UBC Faculty Research and Publications

Effect of beta-blockers on exacerbation rate and lung function in chronic obstructive pulmonary disease… Duffy, Sean; Marron, Robert; Voelker, Helen; Albert, Richard; Connett, John; Bailey, William; Casaburi, Richard; Cooper, J. A; Curtis, Jeffrey L; Dransfield, Mark; Han, MeiLan K; Make, Barry; Marchetti, Nathaniel; Martinez, Fernando; Lazarus, Stephen; Niewoehner, Dennis; Scanlon, Paul D; Sciurba, Frank; Scharf, Steven; Reed, Robert M; Washko, George; Woodruff, Prescott; McEvoy, Charlene; Aaron, Shawn; Sin, Don; Criner, Gerard J Jun 19, 2017

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RESEARCH Open AccessEffect of beta-blockers on exacerbation rateand lung function in chronic obstructivepulmonary disease (COPD)Sean Duffy1,18*, Robert Marron1, Helen Voelker2, Richard Albert3, John Connett2, William Bailey4, Richard Casaburi5,J. Allen Cooper Jr.4, Jeffrey L. Curtis6, Mark Dransfield4, MeiLan K. Han6, Barry Make7, Nathaniel Marchetti1,Fernando Martinez8, Stephen Lazarus9, Dennis Niewoehner10, Paul D. Scanlon11, Frank Sciurba12, Steven Scharf13,Robert M. Reed13, George Washko14, Prescott Woodruff9, Charlene McEvoy15, Shawn Aaron16, Don Sin17,Gerard J. Criner1 and the NIH COPD Clinical Research Network and the Canadian Institutes of Health ResearchAbstractBackground: Beta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have beenwary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern forbronchospasm, but retrospective studies have shown that cardio-selective beta-blockers are safe in COPD andpossibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of themedication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbationrates and longitudinal measures of lung function in two well-characterized COPD cohorts.Methods: We retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPEtrial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primaryendpoints were exacerbation rates per person-year and change in spirometry over time in association withbeta blocker use.Results: Overall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statisticallysignificant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiaccomorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versusa rate of 1.71/person-year in patients not taking beta-blockers. In the STATCOPE cohort, patients taking beta-blockershad an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time.Conclusion: We found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomesin study participants with moderate to severe COPD.Keywords: COPD, Exacerbation, Beta-blocker* Correspondence: sean.duffy2@tuhs.temple.edu1Department of Thoracic Medicine and Surgery, Lewis Katz School ofMedicine at Temple University, Philadelphia, PA, USA18Department of Thoracic Medicine and Surgery, Temple University School ofMedicine, 712 Parkinson Pavilion, 3401 North Broad Street, Philadelphia, PA19140, USAFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Duffy et al. Respiratory Research  (2017) 18:124 DOI 10.1186/s12931-017-0609-7BackgroundChronic Obstructive Pulmonary Disease (COPD) is aprogressive and debilitating disease that burdens thehealthcare system with frequent office visits andhospitalizations. In recent years, studies have exam-ined both traditional treatments for COPD (long act-ing beta agonists, long acting muscarinic antagonists,and inhaled corticosteroids) [1, 2] as well as drugsusually reserved for cardiovascular disease or infection(statins and azithromycin) [3, 4] with respect to theirefficacy in reducing acute exacerbations of COPD(AECOPD).Beta-blockers are regularly prescribed in patientswith cardiovascular disease, a common comorbidity inpatients with COPD. Providers have historically beenreluctant to treat COPD patients with beta-blockersdue to a concern for precipitating bronchospasm.These