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DOI 10.1378/chest.123.1.222 2003;123;222-243 Chest Schroeder and Steven H. Woolf Richard A. Dart, Steve Gollub, Jason Lazar, Chandra Nair, David Asthma and Patients With Pulmonary Disease: COPD Treatment of Systemic Hypertension in http://chestjournal.org/cgi/content/abstract/123/1/222 and services can be found online on the World Wide Web at: The online version of this article, along with updated information ). ISSN: 0012-3692. http://www.chestjournal.org/misc/reprints.shtml ( of the copyright holder may be reproduced or distributed without the prior written permission Northbrook IL 60062. All rights reserved. No part of this article or PDF by the American College of Chest Physicians, 3300 Dundee Road, 2007 Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.org Downloaded from
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Page 1: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

DOI 10.1378/chest.123.1.222 2003;123;222-243 Chest

 Schroeder and Steven H. Woolf Richard A. Dart, Steve Gollub, Jason Lazar, Chandra Nair, David 

AsthmaandPatients With Pulmonary Disease: COPD

Treatment of Systemic Hypertension in

http://chestjournal.org/cgi/content/abstract/123/1/222and services can be found online on the World Wide Web at: The online version of this article, along with updated information

). ISSN: 0012-3692. http://www.chestjournal.org/misc/reprints.shtml(of the copyright holder may be reproduced or distributed without the prior written permission Northbrook IL 60062. All rights reserved. No part of this article or PDFby the American College of Chest Physicians, 3300 Dundee Road,

2007Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest

Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.orgDownloaded from

Page 2: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

Treatment of Systemic Hypertension inPatients With Pulmonary Disease*COPD and Asthma

Richard A. Dart, MD, FCCP; Steve Gollub, MD, FCCP;Jason Lazar, MD, FCCP; Chandra Nair, MD, FCCP;David Schroeder, MD, FCCP; and Steven H. Woolf, MD

We present a two-part review of the English-language literature pertaining to drug therapy forsystemic high BP in patients with pulmonary diseases. Part I examines the literature pertainingto the use of antihypertensive drugs in patients with systemic hypertension and coexistingpulmonary conditions, especially COPD and asthma. Part II of the series reviews studies assessingthe relationship between sleep-disordered breathing (including the role of the sympatheticnervous system) and systemic hypertension, and presents an approach to the management ofthese patients. It is the aim of both parts of this review to make qualified conclusions andrecommendations applying a methodologic critique to assess the current literature. In the firstpart of this series, we review the demographics of hypertension in patients with COPD. This isfollowed by an extensive review of the use of specific classes of antihypertensive drug therapiesin patients with pulmonary disease. The antihypertensive agents reviewed include diuretics,calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptorantagonists, �-adrenergic blocking agents, and �-�-blockers and other non-�-blocker classes.Additionally, the renin angiotensin system is briefly reviewed, with a discussion of howangiotensin-converting enzyme inhibitors induce cough, especially in pulmonary and congestiveheart failure patients. (CHEST 2003; 123:222–243)

Key words: antihypertensive drugs; asthma; COPD; pulmonary disease; systemic high BP

Abbreviations: JNC VI � Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation andTreatment of High BP; PEFR � peak expiratory flow rate; SDB � sleep-disordered breathing

T reatment of patients with systemic hypertensionis frequently complicated by the coexistence of

chronic pulmonary disease and sleep-disorderedbreathing (SDB). The latter can itself exacerbatesystemic hypertension, and certain antihypertensivedrugs can affect pulmonary function. Such patients

present diagnostic and therapeutic challenges. Awide variety of antihypertensive drugs are now avail-able with different mechanisms of action. This raisesquestions, such as whether agents that induce bron-chospasm should ever be used to treat hypertensionin patients with asthma or SDB. What is the physi-ology behind the drug effects? What alternativeclasses of drugs have been tested in clinical settingsand should be considered under specific circum-stances? What type of medical history prompts cau-tion in the use of these agents? The AmericanCollege of Chest Physicians charged this panel toconduct a systematic and critical review of theliterature and summarize relevant recommendationsand conclusions regarding the following: (1) antihy-pertensive drug therapy in patients with chronic

*From the Department of Nephrology and Hypertension (Dr.Dart), Marshfield Clinic, Marshfield, WI; Kansas UniversityMedical Center (Dr. Gollub), Kansas City, KS; Winthrop Uni-versity Hospital (Dr. Lazar), Mineola, NY; Cardiac Center (Dr.Nair), Creighton University School of Medicine and Pharmacy,Omaha, NE; Asheville Cardiology Associates, P.A. (Dr. Schroe-der), Asheville, NC; and Virginia Commonwealth University (Dr.Woolf), Fairfax, VA.Manuscript received November 19, 2001; revision accepted July10, 2002.Correspondence to: Richard Dart, MD, FCCP, Department ofNephrology, Marshfield Clinic, 1000 North Oak Ave, Marshfield,WI 54449-9916; e-mail: [email protected].

special reports

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Page 3: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

pulmonary disease, and (2) SDB as a causative orcontributory factor in systemic hypertension.

In the first part of this series, we review thedemographics of hypertension in patients withCOPD. This is followed by an extensive review of theuse of specific classes of antihypertensive drug ther-apies in patients with pulmonary disease. The anti-hypertensive agents reviewed include diuretics, cal-cium antagonists, angiotensin-converting enzymeinhibitors, and angiotensin II receptor antagonists,�-adrenergic blocking agents, and �-�-blockers andother non-�-blocker classes. Additionally, the reninangiotensin system is briefly reviewed, with a discus-sion of how angiotensin-converting enzyme inhibi-tors induce cough, especially in pulmonary andcongestive heart failure patients. Findings and rec-ommendations are presented. Patient evaluation anddiagnosis were not a part of this review. SDB issueswill be covered in Part II of this series.

Materials and Methods

The rationale used for searching the literature, selectingrelevant articles, and grading evidence for this article are de-scribed in the Appendix.

Database Searches

For this review, the PubMed database was systematicallysearched for articles published between 1972 and 2000, using keywords and the medical subject heading terms to identify studies.Such studies were considered relevant if they addressed asthma,COPD, lung diseases, pulmonary disease, hypertension, arterialhypertension, and/or systemic hypertension. Both medical sub-ject headings and keywords were used in searches, due toconcerns about potential accuracy of National Library of Medi-cine indexing. Additional comodifying terms included names ofclasses of antihypertensive drugs and various permutations onclass names: �-adrenergic receptor blockers, �-blockers, �1-blockers, �2-blockers, �-adrenergic antagonists, sympathetic in-hibitors, adrenergic antagonists, �-receptor antagonists, central�-adrenergic blockers, calcium channel blockers, acetylcholines-terase inhibitors, and �-�-blockers.

