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Beta-blocker use and COPD mortality: a systematic review and meta-analysis Etminan, Mahyar; Jafari, Siavash; Carleton, Bruce; FitzGerald, John M Sep 4, 2012

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RESEARCH ARTICLE Open AccessBeta-blocker use and COPD mortality: asystematic review and meta-analysisMahyar Etminan1,2,3,7*, Siavash Jafari4, Bruce Carleton1,2,5,6 and John Mark FitzGerald3,4AbstractBackground: Despite the benefits of beta-blockers in patients with established or sub-clinical coronary arterydisease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial. Currently,no systematic review has examined the impact of beta-blockers on mortality in COPD.Methods: We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and CochraneLibrary for clinical studies that examine the association between beta-blocker use and all cause mortality in patientswith COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative riskacross studies. Publication bias was assessed using a funnel plot.Results: Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooledrelative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%).Conclusion: The results of this review are consistent with a protective effect of beta-blockers with respect to allcause mortality. Due to the observational nature of the included studies, the possibility of confounding that mayhave affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit inCOPD needs to be evaluated in randomised controlled trials.Keywords: Beta-blockers, COPD, MortalityBackgroundBeta-blockers are one of the most prescribed classes ofcardiovascular medications. In clinical trials they havebeen shown to lower morbidity and mortality secondaryto congestive heart failure [1] (CHF) and coronary arterydisease (CAD) [2]. Chronic Obstructive Pulmonary Dis-ease (COPD) is a progressive debilitating lung diseaseand currently the third leading cause of death in NorthAmerica [3]. Many patients with COPD also have con-comitant CAD. There has been uncertainty with regardto using beta-blockers in COPD patients mainly becauseof concerns that they might induce bronchospasm andworsen lung function [4], especially in those patientswho have a combination of asthma and COPD.Despite these concerns, there is emerging evidencethat beta-blockers may be beneficial in patients withCOPD [5,6]. In one systematic review of 19 randomisedcontrolled trials that included patients with both asthmaand COPD, beta-blockers lowered FEV1 by 7.46% (95%CI, 5.59%-9.32%) [4]. Results from this meta-analysisprompted guidelines to recommend the use of low dosebeta-blockers in COPD patients [7].Recent studies have also shown that beta-blockers maylower mortality in COPD patients [8,9]. This potentialbenefit may arise from a possible protective effect of beta-blockers in patients with established CAD in whom thesedrugs may be underused. Beta-blockers may also be bene-ficial in patients with CAD and overlapping CHF. Finally,similar to statins, beta-blockers, especially cardio-selectivebeta-blockers such as carvedilol, may exert pleiotropiceffects including antioxidant and alpha-adrenorecptorblocking properties [10]. As of to date, no systematic re-view specifically addressing mortality benefit with beta-blockers in COPD patients has been conducted. Wesought to address these questions with respect to a* Correspondence: metminan@popi.ubc.ca1Therapeutic Evaluation Unit, British Columbia Provincial Health ServicesAuthority, Vancouver, Canada2Child & Family Research Institute, University of British Columbia, Vancouver,CanadaFull list of author information is available at the end of the article© 2012 Etminan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Etminan et al. BMC Pulmonary Medicine 2012, 12:48http://www.biomedcentral.com/1471-2466/12/48clinically important outcome mainly all cause mortality byundertaking a systematic review and meta-analysis.MethodsSearch strategyWe searched the following databases to identify pertin-ent studies that examined the association between beta-blockers and all cause mortality: MEDLINE (1966 toMarch 2012), EMBASE (1980 to March 2012), CochraneCentral Register of Controlled Trials (1991 to March2012), Database of Abstracts of Reviews of Effects (1991to March 2012), ACP Journal Club (1991 to March2012), International Pharmaceutical Index (1970 toMarch 2012), BIOSIS Previews (1969 