concerns have been expressed in review articlesand practice guidelines that cited case studies of acutebronchospasm in patients treated with non-selectivebeta blockers [5, 6]. Cardioselective beta-blockers (orbeta-1-blockers) have a 20 fold greater affinity for β-1receptors and less theoretical risk for bronchocon-striction. Within the last decade, studies havehighlighted concern for the use of beta-blockers inpatients with COPD [6, 7]; however, Cochrane Re-views in 2005 and 2010 concluded that cardioselectivebeta blocker use in patients with COPD had nosignificant adverse effects on FEV1, respiratorysymptoms, or responsiveness to beta-agonist inhaledtherapy. Sub-group analysis extended this to patients withsevere obstruction as well as those with bronchodilatorreversibility demonstrated on spirometry [8].Multiple retrospective studies have suggested that beta-blockers may reduce the mortality of patients with COPDas well as the risk of AECOPD [9, 10]. Mortality as anendpoint in studies linking COPD and beta-blockers isconfounded by difficulty determining whether the benefitof the drug is related to its effects on the lung or oncoexistent cardiovascular disease [11, 12]. Examining therelationship between beta-blocker use, serial spirometryand rates of AECOPD may provide a more useful depic-tion of the effect of these medications on lung disease.The COPD Clinical Research Network has conductedseveral randomized, placebo-controlled prospective trialsin study participants with COPD assessing rates ofAECOPD.The STATCOPE study showed no benefit attributableto daily simvastatin, whereas theMACRO trial demonstrated reduced rates of AECOPDwith azithromycin treatment [3, 4]. The STATCOPEcohort and the placebo arm of MACRO provide aunique opportunity to analyze the effect of beta-blockerson AECOPD in a group of COPD patients with a fairlyhigh prevalence of cardiovascular comorbidities (MACRO)as compared with a group in which cardiovascular comor-bidities were mostly excluded (STATCOPE). Given thatbeta-blockers are likely to have a greater impact on patientswith cardiovascular disease, we hypothesized that beta-blockers would associate with lower rates of COPD exacer-bation in the MACRO cohort when compared to theSTATCOPE cohort due to a higher burden of underlyingcardiovascular comorbidity. That is to say, a populationwith a higher prevalence of cardiac comorbidities may havea greater symptomatic benefit from treatment with beta-blockers when compared with a population with little or nocardiac comorbid disease.MethodsPatient populationWe performed a retrospective review of 1219 study par-ticipants who had at least 180 days of follow up fromthe STATCOPE trial or the placebo arm of the MACROtrial. Entry criteria for the MACRO trial included havinga ratio of forced expiratory volume in one second toforced vital capacity (FEV1/FVC) < 70% and being athigh risk for experiencing an AECOPD as a result ofusing supplemental oxygen, or being treated with oralglucocorticoids, antibiotics or being hospitalized in theprevious year for an AECOPD. Patients also had noexacerbation within 4 weeks of enrollment 4. Patients inthe azithromycin treatment arm of the MACRO studywere excluded due to the significant treatment effect ofazithromycin on reducing exacerbation rate. The STAT-COPE trial had similar inclusion criteria, but excludedpatients who were taking a statin, had contraindicationto the use of statins or who were found to have an indi-cation for statin therapy [3]. In both the MACRO andSTATCOPE studies exacerbations were defined as “acomplex of respiratory symptoms (increased or newonset) of more than one of the following: cough,sputum, wheezing, dyspnea, or chest tightness with aduration of at least 3 days requiring treatment with anti-biotics or systemic steroids.”SpirometrySpirometry was obtained at enrollment