Inclusion/Exclusion Criteria

Only randomized or nonrandomized control trials, observa-tional, control cohort (longitudinal), case control, cross sectional,uncontrolled case series/cohort, time series, cross-cultural, eco-logic, descriptive epidemiologic, and case reports were included.The literature search excluded pulmonary hypertension, editori-als, position papers, editorial opinions, abstracts, and letters tothe editor. Exceptions to this rule were editorials, positionpapers, editorial opinions or letters to the editor that providedadditional references thought to be of relevance and not found inthe original search. We also chose not to review unpublishedevidence.

All English-language articles identified in these searches andfitting these criteria were included for review. There is astatistically significant publication bias: investigators tend only topublish significant results.1 Thus, our review of the literatureshould be viewed in that context (see Appendix).

Tabulated Study Grade Assessments

Criteria for judging the retrieved articles was internally devel-oped and uses the following scheme: level 1, randomized (con-trolled trials) or nonrandomized controlled trials; level 2, obser-vational studies, control cohort (longitudinal), case controlincluding prospective and retrospective, cross-sectional, uncon-trolled case series/cohort, time-series, cross-cultural, ecologic,and descriptive epidemiologic studies; and level 3, case reports. Aquality judgment was also added based on attributes of samplesize, appropriate subjects, methods, outcome measures, statisticalanalysis, and confounding variables. This judgment was expressedin an “a, b, c” system, where a � good, b � fair, and c � poor.For example, 1a � evidence of a well-designed, well-conducted,controlled trial with statistically significant results.

Grading the Strength of Recommendations

The strength of a recommendation is expressed in an “A, B, C”system, with the following degrees of relative strength withineach level: level A, evidence provided by well-designed, well-conducted, controlled trials (randomized and nonrandomized)with statistically significant results to support the recommenda-tion (A-1 � all studies meet level A criteria, A-2 � some studiesmeet level A criteria, A-3 � a few studies meet level A criteria);level B, evidence provided by observational studies or by con-trolled trials with less consistent results to support the recom-mendation, or by well-designed trials that are conflicting (B-1 � all studies meet level B criteria, B-2 � some studies meetlevel B criteria; B-3 � a few studies meet level B criteria); andlevel C, expert opinion that supports the recommendation be-cause the available scientific evidence did not present consistentresults, or controlled trials are lacking.

Results and Discussion

Demographic Overview: Hypertension in PatientsWith COPD

Approximately 31% of the US adult popula-tion—50 million persons—has elevated systemic hy-pertension according to estimates based on the thirdNational Health and Nutrition Examination Survey.2Prevalence of arterial hypertension varies with cutoffvalues for systolic/diastolic pressure.3 At values ofsystolic BP � 140 mm Hg or diastolic BP � 90 mmHg, 24% of the adult US population had high BP in1991 according to third National Health and Nutri-tion Examination Survey estimates.2 The estimated1996 cost of hypertension was $23.74 billion, includ-ing medical expenditures and lost wages.4

Systemic hypertension is a relatively frequent co-morbidity with chronic lung diseases. In 1993, theNational Health Interview Survey reported the inci-dence of COPD in the United States to be 6.2%,which broke down to 13.8 million persons withchronic bronchitis and 2.0 million persons withemphysema.5 The incidence of COPD may behigher than 6.2%, as 50% of patients with airflowlimitation are asymptomatic and thus not detected ina survey.6

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Although the prevalence of asthma is difficult toascertain due to lack of a standardized definition, theNational Health Interview Survey identified 13.5million cases of asthma in 1993–94 for a prevalenceof 5.4% in the general population.7 During the sameperiod, asthma accounted for 1.6% of ambulatoryvisits and 1.6% of emergency department visits.8,9

The incidence and mortality rate of asthma has risensteadily over the past 3 decades.10–12

The prevalence of COPD in patients with systemichypertension was reported by the Medical OutcomesStudy.13 This survey evaluated the functioning andwell-being of 9,385 adult outpatients and found37.3% to have systemic hypertension as diagnosed bytheir physicians. The prevalence of COPD andasthma was 7.4% in the patients with diagnosedsystemic hypertension, and 7.8% in the entire studygroup. These data suggest that the prevalence ofCOPD in adults with systemic hypertension is simi-lar to that in the general population.

Although chronic bronchitis is a more frequentcause of COPD than emphysema (50.5 cases/1,000persons vs 6.6 cases/1,000 persons),14 the relativeprevalence of chronic bronchitis and emphysema inthe hypertensive population is not known. The prev-alence of unspecified obstructive lung disease wassomewhat lower (3.4%) in the Hypertension OptimalTreatment study,15 which randomized 19,196 pa-tients aged 50 to 80 years with diastolic BPs of � 100to � 115 mm Hg to different target BPs.

Tobacco smoking is an etiologic factor in bothCOPD and systemic hypertension. The Sixth Reportof the Joint National Committee on Prevention,Detection, Evaluation and Treatment of High BP(JNC VI) emphasized the importance of risk strati-fication for patients with hypertension according toother risk factors for cardiovascular disease, includ-ing smoking and the presence of target organ dam-age.16 Various antihypertensive drug efficacy studieshave found 25 to 43% of hypertensive patients to bepresent or former smokers.17,18 Smoking is known toincrease the impact of hypertension as a risk factorfor cardiovascular disease,19 and epidemiologic stud-ies have shown airflow limitation to be an indepen-dent predictor of future cardiovascular events inpatients with various cardiovascular risk factors.20,21

No study has addressed the incremental risks posedby airflow limitation in hypertensive subjects.

Comorbid systemic hypertension and COPD canbe expected to increase in incidence as the US “babyboom” generation ages. In particular, isolated sys-tolic hypertension and emphysema may more fre-quently occur together, as both conditions arestrongly related to advancing age.5

Given estimates that 50 million US adults havesystemic hypertension, and approximately 5% of

those also have COPD (defined as bronchitis andemphysema), there are at least 2.5 million adults inthe United States with COPD who merit specialconsideration for treatment to lower high BP. Theprevalence of COPD and asthma in patients withdiagnosed systemic hypertension has been found tobe similar to the incidence of COPD in the generalpopulation.

Review of Specific Classes of AntihypertensiveDrug Therapies

In treating the hypertensive patient with pulmo-nary complications, a wide variety of drug classes areavailable in the pharmacopoeia, each of which needsto be understood in terms of its pulmonary sideeffects.