to March 2012)and Web of Science (1961 to March 2012). The initialsearch strategy was developed from the following MeSHsubject headings COPD, Acebutolol, Atenolol, Betaxolol,Bisoprolol, Celiprolol, Esmolol, Metoprolol, Alprenolol,Bucindolol, Carteolol, Carvedilol, Labetalol, Nadolol,Penbutolol, Pindolol, Propranolol, Sotalol, Timolol, adre-nergics, and Beta-blockers in MEDLINE. We reviewedtitles for relevance from this search and examined allsubject headings and abstracts. The scope notes inMEDLINE and EMBASE were also examined to ensurethe correct subject headings were used based on theirdefinitions; other subject headings were included basedon previous indexing and the inclusion of keywordsbased on synonyms used in the scope notes. Proceedingsand conference abstracts were searched through thedatabases PapersFirst (1993) and ProceedingsFirst (1993)up to March 2012. Authors’ names and year of pub-lished work from key papers were entered into the citedreference search in the Web of Science. We screenedthe references of retrieved studies and review articles forany potentially missed articles. In addition, we handsearched the reference lists of retrieved studies as well asjournals related to “pharmacology”, “respirology”, pul-monary”, abstracts and books related to respiratory orlung diseases. There was no language restriction inselecting the studies.Selection criteriaWe considered all experimental or observational studiesthat assessed the association between beta-blocker useand mortality in COPD patients. Studies were includedif they 1) clearly defined COPD as either primary or sec-ondary outcomes; 2) clearly defined beta-blocker use aseither a primary exposure in the study or used in a sub-group of patients with COPD; 3) presented relative risksor odds ratios (for all cause mortality) and their corre-sponding confidence intervals or provided enough datato compute these parameters.Data extractionIncluded articles were reviewed in full by two reviewersindependently (ME and SJ). Study characteristicsincluded in the data extraction form were as follows:authors’ names, publication year, country of study, studydesign, sample size, study population type, mean or agerange, gender of participants, type of risk factors or con-founders adjusted for, outcome of the interest (mortalityreduction), adjusted odds ratio or relative risks (RRs),and 95% confidence intervals (CIs).Statistical analysisThe primary analysis examined the association betweenbeta-blocker (both selective and non-selective) use andmortality in COPD patients. We weighted the study-specific adjusted relative risks (RRs) for cohort studiesby the inverse of their variances. Due to the observa-tional nature of the studies, we used the random effectsmodel to estimate the pooled adjusted RR. Statisticalheterogeneity between studies was evaluated withCochran's Q test and the I2 statistic. Sensitivity analysiswas assessed using the Jackknife procedure by looking atthe individual influence of a study and then repeatingthe analysis by excluding the studies with the largestweights.ResultsOur search resulted in nine retrospective cohort studies[5,6,8,9,11-15] that met our inclusion criteria (Figure 1).Five studies looked at subjects with COPD [11-15] whoalso had vascular disease or chronic heart failure(Table 1). Three studies looked at concurrent beta-blocker and beta agonist use [8,9,13]. The pooled relativerisk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%, p-value=0.00001). Our results indicate a high degree ofheterogeneity among the included studies (Figure 2). Ina sensitivity analysis, we identified one study [11] as thesource of heterogeneity. Exclusion of this study from theanalysis removed the study heterogeneity (I2=29%,P=0.20) while the pooled RR stayed significantly protect-ive (RR=0.74, 95% CI=0.70-0.79). Examination of the fun-nel plot revealed presence of publication bias. The funnelplot clearly demonstrates that studies with a null or posi-tive association which should appear symmetrically onthe right axis to form the funnel are missing (Figure 3).This means that studies that did not find a protective as-sociation for beta-blockers and mortality in COPDpatients (negative studies) were less likely to bepublished.DiscussionThe results of this systematic review are consistent witha mortality benefit with beta-blockers in subjects withEtminan et al. BMC Pulmonary Medicine 2012, 12:48 Page 2 