and at completionof the study. Each cohort’s spirometric data were analyzedfor significant changes over time. The MACRO cohorthad spirometry performed at enrollment then at either 6or 12 months. The STATCOPE cohort had spirometry atenrollment then at 12 or 24 months.StatisticsThe primary study endpoint was rate of acute exacerba-tion of COPD in each of the four study groups; MACROon beta-blocker, MACRO off beta-blocker, STATCOPEon beta-blocker and STATCOPE off beta-blocker. COPDDuffy et al. Respiratory Research  (2017) 18:124 Page 2 of 7exacerbation rates were compared with the use of anevent rate ratio; i.e., the number of exacerbations perpatient year. Additionally, changes in spirometric datawere analyzed over time for each of the four studygroups. P-values for mean rate of decline were computedby t-test. Exacerbation rates were compared among thegroups using SAS data analysis software.ResultsOf the 1219 participants included in our study, 170(13.9%) reported taking beta-blockers at enrollment. Inthe STATCOPE cohort 63 of 688 (9.2%) participantswere taking beta-blockers along with 107 of 531 (20.2%)in the MACRO placebo arm. The majority of partici-pants in the study had severe or very severe airflowobstruction classified as GOLD stage III or IV. Thosetaking beta-blockers tended to have a slightly higherFEV1, however we found no statistically significant dif-ference between the groups with respect to demographiccharacteristics, smoking history or spirometric data(Table 1). As expected, the patients in STATCOPE had asignificantly decreased rate of cardiac comorbidities ascompared with the MACRO cohort (Table 2). Given thedisparity in cardiac comorbidities, the vast majority ofpatients on beta-blockers in the STATCOPE cohortappeared to be taking the medication for hypertensionrather than coronary artery disease (CAD) or a historyof myocardial infarction (MI); whereas, a significantpercentage in the MACRO cohort was taking themedication for CAD or MI (Table 2).Patients in the STATCOPE cohort taking beta-blockers had the lowest rate of AECOPD (1.14/per-son-year, 95% CI = 0.81–1.46), followed by patients inSTATCOPE not taking beta-blockers (1.34/person-year, 95% CI = 1.22–1.46). In the MACRO cohort therate of AECOPD was higher when compared withSTATCOPE, but nearly identical with respect to beta-blocker usage within the cohort (Table 3). We foundno statistically significant difference between patientstaking beta-blockers and the corresponding cohort offbeta-blockers.Table 1 Demographics, smoking history and spirometry. No statistically significant difference between study groups in within eachtrialMacro -BB Macro + BB Statcope -BB Statcope + BBN 469 110 625 63Age - years (SD) 64.6 (8.6) 67.3 (8.0) 62 (8.51) 63.4 (7.9)Men - N (%) 273 (58.2%) 75 (67.6%) 349 (55.8%) 35 (55.6%)Race% Black 16.8 11.7 20.3 25.4% White 79.5 82.9 77.1 73Smoking HistoryPack years - mean (SD) 59.7 (33.7) 59.4 (28.5) 50.0 (26.3)* 49.1 (28.9)Current Smoker - % 22.4 21.6 30.6* 34.9Spirometry - %GOLD 2 21.8 44.1 34.3 38.1GOLD 3 42.4 36 33.9 34.9GOLD 4 35.8 19.8 31.8 27FEV1 - Liters (SD) 1.09 (0.51) 1.31 (0.52) 1.20 (0.57)* 1.30 (0.62)FEV1 - mean % predicted value 38.3 46.8 41.8* 45.8FVC - Liters (SD) 2.61 (0.89) 2.81 (0.79) 2.68 (0.92) 2.65 (0.95)FVC - % predicted value 69.4 74.6 70.7 70.3FEV1/FVC 41.8 46.8 44.6 48.8Chronic Bronchitis - % 44.8 50.5 48.9 52.5* - p < 0.05 when compared with corresponding subgroup MACRO cohortTable 2 Percent of patients self-reporting comorbid conditionsby study groupMacro -BB Macro + BB Statcope -BB Statcope + BBN 424 107 625 63Hypertension 193 (46%) 88 (82%) 180 (29%)* 53 (84%)Diabetes 49 (12%) 25 (23%) 21 (3%)* 3 (5%)*CAD 54 (13%) 53 (50%) 12 (2%)* 2 (3%)*MI 40 (9%) 38 (36%) 5 (1%)* 3 (5%)** - p < 0.05 when compared with corresponding subgroup MACRO cohortDuffy et al. Respiratory Research  (2017) 18:124 Page 3 of 7Percent of subjects free of exacerbation over time isdepicted in Fig. 1. In both the MACRO and STATCOPEcohorts, the patients taking beta-blockers had a higherpercentage of patients free of exacerbation though thisdifference did not reach statistical significance in eithergroup. Of note, there was no patient dropout during thisperiod as all patients had at least 180 days of follow up.Additionally, we studied the change in spirometricdata over time for all patients (1063/1219, 87.2%) whohad follow-up spirometry. The data shows that thepresence of beta-blocker medications had no clinicallyor statistically significant effect on the change in airflowlimitation in this cohort.DiscussionWe found no harmful effect of beta-blockers withrespect to change in FEV1 over time and no statisticallysignificant difference in the rate of acute exacerbation ofCOPD in an at-risk population, regardless of thepresence of cardiac comorbidity.Other retrospective studies have shown beta-blockersto be beneficial in patients with COPD but those obser-vations may represent cardiovascular benefits of beta-blockers rather than pulmonary specific improvementsin COPD symptoms or severity.One recent Swedish nationwide observational studyconcluded that patients with COPD discharged on abeta-blocker after an MI had a lower all-cause mortalitycompared with those not discharged on a beta-blocker[13]. However, a large retrospective study showed thatpatients with severe COPD or asthma had no mortalitybenefit from taking beta-blockers after MI [14]. Morta-lity has been shown to be improved in COPD patientsspecifically taking beta-blockers as monotherapy forhypertension [15]. The reduced prevalence of cardiaccomorbidity in the STATCOPE cohort provided anopportunity to compare the effectiveness of beta-blockers in a COPD population with (MACRO) andwithout (STATCOPE) self-reported cardiac disease. Wefound no significant difference in rates of AECOPD withrespect to beta-blocker use in the cohort with increasedcardiac comorbidities. However, there was a slightlylower rate of AECOPD in the patients taking beta-blockers in the STATCOPE cohort and the percent freeof exacerbation at 90 and 180 days was higher in pa-tients taking beta-blockers in each cohort. Our inabilityto detect a statistically significant difference betweenpatients with versus without cardiac disease may be aresult of the relatively low number of patients who weretaking beta-blockers and reported cardiac comorbidi-ties. Importantly, we did find that COPD patientstaking beta-blocker medications did no worse with re-spect to exacerbation or change in spirometry over arelatively long follow up period when compared withpatients who were not taking beta-blockers (Table 4).In accordance with prior studies [13–16], this findingprovides further proof that beta-blockers are safe touse in COPD patients.Proposed mechanisms by which beta-blockers mayhave an effect on the COPD process and potentiallydecrease exacerbation frequency include reduction ofischemic burden and tempering the sympathetic nervoussystem. COPD has been associated with systemicTable 3 AECOPD per person year by study groupStatcope N Exacerbation rate per person-year(95% CI)+BB 63 1.14 (0.81,1.46)−BB 625 1.34 (1.22,1.46)Macro+BB 107 1.72 (1.37,2.08)−BB 424 1.71 (1.53,1.88)ABFig. 