Diuretics: The JNC VI16 recommends diuretics asa first-line choice of drug therapy in the treatment ofsystemic hypertension. Despite being advocated asfront-line therapy, there is paucity of outcome datafrom randomized controlled trials designed to eval-uate the effects of diuretics in the treatment ofhypertension in patients with lung disease. There aretheoretical benefits derived from using this class ofdrugs. Peripheral edema is common in this group ofpatients and may be related to multiple factors,including right heart failure, venous insufficiency,and malnutrition, etc. There may be favorable effectson pulmonary vascular remodeling as well astheoretical risks, including alkalemia (acetazolamideincreased minute ventilation in patients withCOPD),22 increased hematocrit, and hemodynamicembarrassment in patients who are preload depen-dent in the setting of right-heart failure. In the rabbitmodel, low-dose acetazolamide treatment impairsrespiratory muscle function23 and magnesium deple-tion.24 Furthermore, the inhaled administration ofnebulized amiloride does not improve pulmonaryfunction in cystic fibrosis,25 and inhaled furosemideis not useful as adjuvant therapy to salbutamol inpatients with acute or chronic asthma.26

In conclusion, the JNC VI has recommended theuse of diuretics in uncomplicated hypertensive pa-tients as a first-line therapy. However, there havebeen no direct studies of the use of these agents inthe case of hypertensive COPD or asthma patients.Beneficial or deleterious side effects in these pa-tients may only be presumed based on theoreticalconsiderations, indirect animal studies, and poten-tially relevant observations in patients treated forother conditions. Use of diuretics in hypertensivepatients with pulmonary disease is currently un-tested, and therefore alternatives should be consid-ered (levels B-2, C).

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Calcium Antagonists: A systematic literaturesearch was unable to find outcome data from ran-domized controlled trials designed to evaluate theeffects of calcium antagonists in the treatment ofsystemic hypertension in patients with COPD (Ta-bles 1, 2).27–42

Calcium antagonists have long been established tolower BP and regress the left ventricular hypertro-phy that may be a sequela of arterial hypertension(Tables 1, 3).42–49 As compared to angiotensin-converting enzyme inhibitors, the calcium antagonistverapamil was found less effective in lowering sys-

Table 1—Abbreviations Used in Tables

Abbreviation Definition Abbreviation Definition

a beforeACE angiotensin-converting enzymeAE adverse effectsAHI apnea/hypopnea indexAP apneaASYM asymptomaticAT atenololBB �-blockersBC bronchoconstrictionBD bronchodilationC captoprilCO cross-overCS cardioselectiveD diltiazemDB double blindDBP diastolic BPDBRCT double-blind randomized control trialDBPCS double-blind placebo-controlled studyE enalaprilEIB exercise-induced bronchoconstrictionF femaleFnc functionF/u follow-upGXT treadmill testHC histamine challengeHCTZ hydrochlorothiazideHMO health maintenance organizationHPLC high pressure liquid chromatographyHR heart rateHTN hypertensivesHx historyISA intrinsic sympathomimetic activityL lisinoprilLLD lipid-lowering drugsM maleMC methacholine challengeMCDBRCT multicenter, double-blind randomized

control trialMD medical doctorME metoprololmeds medicinesMEV maximum expiratory volumeMMEF mid-maximal expiratory flown number of subjectsN nifedipineNA not applicableNS no significantNT nitrendipineOSA obstructive sleep apneap afterPC placebo controlledPCC prospective case controlPCS prospective case study

PEF peak expiratory flow ratePFT pulmonary function testPI pindololPL placeboPR propranololPRC prospective randomized controlPRED predictedPts patientsQOL quality of lifeRCR retrospective chart reviewRPCCT randomized placebo-controlled crossover

trialRX use of antihypertensive drugsRxns reactionsSAL salbutamolSB single blindSDB sleep-disordered breathingsl sublingualSR slow releasesx symptomTHEO theophyllineV verapamilVC vital capacityy/o year oldDesign flaws/limits1: patient characteristics

1a small population in study groups1b excessive loss to follow-up1c varying patient characteristics during follow-

up1d skewed study group (selection bias)1e low body mass index1f failure to control for confounding factors1g errors in group classification1h variable duration of sleep disorder1i measured parameters not well-defined1j excessive exclusions1k variable duration of hypertension

2: treatment characteristics2a variable treatment duration2b inconsistent documentation/control of

hypertension2c poorly characterized/no intervention2d not well controlled2e short treatment duration

3: measurement characteristics3a inconsistent measurements3b systolic BP not considered3c measurement bias (eg, self-administered

questionnaire)3d no dose-response measurement

4: study design limitations4a short-term study

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tolic BP in patients with hypertension and asthma,50

whereas nifedipine was found equally effective asdiuretics and angiotensin-converting enzyme inhibi-tors in lowering systolic and diastolic BP in patientswith COPD.42 The JNC VI advocates the use oflong-acting dihydropyridine calcium antagonists assecond-line therapy for older persons with isolatedsystolic hypertension.16 This new recommendationwas based on the results of the Systolic Hypertensionin Europe trial, which randomized 4,695 patients� 60 years old with isolated systolic hypertension(systolic BP � 160 mm Hg and diastolic BP � 95mm Hg) to nitrendipine or placebo.17 After 2 years,

there was a 42% reduction in total stroke and 26%reduction in all cardiac end points, a trend toward a27% reduction in cardiovascular mortality, and nosignificant change in all-cause mortality. There wereno comments about the presence of COPD in theSystolic Hypertension in Europe trial population.Thus, no specific comments regarding any benefitsof long-acting dihydropyridine in patients with mild-to-moderate lung disease can be made.

African Americans as a group are more responsiveto calcium antagonists than to �-blockers or angio-tensin-converting enzyme inhibitors, except with theaddition of diuretics that have been shown to im-

Table 2—Calcium Channel Blocker Studies

Source Study PopulationStudy

Design Intervention Methods Duration

DesignFlaws/Limits Results Grade

Barnes et al,27 1981 Asthma with positiveskin test (n � 8)

PRC N 20 mg vs PL GXT, HC, PEF 30 min 1a, 2e, 4a N prevented EIB 1b

Cerrina et al,28

1981Mild asthma (n � 20) PCC N sl vs PL Bicycle ergometry;

flow-volume curves60 min 1a, 2e, 4a N prevented EIB 2b–c

Williams et al,29

1981Asthma (n � 10) PRC N 20 mg po vs PL HC, FEV1, VC, MMEF 1 h 1a, 2e, 4a N prevented HC 1b

So et al,30 1982 Asthma with positiveskin test (n � 8)

PCS V 2–4 mg inhaledvs N 20 mg sl

Bronchial provocationwith allergen

30 min 1a, 2e, 4a N and V without effecton FEV1 or BC

2b–c

Nair et al,31 1984 Asthma, COPD,angina (n � 60)

PCS N 20 mg; short-termand long-term safety

Spirometry 2 h; 2 wk 1a, 2e, 4a No AE; N improvedFEV1

2a

Ahmed et al,32 1985 ASYM asthma;ragweedhypersensitivity(n � 10)

