe-than 3 million deaths annually. In China alone, there willbe nearly 1.5 million deaths this year from COPD [37].Discouragingly, over the next 20 years, the worldwideKliber et al. Respiratory Research 2010, 11:56http://respiratory-research.com/content/11/1/56Page 11 of 13mortality from COPD will double [38]. The totality ofdata from many large, randomized clinical trials indicatesthat the combination of inhaled corticosteroids and long-acting beta-2 agonists prolongs survival in COPD butlong-acting beta-2 agonists and tiotropium by themselvesdo not. The survival effect, however, is fairly modest andsuggests a pressing need for additional pharmacothera-pies that can reduce the overall mortality in COPD, whichin less than 10 years will be the 3rd leading cause of deathworldwide.Additional materialAbbreviationsBUD/F: budesonide/formoterol combination; CI: confidence interval; COPD:chronic obstructive pulmonary disease; ICS: inhaled corticosteroid; LABA: long-acting beta-2 agonist; M-H: Mantel-Hanzel; QUOROM: quality of reporting ofmeta-analyses; RR: relative risk; SALM: salmeterol; SFC: salmeterol/fluticasonecombination; TORCH: TOwards a Revolution in COPD Health; UPLIFT: Under-standing Potential Long-Term Impacts on Function with TiotropiumCompeting interestsAK: none to declareLDL has grant-in-aid from AstraZenecaDDS has received honoraria for speaking engagements from GlaxoSmithKline(GSK), AstraZeneca (AZ) and Pfizer, and research funding from GSK, AZ, WyethPharmaceuticals, Boehringer Ingelheim, and Pfizer over the last 3 years.Authors' contributionsDDS conceived the idea, designed the study, acquired the primary data, per-formed the statistical analysis and wrote the paper.AK acquired the primary data and wrote the paperLDL participated in the study design, assisted on the statistical analysis, andedited the paper.All authors have read and approved the final manuscript.AcknowledgementsThis project is supported by the Michael Smith Foundation for Health ResearchDDS is a Canada Research Chair in COPD and a senior scholar with the Michael Smith Foundation for Health Research (MSFHR) and LL is a New Investigator with CIHR and a scholar with the MSFHR.Author Details1Department of Medicine (Respiratory Division), University of British Columbia, 6040 Iona Drive, Vancouver, V6T 2E8, Canada, 2Faculty of Pharmaceutical Sciences, University of British Columbia, 6040 Iona Drive, Vancouver, V6T 2E8, Canada, 3Providence Heart and Lung Institute, St. Paul's Hospital, 1081 Burrard Street, Vancouver, Canada, V6Z 1Y6 and 4James Hogg Research Laboratories, 1081 Burrard Street, Vancouver, British Columbia, Canada, V6Z 1Y6References1. 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