of 6http://www.biomedcentral.com/1471-2466/12/48COPD. There was a high degree of heterogeneityamongst the studies. The source of heterogeneity wasfound to be from the study by Gottlieb et al [11]. Thestudy by Gottlieb et al [11] was a retrospective analysisof those taking beta-blockers who had a previous historyof myocardial infarction. The authors only reported arate ratio of mortality amongst users of beta-blockerswith a diagnosis of COPD. It is unclear from this studywhether this reported rate ratio was adjusted for poten-tial confounders.Beta-blockers are a popular class of cardiovasculardrugs used for multiple cardiovascular conditions in-cluding hypertension, congestive heart failure andmanagement of ischemic heart disease. The possibilityof bronchospasm with beta-blocker therapy in COPDmay have discouraged some clinicians from prescribingthese drugs to their COPD patients especially thosewith concomitant cardiovascular disease. In recentyears, there has been emerging literature pointing to-ward a protective effect from beta-blockers in COPD[5,6,8]. A systematic review by Salpeter and colleaguesassessed the effect of beta-blockers in randomisedtrials of patients with asthma or COPD [4]. The reviewfound that beta-blockers decreased FEV1 by 7.46%(95% CI, 5.59%-9.32%) and increased response to betaagonists by 4.63% (95% CI, 2.47%-6.78%) [4]. The limi-tation of this review was that it included patients withboth asthma and COPD. A recent review completedby the same investigators failed to show any benefit orharm with cardioselective beta-blockers on FEV1 inCOPD patients [16].The mortality benefits of beta-blockers in COPD arethought to be due to the cardioprotective effect of thedrugs. Two other postulated mechanisms may also ex-plain the potential benefits of beta-blockers in COPD.Increased beta-agonist activity has shown to play an im-portant role in the pathology of CHF [17,18]. Thuspatients taking beta-blockers with concomitant COPDand CHF may experience a lower degree of beta agoniststimulation.Finally, it is yet unclear as to whether a protectiveeffect with these drugs is a class-effect or whether thisbenefit differs with the receptor selectivity (B1 selectivevs non-selective such as carvedilol). Carvedilol hasshown to have pleiotropic properties including antioxi-dant exerting effects [10] and has shown to lowermortality in patients with CHF. Thus, carvediolol’smortality reduction in COPD patients may be moreprofound than that of beta-selective beta-blockers. It ispossible that the beneficial effects of beta-blockers gobeyond their cardioprotective properties. Heindl et al.examined the sympathetic nerve activity in six COPDpatients with no previous history of coronary arterydisease and six healthy controls [19]. COPD subjectsshowed a significantly higher peripheral sympatheticactivity than the controls. Rutten et al. assessed the ef-fect of beta-blockers in a sub-group of COPD patientswith less severe coronary artery disease [9]. The rela-tive risk of mortality amongst COPD patients whoused beta-blockers and only had hypertension wassimilar to those with more severe form of coronary ar-tery disease (RR=0.67, 95% CI: 0.45-0.99: RR=0.68, 95%CI: 0.56-0.83 respectively).This review, as with all systematic reviews of observa-tional studies, has limitations. None of the studies wererandomised trials and although statistical adjustmentwas used in all the studies to control for potential con-founders, not all confounding variables could have beenTotal titles retrieved (478)Abstract Reviewed(133)9 Observational Included in the Meta-analysisExcluded (47)- Basic scienceExcluded (173)- DuplicatesTitles reviewed(305)Excluded (172)- Basic science (91)- Review (69)- Commentary (12) Excluded (77)- COPD was not a direct outcome  Full text reviewed(86)Figure 1 Selection of studies for inclusion in the systematicreview and meta-analysis.Etminan et al. BMC Pulmonary Medicine 2012, 12:48 Page 3 of 6http://www.biomedcentral.com/1471-2466/12/48adjusted in some of the studies. Information on beta-blocker use was also incomplete in most of the studiesand did not provide information on the patterns of ex-posure including, adherence or a dose–response relationfor beta-blockers in their relation to COPD mortality.Moreover, many of the studies did not describe in detailhow mortality data was obtained. Finally, several types ofbiases specific to pharmacoepidemiologic studies