PCS V 160 mg po vs V 20mg inhaled

Spirometry, airwayresistance

45 min 1a, 2e, 4a Inhaled V was best atreducingbronchoconstriction

2b–c

Russi et al,33 1985 ASYM asthma;ragweedhypersensitivity(n � 12)

PCS N, V Ragweed provocation;airway conductance

4 d 1a, 1e, 2e, 4a N variably blocked BCin 8/12 pts, Veffective in 2

2b–c

Ballester et al,34

1986ASYM asthma

(n � 13)RPCCT N vs PL MC; FEV1, Pao2 7 d 1a, 2e, 4a N reduced airway

reactivity but loweredpost-methacholinePao2

1b–c

Jackson et al,35

1986Healthy controls

(n � 8)PCS N SR 20 mg N levels (HPLC) 5 d 1a N did not affect THEO

levels2b–c

Schwartzstein andFanta,36 1986

Angina, COPD(n � 10)

RPCCT N 20 mg, albuterol,PL

Spirometry 2 h 1a, 2e, 4a N increased FEV1 butless than albuterol

1b

Smith et al,37 1987 Asthma (n � 10) RPCCT N SR 20 mg vsPL

PEF; symptom score 2 wk 1a, 2e, 4a No change in PEF orsymptoms; decreasein serum THEO

1b

Sirmans et al,38

1988Healthy controls

(n � 12)RPCCT N, V, D Serum THEO 8 d 1a THEO half-life

increased by V andD, not N

1b

Mulloy et al,39 1990 Asthma (n � 8) RPCCT nt 20 mg vsPL

HC, PEF, oximetry 2–3 h 1a, 4a NT without effect 1b–c

Kantola et al,40

1991HTN snorers; 12 M PCS Isradipine vs

metoprololBallistocardiogram,

respiratory movement8 wk 1a, 2e, 4a Metoprolol increased

and isradipinedecreased OSA

2a–b

Yilmaz et al,41 1991 HTN and asthma(n � 13 F)

PCS N 10 po bid Serum THEO; BP;FEV1; PEF

45 d 1a N lowered BP, noeffect on FEV1,lower serum THEOat 45 d

2a

Lin et al,42 1996 HTN and COPD(n � 66)

PRC Diuretics with orwithout N, lisinopril

BP control; coughreporting

1 yr 1a, 2e, 4a No AE 1b–c

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prove response.16 It is unknown whether these re-sults may be extrapolated to the African-Americanpatient with COPD.

Although the oral and sublingual administration ofcalcium antagonists does not affect resting bronchialtone, the drugs sometimes attenuate broncho-spasm induced by exercise, methacholine, and anti-gen.27–34,36,39 However, single-dose effect, use ofshort-acting preparations, and lack of BP data limitthe applicability of these data. The beneficial effectsof calcium antagonists in reducing airway reactivityappear to be offset by worsening of ventilation-perfusion mismatch.34 Short-acting preparations ofverapamil and nifedipine do not worsen pulmonarysymptoms after up to 1 year of treatment.42,50

With regard to drug interactions, calcium antago-nists lower serum theophylline levels by a small andinsignificant extent.35,37,38,41 In the management ofhypertension associated with sleep apnea, one studyfound dihydropyridine calcium antagonist to causefewer obstructive breathing patterns as compared to�-blocker.40 However, neither drug had a significanteffect on BP values.

At present, there are insufficient data on which tobase any specific recommendations about the use ofcalcium antagonists in the management of systemichypertension in patients with concomitant COPD orsleep apnea syndrome. Most studies to date havedemonstrated calcium antagonists modestly decreasebronchial reactivity. Additional studies are needed toinvestigate the clinical outcomes of patients withCOPD using calcium antagonists to lower arterialBP. While there may be some benefit in the reduc-tion of bronchial reactivity, the use of calcium antag-onists in hypertensive patients with pulmonary dis-ease cannot yet be advocated, and alternativesshould be considered (level B-2).

Angiotensin-Converting Enzyme Inhibitors: An-giotensin-converting enzyme inhibitors have beensuccessfully used in the treatment of systemic hyper-tension, congestive heart failure, and more recentlyin treating diabetic nephropathy. Angiotensin-converting enzyme inhibitors are recognized as first-line agents in the JNC VI report.16 However, adversedrug reactions considered a class effect have beenreported, including hypotension, cough, hyperkale-mia, renal failure, fetal anomalies, angioedema, anddysgeusia. Other adverse reactions, not believed tobe a class effect but related to the presence of asulfhydryl group, include rash, neutropenia, and anephrotic type proteinuria.

Of the associated side effects, cough is the mostcommon and widely reported class effect of theangiotensin-converting enzyme inhibitors.51 Havelkaet al52 first reported cough as a captopril-related

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Page 8: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

adverse reaction � 15 years ago. Unfortunately, theassociation between cough and angiotensin-converting enzyme inhibitors was not widely ac-cepted until several years later.53,54

Cough associated with angiotensin-converting en-zyme inhibitors is more of a nuisance than a hazardin the general population of hypertensive patientsreceiving the drugs. Studies estimate the incidenceof angiotensin-converting enzyme inhibitor-inducedcough ranges from 10 to 20%.55,56 Most of thesereports were from patients without comorbid dis-eases. In patients with sensitive airway disease ordecreased pulmonary function, cough could be aserious adverse reaction to this class of drugs. Coughand possible bronchospasm may also be an importantdeterminant regarding compliance.

With regard to the angiotensin-converting enzymeand the renin-angiotensin system, the renin-angio-tensin system/kallikrein-kinin system plays an impor-tant role in BP regulation. Two key elements in thesystem are angiotensin II and bradykinin. Angioten-sin II is a potent smooth-muscle vasoconstrictor.57 Itcauses sodium retention through aldosterone re-lease, increased vascular tone through sympatheticactivation,58 and increased fluid retention throughincreased antidiuretic hormone.59,60 Bradykinin,however, is a potent vasodilator whose effects aremediated through the �2 receptor.61 Many of itseffects are through the production of arachidonicacid, nitric oxide, endothelium-derived hyperpolar-izing factor, and natriuresis.62,63 Bradykinin increasesvascular permeability, mucus secretion, and C-fiberstimulation. This molecule also causes smooth-muscle contractions in specific organs, such as thesmall intestine and uterus.64

Angiotensin-converting enzyme or kininase II reg-ulates the balance between angiotensin II and bra-dykinin. The enzyme is found in several locations, asoluble form present in blood and a membrane-bound form located in epithelial cells and braintissue.65 Although the clinical significance has notbeen established, several studies have shown a bettercorrelation between tissue angiotensin-convertingenzyme and systemic hypertension than circulatingangiotensin-converting enzyme.52,66 The hemody-namic effects of bradykinin and angiotensin II aresuch that, with increased bradykinin levels bloodvolume is decreased and BP reduced, while withincreased levels of angiotensin II blood volume andBP are increased.