1 Panel (a) - Percent free of exacerbation by beta-blocker use inthe Macro placebo arm at 0, 30, 60, 90 and 180 days. Panel (b) –Percent free of exacerbation by beta-blocker use in theSTATCOPE trialDuffy et al. Respiratory Research  (2017) 18:124 Page 4 of 7inflammation, and it has been proposed that the negativeeffects of neurohumoral activation (such as inflamma-tion, cachexia) can contribute to the cycle of COPD ex-acerbation and pathophysiology. Beta blockadetheoretically could have an impact on neuro-humoral ac-tivation and COPD. [17] In addition, animal models haveshown that beta-blockers given chronically can increasethe density of beta-receptors and reduce airway respon-siveness in mice with asthma [18]. Those on beta-blockers may have had more effective blood pressurecontrol and a reduction in complications of less opti-mally treated diastolic dysfunction which has beenlinked to the development of acute exacerbations [19].Other observational studies have shown conflicting re-sults. For instance, Bhatt and colleagues evaluated a co-hort of over 3000 patients from the COPDGene cohortand found that patients taking beta-blockers had a de-creased incidence on AECOPD. This association heldtrue for severe exacerbations as well as mild to moderateexacerbations [20]. Short et.al. performed a retrospectivereview of COPD patients on and off beta-blockers andshowed that patients taking beta-blockers had lowerrates of AECOPD and mortality regardless of the inhaledpulmonary medication regimen in each group [21].However, in both of these trials, patients had lesssevere airflow obstruction in comparison to our popu-lation (Table 5). Our inability to find a significant ef-fect of beta-blockers may be secondary to the severityof COPD in this cohort. These patients were enrolleddue to an increased risk for COPD exacerbation andhad relatively severe obstruction on spirometry. Thishigh burden of respiratory disease may overshadowthe relatively lesser burden of cardiovascular diseasein this population. We also found a high prevalenceof chronic bronchitis in each cohort, which was notreported in the other studies, but may have influ-enced the rate of exacerbation and limited the efficacyof beta-blocker therapy.Additionally, the expected outcome of beta-blockershaving a greater effect on the cohort with cardiacTable 4 Change in spirometry over time with respect to beta-blocker useStatcope ΔFEV1 in mL (SD) Δ %FEV1 (SD) Δ FVC in mL (SD) Δ %FVC (SD)+BB (N = 54) −13.1 (268.8) 0.33 (9.7) −21.7 (382.9) 0.59 (10.2)−BB (N = 531) −53.9 (241.3) −1.24 (8.96) −88.8 (444.4) −1.43 (12)P- value 0.29 0.25 0.23 0.18Macro+ BB (N = 96) −13.9 (233.9) −0.55 (8.61) n/a −0.52 (12.3)−BB (N = 381) −12.7 (196) −0.31 (6.5) n/a −0.47 (12.4)P- value 0.96 0.76 0.97n/a not included as data reported for only 4 participantsTable 5 Demographic comparison of retrospective studies on beta-blocker use in COPDStudy Bhattet al. [20]Ruttenet al. [11]Shortet al. [21]Van Gestelet al. [16]Current StudyMACRO4 STATCOPE3N (on Beta blockers) 474 665 796 462 110 63Age 66.8 64.7 69.8 69 67.3 63.4% Men 60.1% 49.8% 42.7% 82.0% 67.6% 55.6%Mean Pack years 56.8 n/a 44.3 n/a 59.4 49.1% Current Smoker n/a 34.6% n/a 35.0% 21.6% 34.9%FEV1 (L) 1.5 n/a n/a n/a 1.31 1.3FEV1 mean % predicted 53.2% n/a 65% n/a 46.8% 45.8%% GOLD 3/4 38.4% n/a n/a n/a 55.8% 61.9%%Chronic bronchitis n/a n/a n/a n/a 50.5% 52.5%% CAD or revasc 44.7% 38.3% (IHD) 70% (CV dz) 25% 50% 3%% Diabetes 24.1% 24.1% 21% 17% 23% 5%% Hypertension 84.4% 66.8% n/a 49% 82% 84%% History of MI n/a 9.6% n/a 33% 38% 5%n/a data not availableDuffy et al. Respiratory Research  (2017) 18:124 Page 5 of 7comorbidity (MACRO) may not have been present dueto baseline differences in the two groups. The MACROcohort on beta-blockers trended to be an older popula-tion, with an increased number of pack-years which maybe reflective of a sicker patient population when com-pared with the STATCOPE cohort on beta-blockers(Table 1).Study limitationsThe relatively low number of patients taking beta-blockersat enrollment in these studies limited our ability to show astatistically significant difference between the groups withrespect to demographic and baseline spirometry (Table 1).Medications and comorbidities were self-reported by thepatients at enrollment. Information regarding dosage andspecific type of beta-blocker (i.e. beta-1 selective or