of re-spiratory disease may have potentially affected theresults of the studies included in this review. We brieflydiscuss four types of biases including immortal timebias, immeasurable time bias, calendar time bias andconfounding by contraindication.Selection biasSelection bias refers to systematic differences betweenthe exposed and unexposed groups in a cohort study.One example of study that may have been affected by se-lection bias is the study by Au et al [6]. In this study,antihypertensive use was defined as adherence to amedication of 80% or more during the 90 days prior tothe event date [6]. Beta-blockers are generally less toler-ated than calcium channel blockers mainly due to a lessfavourable adverse events profile. Thus beta-blockerusers may have been ‘healthier’ than calcium channelblocker users and hence may have had a lower overallmortality.Immortal time biasImmortal time bias, first described by Suissa [20], refersto a type of bias that arises mainly from pharmacoepide-miologic studies that use health claims databases. Thebias occurs when there is a period of time where drugexposure information prior to hospitalization is missing,as health claim databases usually do not capture in-hospital prescription drug data. Since cases are morelikely to experience multiple hospitalizations possiblyleading to death, they are less likely to be prescribed aTable 1 Characteristics of included studies in the systematic reviewStudy Design Sample size andcohort descriptionType of BB Relative Risk* CovariatesShort (2011) [8] RetrospectiveCohort5,977 COPD patientsin ScotlandCardio-selective 0.78 (0.67-0.92) CAD and Respiratory disease,age, sex, diabetes, smoking,FEV1, cardiovascular drugsAu (2004) [6] RetrospectiveCohort1966-Veteran AffairsCohort with COPDNot specified 0.57 (0.33-0.89) Comorbidity, age, history ofCOPD, bronchodilators,smoking, coronaryartery disease, diabetesDransfield (2008) [5] RetrospectiveCohort825 subjectsadmitted to hospitalfor COPDNot specified 0.39 (0.14-0.99) Age, CHD, CHF, Liver disease,COPD exacerbations,malignancy, smoking, FEVRutten (2007) [9] RetrospectiveCohortElectronic recordsof 2,230 patientswith COPD in theNetherlandsSelective andnon-selective0.68 (95% -0.56-0.83),for all BBs: 0.67(0.55-0.83) for B1selective BBs. 0.82(0.61-1.10) fornon-selective BBsAge, sex, diabetes,hypertension, CAD,CVD drugs, pulmonarydrugsGottlieb (1998) [11] RetrospectiveCohort41,814 COPD subjectswith previous historyof myocardialinfarctionNot specified 0.60 (0.57-0.63) Not specifiedStaszewsky (2007) [12] RetrospectiveCohort628 subjects withclass II-IV HeartFailure and COPDNot specified 0.55 (0.37-0.82) Not specifiedVan Gestel (2008) [13] RetrospectiveCohort1,205 with vasculardisease and COPDin NetherlandsCardio-selective 0.73 (0.60-0.88) Age, sex, hypertension,hypercholesterolemia,diabetes, renal function,smoking, BMI, CAD, FEV1,cardiovascular drugsChen (2001) [14] RetrospectiveCohort43,974 subjects withprevious history ofmyocardial infarctionand COPD or AsthmaNot specified 0.86 (0.73-1.0) Age, gender, co-morbidities,CAD, cardiovascular drugs,physician specialityHawkins (2009) [15] RetrospectiveCohort1,258 patients with COPDand previous history of MINot specified 0.74 (0.68-0.80) Not specified* = Relative risk and 95% confidence interval for beta-blocker use and mortality in COPD.Etminan et al. BMC Pulmonary Medicine 2012, 12:48 Page 4 of 6http://www.biomedcentral.com/1471-2466/12/48beta-blocker in the period prior to death than controlpatients [20]. Thus, a lower probability of exposureamongst the cases may lead to a biased protective rateratio. In this review, the study by Dransfield et al [5] hadaccess to in-hospital medication which makes the possi-bility of this bias unlikely. However, in the studies thatused health claim databases [6,11] the possibility thatimmortal time bias may have influenced the studyresults was not discussed and thus cannot be excluded.Calendar time biasCalendar time bias refers to a bias that may be causedby time-trends that may lead to differential prescribingof one drug over another. For example, the Study by Auet al [6] compared the risk of mortality amongst COPDpatients who took beta-blockers to those who took otherantihypertensives including calcium channel blockers.Antihypertensive drug therapies especially calcium chan-nel blockers’ prescribing trends may vary in time andmay be affected by publication of land-mark