With regard to the cough mechanism, a number ofhypotheses have been put forward to explain thecauses of angiotensin-converting enzyme inhibitor-induced cough. For example, it is believed that whenangiotensin-converting enzyme is inhibited, kininlevels are increased in lung tissue. In addition to

converting angiotensin I to angiotensin II, angioten-sin-converting enzyme is also a kininase enzyme thatreduces the levels of several inflammatory com-pounds such as bradykinin, substance P, and neuro-kinin A. These kinins can stimulate phospholipaseA2, causing an increase in the prostanoid synthesis ofprostaglandins I2 and E2. Rapidly adapting stretchreceptors and C fibers are stimulated directly bybradykinins, prostaglandin I2 and prostaglandin E2,both of which are involved with the vagal afferentlimb of the cough reflex.66 Other irritants or proin-flammatory agents that are released or formed areleukotrienes and histamines from mast cells.67,68

Bradykinin and substance P activate mast cells,causing histamine release. Histamines are chemotac-tic agents inducing an inflammatory response andcellular migration of eosinophils and neutrophils.69

When kinins accumulate in lung tissue, cough andbronchospasm might occur, causing a serious ad-verse event in susceptible patients with certain dis-ease states.70–72

Prostaglandin and leukotrienes are formedthrough the direct stimulation of phospholipase A2

and the arachidonic acid pathway.73 Inhibition ofprostaglandin formation appears to attenuate thecough reflex. Malini et al74 reported a reduction inangiotensin-converting enzyme inhibitor-inducedcough by using the thromboxane antagonist picota-mide. Picotamide is a potent platelet antiaggregantthat acts by inhibiting thromboxane synthesis and isa thromboxane receptor antagonist. Picotamide waseffective in stopping cough in eight of nine patientswho had cough as a result of taking enalapril. Thecough was suppressed up to 6 months. Ozagrel, athromboxane A2 inhibitor, also reduced or elimi-nated cough in patients receiving an angiotensin-converting enzyme inhibitor.75 Other drugs affectingprostanoid synthesis have not been shown to be aseffective. Two different studies using the nonsteroi-dal anti-inflammatory drugs, sulindac or indometha-cin, showed efficacy in approximately 50% of pa-tients studied.76,77 One possible explanation could bean incomplete inhibition of the cyclo-oxygenasepathway leading to thromboxane A2 synthesis.

Substance P, a potent bronchoconstrictor, is alsodegraded by angiotensin-converting enzyme. It is theproposed neurochemical mediator of the cough re-flex.78 Baclofen, an agent used to treat musclespasticity, has been shown to suppress the release ofsubstance P in an animal model.79 The drug also hasbeen shown to be effective in reducing bronchialhyperresponsiveness in patients with spinal cordinjury.80 In an open-label clinical trial, baclofenreduced the severity of cough in patients with severeangiotensin-converting enzyme inhibitor-induced

228 Special Reports

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Page 9: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

cough. Subjects continued to demonstrate coughsuppression 25 to 74 days after discontinuation ofbaclofen therapy.81

With regard to special populations, pulmonarypatients, it is very probable that several mechanismsare involved in the increased incidence of cough andincreased airway sensitivity associated with angio-tensin-converting enzyme inhibitors. Therefore, con-cerns arise regarding potential risk in patients withCOPD and asthma who are administered angio-tensin-converting enzyme inhibitors to lower BP.Semple and Herd82 described an asthmatic patientwho experienced worsening dyspnea and wheezingafter receiving enalapril for hypertension. Popa83

reported a patient with no previous history ofasthma, hay fever, or allergies who had a severeasthma attack after receiving captopril.

The reported effects of angiotensin-convertingenzyme inhibitors on lung function in patients withCOPD or asthma are from individual case reportsand a limited number of small clinical trials. As is thecase with many small studies, statistical power islacking and results are conflicting. In some of thestudies, no negative effects were observed. Many ofthese studies were uncontrolled and of short dura-tion, and the patients were stable as defined by norecent exacerbation of their disease. In many of theearlier studies, a drug was administered for a veryshort period of time, and sometimes only a singledose was administered, making it difficult to drawany valid conclusions.43–45,84–86 While some of thestudies showed no effect, two uncontrolled casestudies did report immediate deterioration of lungfunction in asthmatics after receiving an angiotensin-converting enzyme inhibitor.83,87

The longitudinal assessment of asthmatic patientsis difficult even in a controlled trial. Most of thestudies retrieved for review excluded unstable pa-tients. Continued use of inhaled glucocorticoids andbronchodilators may have masked the effects ofangiotensin-converting enzyme inhibitors in somestudies. There is also reason to believe that anincrease in cough or bronchoreactivity might requireseveral weeks or months of angiotensin-convertingenzyme inhibitor therapy before effects are ob-served.88

In a MEDLINE search of English-language liter-ature from 1985 to 2000, only a limited number ofclinical studies were found to have investigatedbronchial reactivity and cough in patients withCOPD or asthma (Tables 1, 4).89–110 Evaluation ofthe studies was conducted as described in the “Ma-terials and Methods” section.

In one of the earlier studies, Sala et al43 reportedno difference in bronchial responsiveness in 16asthmatic patients before and after a 4-week treat-

ment using captopril. FEV1 and a dose-responsecurve with methacholine were measured before andafter treatment. The incidence of cough was notreported. Schalekamp et al44 reported a similar lackof differences in a group of patients with COPD andsystemic or pulmonary hypertension treated withcaptopril. Nine patients with COPD and pulmonaryhypertension were treated with a single dose, while10 patients were treated for 60 days. Mean pulmo-nary wedge pressure, mean pulmonary artery pres-sure, and total pulmonary arterial resistance weresignificantly decreased after the single dose in pa-tients with pulmonary hypertension. In patients withCOPD and essential hypertension treated for 60days, no airflow differences were observed beforeand after treatment. No side effects were observedand no bronchospasms occurred, even in those pa-tients responsive to bronchodilator treatments.This study did not report incidence of cough andwheezing. The authors concluded that angiotensin-converting enzyme inhibitors are safe and effectivein patients with COPD and systemic hypertension.

In one of the few prospective, double-blind cross-over studies, Riska et al50 reported no differences inFEV1 values in patients receiving captopril or vera-pamil before and after treatment. These results werebased on a total of 17 patients. Patients were treatedfor 4 weeks in each arm of the study and allowed tocontinue using steroids and bronchodilators, possiblymasking effects of the angiotensin-converting en-zyme inhibitors. There were no differences in in-creased use of steroids and �2-sympathomimeticbronchodilators between the two groups during thetrial. The incidence of increased cough during activedrug treatment or placebo phase was similar for thetwo medications.