nonse-lective) medication was not available. Though there is in-herent weakness in the design of all retrospective analyses,the data presented are derived from well-constructed,prospective, large multicenter trials. Despite the limita-tions, our study is the first to compare the efficacy ofbeta-blockers in a COPD population with higher versuslower prevalence of cardiac comorbidities.ConclusionWe found no evidence that beta-blockers significantlyaffected the rate of AECOPD regardless of whether thepatients did or did not report cardiac comorbidities. Wedid find that beta-blockers had no detrimental effect onlung function in a population that was at increased riskfor AECOPD. Because previous observational studieshave reported conflicting data, the question will requirea large, prospective and randomized trial to determinethe benefits of beta-blocker therapy in COPD patients.AcknowledgementsNot ApplicableFundingAs a retrospective review, no additional funding was required as it pertainsto this manuscript. Original data collection funded as noted in MACRO4 andSTATCOPE3 trials.Availability of data and materialsData is from the cohorts from STATCOPE and MACRO trials.Authors’ contributionsConcept and design, data interpretation, writing of manuscript, revision ofmanuscript: SD, RM, GJC. Data Analysis and interpretation: HV, JC. Originaldata collection and revision of manuscript: RA, WB, RC, JAC, JLC, MD, MKH,BM, NM, FM, SL, DN, PDS, FS, SS,RMR, GW, PW, CM, SA, DS. All authors readand approved the final manuscript.Competing interestsSean Duffy, MD- NoneRobert Marron, MD- NoneHelen Voelker, BA- NoneRichard Albert, MD- No financial considerations for this manuscript. Hehas acted as a consultant for Gilead Sciences and provided experttestimony for the Bruce Fagel Law Firm in Beverly Hills, CA. He has apatent pending for a bed head elevation monitor. He has receivedroyalties for book editing for Elsevier.John Connett, PhD- No financial considerations for this manuscript. He hasbeen awarded NHLBI-Lung division, NCI, and NIAID grants for other work. Heis or has been a board member for NHLBI and NEI.William Bailey, MD- NoneRichard Casaburi, MD, PhD- No financial considerations for thismanuscript. He has been compensated as an Advisory board memberfor Novartis Pharma and Forest Pharma. He has been compensated as aconsultant for Theratechnologies, Inc, Breathe Technologies, MedtronicInc. Spinal and Biologics, Boehringer-Ingelheim, Respironics Inc, NovartisPharma, Actelion Pharma. His institution has been awarded grants byNovartis Pharma, Roche Pharma, Boehringer-Ingelheim Pharma, OsirisPharma, Forest Pharma, Glaxo SmithKline Pharma, Breathe Technologies,and Theratechnologies Inc. He has been compensated as a speaker byBoehringer-Ingelheim Pharma, Astra Zeneca Pharma, and Pfizer Pharma.He has Stock or Stock options in Inogen, Inc.J Allen Cooper, Jr, MD- No financial considerations for this manuscript. Hehas received a grant from Glaxo SmithKline and Novartis for work notassociated with this manuscript. He has provided expert testimony formultiple law firms in malpractice cases and occupational lung disease cases.Jefferey L. Curtis, MD- No financial considerations for this manuscript. He hasreceived a grant to his institution from Boehringer-Ingelheim.Mark Dransfield, MD- No financial considerations for this manuscript. He hasreceived NIH grants to his institution in the past. He has been compensatedas a consultant by Glaxo SmithKline, Boehringer Ingelheim, and Forest. Hehas received grants or has them pending from GSK, Boehringer Ingelheim,NIH, Boston Scientific. He has been compensated for lectures by GSK andBoehringer Ingelheim.MeiLan K. Han, MD- No financial considerations for this manuscript. Hasreceived a grant from NHLBI in the past to their institution. Has beencompensated as a board member by CSL Behring, Glaxo