trials,hypertension guidelines or changes in policy. Thuschanges in antihypertensive prescribing over time maylead to differential prescribing of antihypertensiveswhich may also affect COPD patients.Confounding by contraindicationConfounding by indication is possibly the most import-ant type of confounding that threatens the validity ofpharmacoepidemiologic studies. This type of confound-ing refers to a situation where the observed associationwith a drug is in fact due to the condition for which thedrug is used. Confounding by contraindication is inher-ently the opposite of this situation where the drug isknowingly withheld by a clinician due to concerns thatthe drug may worsen a patient’s condition. Beta-blockeruse in COPD is a classic example where confounding bycontra-indication may occur as historically clinicianshave been hesitant in prescribing beta-blockers to COPDpatients. This type of confounding may explain the pro-tective effect observed with beta-blockers in the COPDpopulation mainly due to a small number of patientswith COPD who received beta-blockers compared toother types of antihypertensives. Another possibility isthat clinicians may prescribe beta-blockers to those witha less severe form of COPD who may have a lower riskof mortality.ConclusionThe mortality benefit from this review is similar in mag-nitude to that of statins which have been previouslystudied in this setting [21,22] and are currently beingtested in randomised controlled trials [23]. Although theresults of this review are consistent with a protective ef-fect of beta-blockers and COPD mortality, several typesof biases may have affected these results. We believe thatour review generates a strong hypothesis that beta-blockers may have mortality benefit in COPD patients.However, this potential benefit must be critically exam-ined in a large RCT. Patients with underlying COPDwho are already receiving beta-blockers for other med-ical conditions may benefit from beta-blocker therapy.However, initiation of beta-blocker therapy in COPDpatients to achieve mortality benefit must be reserveduntil results from RCTs specifically addressing this ques-tion are available.Figure 2 Forest plot of association between beta-blockers and COPD mortality.Figure 3 Funnel plot of studies of beta-blocker use andmortality in patients COPD.Etminan et al. BMC Pulmonary Medicine 2012, 12:48 Page 5 of 6http://www.biomedcentral.com/1471-2466/12/48Competing interestThe authors declare that they have no competing interests.Authors’ contributionsME had full access to all of the data in the study and takes responsibility forthe integrity and accuracy of the data. Study concept and design: ME, SJ,JMF. Acquisition of data: ME, SJ. Analysis and interpretation of data: ME, SJ.Drafting of the manuscript: ME, SJ, JMF. Critical revision of the manuscript:ME, SJ, BC, JMF. Statistical analysis: ME, SJ. Administrative, technical, ormaterial support: ME. Funding/Support: This was an unfunded project. Allauthors read and approved the final manuscript.Author details1Therapeutic Evaluation Unit, British Columbia Provincial Health ServicesAuthority, Vancouver, Canada. 2Child & Family Research Institute, Universityof British Columbia, Vancouver, Canada. 3Department of Medicine, Universityof British Columbia, Vancouver, Canada. 4Division of Respiratory Medicine,University of British Columbia, Vancouver, Canada. 5School of Population andPublic Health, Faculty of Medicine, University of British Columbia, Vancouver,Canada. 6Division of Translational Therapeutics, Department of Pediatrics,University of British Columbia, Vancouver, Canada. 7Child & Family ResearchInstitute, A4-198 WS 2, 709-650 West 28th Avenue, Vancouver, BC V5Z-4H4,Canada.Received: 9 May 2012 Accepted: 30 August 2012Published: 4 September 2012References1. 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Simvastatin therapy for moderate and severe COPD (STSTCOPE).: United StatesNational Institute of Health; http://clinicaltrials.gov/ct2/show/NCT01061671(Accessed August 31,2012).doi:10.1186/1471-2466-12-48Cite this article as: Etminan et al.: Beta-blocker use and COPD mortality:a systematic review and meta-analysis. BMC Pulmonary Medicine 201212:48.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitEtminan et al. BMC Pulmonary Medicine 2012, 12:48 Page 6 of 6http://www.biomedcentral.com/1471-2466/12/48


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