In a double-blind study, Kaufman et al47 evaluatedpulmonary function in 21 patients receiving twodifferent angiotensin-converting enzyme inhibitors(14 patients with asthma, and 7 patients with allergicrhinitis). After a washout period, baseline FVC,FEV1/FVC ratio, and provocative dose of methacho-line causing a 20% fall in FEV1 were measured.Patients were then started on either spirapril orenalapril for a period of 3 weeks, after which timethe pulmonary function tests and methacholine chal-lenge were repeated. The authors reported no sig-nificant change in spirometric measurements ormethacholine challenge test before or after treat-ment. Unfortunately, this study also allowed patientsto continue asthmatic medications, such as theoph-ylline preparations and oral or inhaled �-agonists,until 36 h prior to spirometry and methacholineprovocation. Increased use of inhalers was not re-ported. This study lacked an active control andcombined asthmatics with patients having allergic

www.chestjournal.org CHEST / 123 / 1 / JANUARY, 2003 229

Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.orgDownloaded from

Page 10: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

Tab

le4

—�

-Adr

ener

gic

Rec

epto

rB

lock

erSt

udi

es

Sour

ceSt

udy

Popu

latio

nSt

udy

Des

ign

Inte

rven

tion

Met

hods

Dur

atio

n

Des

ign

Fla

ws/

Lim

itsR

esul

tsC

omm

ents

Gra

de

Ast

rom

,8919

75M

ild-t

o-m

oder

ate

asth

ma

(n�

5)

PCC

Ate

nolo

l7–9

mg

IVon

day

1,

prop

rano

lol0

.2–1

.0m

gIV

on

day

2

Air

way

cond

ucta

nce

aan

dp

med

s

1d

1aA

irw

ayco

nduc

tanc

ede

crea

sed

with

PR

2pt

sha

din

crea

sed

sym

ptom

s

pPR

2c

For

mgr

en,90

1976

Ast

hma

plus

HT

N,1

2M

,5F

;

13on

long

-ter

mst

eroi

ds;a

ll

onor

alte

rbut

alin

epl

us

aero

solB

D

PRC

Prac

tolo

l100

,200

mg

bid;

ME

50,1

00m

gbi

d

FE

V1

31d

1a,1

d,2e

,

4a

FE

V1

drop

ped

with

both

med

s

only

athi

gher

dose

;in

4pt

s

asth

ma

incr

ease

d,2

seve

rely

Mos

ton

long

-ter

mst

eroi

ds1a

Vils

vik

and

Scha

anni

ng,91

1976

Ast

hma

(n�

12);

9on

ster

oids

PRC

AT

100

mg,

prac

tolo

l300

mg

PFT

s,bi

cycl

eer

gom

etry

,

resp

onse

tois

opre

nalin

e

1d

1aPr

acto

lold

ecre

ased

PFT

s;no

effe

cton

BD

Ate

nolo

lmor

eca

rdio

sele

ctiv

e

than

prac

tolo

l

1c

Chr

iste

nsen

etal

,92

1978

Ast

hma

(n�

20);

noH

TN

RPC

CT

PI5

mg

vsPL

PFT

;res

pons

eto

SAL

1d

1a,2

e,4a

SAL

incr

ease

dF

EV

1p

PL,n

ot

PI

PIR

xw

asas

soci

ated

with

asth

ma

(n�

1)

1b

Dec

alm

eret

al,93

1978

Ast

hma

(n�

10)

RPC

CT

PL,A

T10

0m

g,M

E10

0m

g,

aceb

utal

ol30

0m

g,PR

100

mg,

oxpr

enol

ol10

0m

g,PI

5

mg,

and

timol

ol10

mg

FE

V1

1d

1a,2

e,4a

All

med

sde

crea

sed

FE

V1

exce

pt

AT

;onl

yC

SB

Bpe

rmitt

ed

BD

,onl

yA

Tal

low

edno

rmal

BD

tois

opre

nalin

e

ISA

was

not

asth

ma

prot

ectiv

e1b

And

erso

net

al,94

1979

2pa

tient

sw

ithm

ildas

thm

aR

CR

One

pton

ME

100

mg

bid,

the

othe

rox

pren

olol

240

mg

qd

Sym

ptom

s18

mo

f/u1a

Bot

hde

velo

ped

seve

re

prol

onge

das

thm

a

Ast

hma

pers

iste

dm

onth

sp

stop

ping

BB

3b

Lof

dahl

and

Sved

myr

,9519

81

Ast

hma

(n�

8);2

0–50

%

reve

rsib

ility

with

terb

utal

ine

RPC

CT

PLM

E10

0m

g,A

T10

0m

gH

R,B

P,E

CG

,tre

mor

,FE

V1,

FV

C,r

espo

nse

tote

rbut

alin

e

1d

1a,2

e,3d

,

4a

AT

and

ME

decr

ease

dH

Ran

d

FE

V1

and

redu

ced

resp

onse

to

terb

utal

ine

Diff

eren

ces

inca

rdio

sele

ctiv

ity

betw

een

AT

and

ME

coul

d

not

besh

own

1b

Rai

neet

al,96

1981

1pa

tient

with

asth

ma

RC

RN

adol

olSy

mpt

oms

1w

k1a

23y/

ode

velo

ped

resp

irat

ory

arre

stp

drug

Nea

r-fa

talb

ronc

hosp

asm

afte

r

oral

nado

lol

3b

Ruf

finet

al,97

1982

Mild

-to-

mod

erat

eas

thm

a

(n�

12)

PRC

PR40

,160

mg;

AT

50,2

00m

g;

PI5,

20m

g

HR

,FE

V1,

MM

EF

,tre

mor

,

HC

,GX

T,i

nhal

edfe

note

rol

6d

1a,2

e,3d

,

4a

PIca

used

the

leas

t,PR

the

grea

test

decr

ease

inPF

Ts

vs

plac

ebo

Sens

itivi

tyto

hist

amin

edi

dno

t

pred

ict

redu

ctio

nin

PFT

sp

ther

apy

1b

Law

renc

eet

al,98

1983

Ast

hma

plus

HT

N(n

�14

)R

PCC

TM

E10

0m

gbi

d,A

T10

0m

gqd

PFT

3w

k1a

,2e,

3d,

4a

Prop

rano

lold

ecre

ased

FE

V1

and

resp

onse

tosa

lbut

amol

vs

aten

olol

orm

etop

rolo

l

Ate

nolo

lsup

erio

rto

met

opro

lol

inas

thm

atic

atta

cks,

asth

ma-

free

days

,PF

T

1a

Lam

mer

set

al,99

1985

Ast

hma

(n�

1);c

hron

ic

bron

chiti

s(n

�7)

;DB

P

�95

mm

Hg

Fir

st4

wk

SB

plac

ebo,

then

DB

,PC

,CO

;

4w

kR

X

peri

ods;

PFT

s

aan

dp

each

Rx

peri

od

PI10

mg

bid,

ME

100

mg

bid

FE

V1,

FV

C,P

EF

,BP

4w

k1a

,1d

FE

V1

decr

ease

dw

ithM

Ebu

t

not

PI;i

nhal

atio

nof

terb

utal

ine

prod

uced

smal

l

incr

ease

inla

rge

airw

ay

func

tion

ppl

aceb

oan

dM

E

but

not

pPI

Oth

erex

pira

tory

flow

para

met

ers

did

not

chan

gew

ithth

erap

y

1b

Cha

tter

jee,

100

1986

12pt

s;m

ean

FE

V1

�1.