SmithKline, andBoehringer Ingelheim. Has been compensated as a consultant byGenentech and Novartis. Has received or has grants pending from LAMFoundation, NHLBI, Chicago Community Trust to their institution. Hasreceived payment for lectures from GSK, CSL Behring, BoehringerIngelheim, Pfizer, National Association for Continuing Education. Hasreceived royalties from UpToDate and payment for the development ofeducational presentations from the National Association for ContinuingEducation. Has received compensation for travel expenses from AstraZeneca when attending a COPD symposium.Barry Make, MD- No financial considerations for this manuscript. Hasreceived a grant to his institution from NIH-NHLBI in the past andreceived compensation for travel for study design and implementation.Has been compensated as a board member by Forest, Astra Zeneca,Novartis, Dey, Nycomed, Respironics, Schering, Sequal, Embryon,Boehringer-Ingelheim, Pfizer, and Glaxo SmithKline. Has beencompensated as a consultant by Astellas, Talecris, and Chiesi. Hasreceived a grant or has one pending to his institution from AstraZeneca, GSK, Pfizer, NABI, Boehringer-Ingelheim, and Sunovian. Hasreceived compensation or lectures by GSK, Boehringer-Ingelheim, Pfizer,Forest, and Astra Zeneca. Has received compensation from Boehringer-Ingelheim and Pfizer for video presentations. His institution has receivedcompensation from Spiration for review of documents related to a clinical trial.Nathaniel Marchetti, DO- No financial consideration for this manuscript. Hasreceived a grant to his institution from NHLBI for past work and beencompensated for relevant travel.Fernando Martinez, MD- No financial consideration for this manuscript. Hasreceived a NIH grant to his institution in the past. Has received compensationas a board member by Glaxo SmithKline, MedImmune/Astra Zeneca, Merck,Pearl, Novartis, UBC, MPex, and Ikaria. Has worked as a consultant and beencompensated by Forest/Almirall, Boehringer Ingelheim, Nycomed/Forest,Roche, Bayer, Schering, HLS, Talecris, Comgenix, fb Communications,BoomComm, Actelion, Elan, Genzyme, Quark, Merck, Pfizer, and Sanofi-Aventis.Has received grants or has them pending to himself or his institution fromBoehringer Ingelheim, Gilead, Johnson & Johnson/Centocor, Actelion, GSK,NACE, MedEd, Potomac, Pfizer, Schering, Vox Medic, American Lung Association,WebMD, ePocrates, Astra Zeneca, France Foundation, and Altana/Nycomed. Hasreceived book royalties from Associates in Medical Marketing and CastleConnolly. Has received payment for the development of educationalpresentations by HIT Global, UpToDate, and the France Foundation.Duffy et al. Respiratory Research  (2017) 18:124 Page 6 of 7Stephen Lazrus, MD- No financial considerations for this manuscript. Hasreceived a grant from NIH-NHLBI for a past study and has received compensationfor travel expenses to travel to CCRN Steering Meetings.Dennis Niewoehner, MD- No financial consideration for this manuscript. Inthe past his institution has been awarded an NHLBI grant. Has beencompensated as a consultant by Boehringer Ingelheim, Astra Zeneca, GlaxoSmithKline, Forest Research, Merck, Sanofi Aventis, Bayer Schering, Nycomed,Protaffin, and Pfizer.Paul D. Scanlon, MD- No financial consideration for this manuscript. In the pasthas received institutional NHLBI grants and travel compensation. Has alsoreceived institutional grants from Dept. of Energy, Altana, Boehringer Ingelheim,Dey L.P. Pharmaceutical, Forest, Glaxo SmithKline, Novartis AG, and Pfizer. Hasreceived royalties from Lippincott, Williams & Wilkins/Wolters Kluwer.Frank Sciurba, MD- No relevant disclosures in 36 months prior to thesubmission of this manuscript.Stephen Scharf, MD- No financial consideration for this manuscript. Hasreceived an NIH grant to his institution, as well as NIH travel compensationand