74,

FE

V1

incr

ease

sby

�15

%

with

SAL

,mild

-to-

mod

erat

e

HT

N

RPC

CT

AT

100

mg

qd,b

isop

rolo

l10,

20m

g,PL

FE

V1,

VC

,PE

F,a

irw

ay

resi

stan

cep

SAL

1m

o1a

,2e,

3d,

4a

AT

incr

ease

dai

rway

resi

stan

ce;

NS

chan

gein

PEF

,FE

V1,

VC

with

eith

er;r

espo

nse

toSA

L

pres

erve

d

Bis

opro

lolh

asgr

eate

r�

1

sele

ctiv

ityth

anat

enol

ol

1b

Dor

owet

al,10

119

86C

OPD

plus

angi

na(n

�12

)R

PCC

TPL

,AT

100

mg,

biso

prol

ol

20m

g

FE

V1,

airw

ayre

sist

ance

,

resp

onse

toSA

L

24h

1a,2

e,3d

AT

incr

ease

dai

rway

resi

stan

cevs

biso

prol

olan

dpl

aceb

o

Bis

opro

lols

afe

inpt

sw

ithH

TN

and/

oran

gina

&C

OPD

1b

230 Special Reports

Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.orgDownloaded from

Page 11: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

Dor

owet

al,10

219

86A

sthm

apl

usH

TN

(n�

66)

PRC

Chl

orth

alid

one

12.5

,25,

37.5

mg

vsce

lipro

lol2

00,4

00,6

00m

g

qd;d

ose

titra

tion

toB

P

Seri

alPF

T12

wk

1a,2

d,2e

,

4a

PFT

ssi

mila

rfo

rbo

thm

eds;

sym

ptom

sde

crea

sed

with

both

med

svs

plac

ebo

run-

in

No

AE

sfr

omce

lipro

loli

npt

s.

with

asth

ma

and

HT

N

1b

Dos

han

etal

,103

1986

Ast

hma

(n�

16)

RPC

CT

PL,A

T10

0m

g,ce

lipro

lol4

00

mg,

600

mg

Seri

alPF

T;r

espo

nse

toSA

L1

d1a

AT

decr

ease

dF

EV

1an

d

MM

EF

vsPL

;BD

resp

onse

toal

bute

rolb

est

with

celip

rolo

l

Cel

ipro

lolf

ound

tobe

bron

chos

pari

ng

1b

Bru

schi

etal

,104

1988

Ast

hma,

8M

,2F

;FE

V1

�80

%PR

ED

RPC

CT

PL,M

E10

0m

g,ce

lipro

lol

400

mg

FE

V1

and

airw

ayre

sist

ance

pM

C&

SAL

3h

1a,2

eM

E,n

otce

lipro

lolr

educ

ed

FE

V1;

incr

ease

dre

sist

ance

;

grea

ter

reco

very

from

MC

with

celip

rolo

ltha

nM

E

Bro

nchi

alas

thm

a,bu

tno

rmal

vent

ilato

ryfu

nctio

n

1b

Lof

dahl

etal

,105

1988

Ast

hma

(n�

10)

RPC

CT

PL,A

T10

0m

g,M

ESR

100,

200

mg

Seri

alPF

Ts

with

resp

onse

to

terb

utal

ine

1d

1aF

EV

1p

terb

utal

ine

low

erw

ith

AT

than

ME

Con

trol

led

rele

ase

met

opro

lol

has

few

erA

Es

than

aten

olol

1b

van

Zyle

tal

,106

1989

12pt

s;95

�D

BP

�11

5m

m

Hg;

FE

V1

�85

%PR

ED

;

FE

V1

incr

ease

sby

15%

p

salb

utam

ol

RPC

CT

AT

100

mg

qd,c

elip

rolo

l

400

mg

qd

FE

V1,

FV

C,P

EF

pSA

L4

wk

RX

peri

ods

1aF

EV

1,F

VC

,PE

Fre

duce

dw

ith

AT

not

celip

rolo

l;re

spon

seto

SAL

reta

ined

with

both

;

coug

h,as

thm

asx

scor

e,PE

F

and

BD

use

was

nodi

ffer

ent

with

med

svs

plac

ebo

Day

-to-

day

asth

ma

cont

rol

inte

rpre

ted

from

patie

nt

reco

rdin

gsof

peak

flow

,

inha

ler

use,

and

sym

ptom

scor

es

1a

Fog

arie

tal

,107

1990

10M

;95

�D

BP

�11

5m

mH

g;

FE

V1

�70

%PR

ED

and

incr

ease

sby

20%

p

salb

utam

ol

RPC

CT

PR80

mg

qd,o

xpre

nolo

l80

mg

qd,A

T10

0m

gqd

,and

celip

rolo

l200

mg

qd

FE

V1,

FV

C,H

R,B

Pm

easu

red

aan

dp

salb

utam

ol

1w

k1a

,1d,

2e,

4a

PR,o

xpre

nolo

ldec

reas

edF

EV

1

by14

%,p

�0.

05;A

Tan

d

celip

rolo

lonl

ym

inim

ally

decr

ease

dPF

Ts

(NS)

and

perm

itted

BD

No

clin

ical

dete

rior

atio

n;�

1

sele

ctiv

itym

ore

impo

rtan

t

than

ISA

inpt

sw

ithas

thm

a

1b

Wei

chle

ret

al,10

8

1991

OSA

(n�

24);

�10

AP/

h;D

BP

�95

mm

Hg

PRC

ME

100

mg

qd,c

ilaza

pril

2.5

mg

qd

Slee

pst

udie

s8

d1a

,2e,

4aA

HI

decr

ease

dw

ithbo

thm

eds

Slee

pap

nea

stud

y1b

Gra

ftet

al,10

919

92C

laim

s-ba

sed

surv

eilla

nce

syst

emfo

rm

onito

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rhinitis who had no clinical signs of asthma. Com-pared to baseline, coughing and wheezing did in-crease in the two groups, but not more than reportedin the general population (14% cough, 5% wheeze).Mue et al46 reported a similar lack of differences ina small group of patients with stable asthma (n � 6)treated with enalapril for 2 to 4 weeks. Serum levelsof substance P and bronchoreactivity were measuredbefore and after drug treatment. There were nodifferences in bronchoreactivity as measured bythe methacholine challenge test, or differences inmeasured serum substance P values before or aftertreatment. There were no treatment-associatedchanges in the frequency of cough or asthmaticattacks. Patients in this study were also allowed tocontinue on their asthmatic medications, which in-cluded theophylline and occasional �-adrenomi-metic drugs via a metered-dose inhaler. Associatedantiasthmatic medication did not increase.