payment from the NIH for writing or reviewing of a manuscript.Robert M. Reed, MD- NoneGeorge Washko, MD- No financial consideration for this manuscript. He hasbeen compensated as consultant by MedImmune and Spiration.Prescott Woodruff, MD, MPH- No financial consideration for this manuscript.Has been compensated as a consultant by MedImmune. Has received aninstitutional grant from Genentech. Has a patent or a patent pending for anasthma biomarker.Charlene McEvoy, MD, MPH- No financial consideration for this manuscript.Has received a grant and travel expenses reimbursement by the NHLBI inthe past. Has received and institutional grant from NHLBI, Boston Scientific,COPD Foundation, and Glaxo SmithKline. Has received speaking fees fromBoehringer Ingelheim and Glaxo SmithKline.Shawn Aaron, MD- NoneDon Sin, MD, MPH- No financial considerations for this manuscript. In thepast 36 months he has received grants from Astra Zeneca, Merck, andBoehringer Ingelheim.Gerard J. Criner, MD-No financial considerations for this manuscript. He hasbeen awarded a grant for his institution from the NHLBI for other work.Other grants from Boehringer-Ingelheim, Novartis, Astra Zeneca. He hasreceived royalties from Springer for a book publication.Consent for publicationNot ApplicableEthics approval and consent to participateIRB approval for this retrospective data review in accordance with COPDClinical research network.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Thoracic Medicine and Surgery, Lewis Katz School ofMedicine at Temple University, Philadelphia, PA, USA. 2University ofMinnesota, Minneapolis, MN, USA. 3Denver Health Medical Center, Denver,CO, USA. 4University of Alabama at Birmingham, Birmingham, AL, USA. 5LosAngeles Biomedical Research Institute at Harbor-UCLA Medical Center,Torrance, CA, USA. 6University of Michigan Health System, Ann Arbor, MI,USA. 7National Jewish Health, Denver, CO, USA. 8Weill Cornell MedicalCollege of Cornell University, New York, NY, USA. 9Univ of California SanFrancisco, San Francisco, CA, USA. 10Minneapolis VA Medical Center,Minneapolis, MN, USA. 11Mayo Clinic, Rochester, MN, USA. 12University ofPittsburgh Medical Center, Pittsburgh, PA, USA. 13University of Maryland,Baltimore, MD, USA. 14Brigham & Women’s Hospital, Boston, MA, USA.15HealthPartners, Saint Paul, MN, USA. 16The Ottawa Hospital ResearchInstitute, Ottawa, ON, Canada. 17Providence Heart + Lung Institute,Vancouver, BC, Canada. 18Department of Thoracic Medicine and Surgery,Temple University School of Medicine, 712 Parkinson Pavilion, 3401 NorthBroad Street, Philadelphia, PA 19140, USA.Received: 3 February 2017 Accepted: 12 June 2017References1. 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Impact of cardioselective b-blockers on mortality in patients with chronic obstructive pulmonarydisease and atherosclerosis. Am J Respir Crit Care Med. 2008;178:695–700.17. Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohumoral activationas a link to systemic manifestations of chronic lung disease. Chest.2005;128(5):3618–24.18. Callaerts-Vegh Z, Evans KL, Dudekula N, et al. Effects of acute and chronicadministration of beta-adrenoceptor ligands on airway function in a murinemodel of asthma. Proc Natl Acad Sci U S A. 2004;101:4948–53.19. Abusiad GH, Barbagelata A, Tuero E, et al. Diastolic dysfunction and COPDexacerbation. Postgrad Med. 2009;121(4):76–81.20. Bhatt SP, Wells JM, Kinney GL, et al. β-Blockers are associated with areduction in COPD Exacerbations. Thorax. Published Online First: [August 17,2015] doi:10.1136/thoraxjnl-2015–207251.21. Short PM, Lipworth SI, Elder DH, et al. Effect of beta blockers in treatment ofchronic obstructive pulmonary disease: a retrospective cohort study. BMJ.2011;342:d2 549.Duffy et al. Respiratory Research  (2017) 18:124 Page 7 of 7


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