A summary of drug-related adverse respiratoryevents reported to both the World Health Organiza-tion (up to 1992) and the Swedish Adverse DrugReaction Advisory Committee (from 1981 to 1991)revealed a large number of adverse reactions.48 Atotal of 1,215 adverse reactions to angiotensin-converting enzyme inhibitors was reported to theSwedish Adverse Drug Reaction Advisory Commit-tee. Of these, 424 reactions (34.9%) were adverserespiratory reactions. Cough accounted for the larg-est number (n � 374) of adverse respiratory reac-tions. The remaining 50 reactions were dyspnea(n � 19), aggravated asthma (n � 11), broncho-spasm (n � 6), rhinitis (n � 5), laryngeal edema(n � 4), nasal congestion (n � 3), interstitial pneu-monia (n � 1), and pleuritis (n � 1). Of the reportedevents, 36 patients had dyspnea, aggravated asthma,or bronchospasm, representing 8.2% of the totaladverse events. When extrapolated back to the num-ber of prescriptions sold, a risk of one event per6,200 new prescriptions could be calculated. Reportsto the World Health Organization showed a total of8,094 respiratory reactions, of which cough ac-counted for 89.7%, and asthma, bronchospasm, ordyspnea accounted for 10.3%. What percentage oftotal prescriptions this represented was not calcu-lated. Cough was reported 8 to 10 times more oftenthan wheezing or dyspnea. More than one half of thepatients (53%) with wheezing and dyspnea acquiredsigns within the first 2 weeks of treatment. Severalpatients in the Swedish database had serious respi-ratory adverse events requiring hospitalization andbronchodilator treatment. Of the total reported ad-verse respiratory events, the incidence of dyspnea,aggravated asthma, or bronchospasm was similar forthe two reports: 8.2% and 10.3%. The authorssummarized that the adverse respiratory symptoms

of dyspnea, asthma, or bronchospasm associated withangiotensin-converting enzyme inhibitor therapy arerare, but should be recognized as serious adversereactions.

In a controlled postmarketing study, Wood49 com-pared the occurrence of cough and bronchospasm inpatients receiving an angiotensin-converting enzymeinhibitor or the lipid-lowering drug, benzafibrate.Cohorts of patients were compared for the occur-rence of cough, new bronchospasm, or a relapse of aprevious cough or bronchospasm. The study ran-domized 6,000 patients from the New Zealand In-tensive Medicine Monitoring Program. Data on eachpatient were obtained from a physician question-naire. Of the 6,000 patients randomized, data wereobtained on 1,013 patients receiving angiotensin-converting enzyme inhibitors and 1,017 patientsreceiving benzafibrate. Patients receiving angio-tensin-converting enzyme inhibitors had a higherincidence of cough (12.3% vs 2.7%, p � 0.0001).Although patients receiving angiotensin-convertingenzyme inhibitors reported a higher frequency ofcough and bronchospasm, those patients with a priorhistory of asthma or bronchospasm did not report ahigher incidence of respiratory adverse reactions(16%) than those patients receiving an angiotensin-converting enzyme inhibitor without a prior historyof bronchospasm (13%, p � 0.447), suggesting thatpatients with a history of asthma were not at in-creased risk of bronchospasm or cough. This studyevaluated patients over a period of 3 to 5 years. Ofthe 6,000 patients randomized, only data for 2,030patients were available for analysis due to poorphysician response or grossly inadequate informationsupplied. Also, patients with a history of asthmawould be expected to continue their antiasthmaticmedications.

In a prospective, randomized study comparingthree different antihypertensive therapies in patientswith COPD, Lin et al42 reported overall side effectswere similar in patients receiving lisinopril with orwithout diuretics (16 of 22 patients) compared tonifedipine with or without diuretics (17 of 22 pa-tients), or diuretics with or without vasodilators (19of 22 patients). The primary objective in this studywas BP control in patients with COPD. The studywas conducted over a 1-year period. Bronchoreac-tivity or pulmonary function tests were not done.Only the incidence of cough was reported higher inthe lisinopril group than in the other two cohorts(significance not reported).42

With regard to congestive heart failure, angio-tensin-converting enzyme inhibitors favorably altercardiac function in patients with left ventricularsystolic dysfunction. Since 1987, several large, pro-spective, randomized, placebo-controlled trials have

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demonstrated that angiotensin-converting enzymeinhibitors can favorably affect mortality and morbid-ity in patients with congestive heart failure and leftventricular systolic dysfunction.111–113 These studieshave had a major impact on the management ofcongestive heart failure. Unfortunately, as cough isthe major side effect, data are somewhat limited onthe incidence of cough and the cause for angio-tensin-converting enzyme inhibitor withdrawal inthe congestive heart failure patients. This is incontrast to the abundant literature on angiotensin-converting enzyme inhibitor-induced cough in pa-tients with systemic hypertension.

In the angiotensin-converting enzyme inhibitormortality trials, cough was not a major reported sideeffect.42,48 Only in the Veterans Administration Co-operative Vasodilator-Heart Failure Trial, comparingenalapril to hydralazine plus isosorbide dinitrate, didpatients receiving an angiotensin-converting enzymeinhibitor report a significantly higher incidence ofcough than the hydralazine plus isosorbide dinitrategroup (37% vs 29%, p � 0.05).42 There were nosignificant differences in withdrawal rates or inci-dence of bronchospasm between the two groups. Ina later study, Ravid et al114 did show significantdifferences in the development of cough betweenpatients receiving an angiotensin-converting enzymeinhibitor for systemic hypertension (n � 164), andpatients receiving an angiotensin-converting enzymeinhibitor for congestive heart failure (n � 104).Cough developed in 50 patients (18.6%) receiving anangiotensin-converting enzyme inhibitor. Cough de-veloped in 23 patients (14%) with systemic hyper-tension at 24.7 � 17.1 weeks, and cough developedin 27 patients (26%) with congestive heart failure at12.3 � 12 weeks. In the 50 patients in whom coughdeveloped, 25 patients (50%) had treatment perma-nently discontinued. These differences accountedfor an incidence of intolerable angiotensin-convert-ing enzyme inhibitor-induced cough of 4.0% inpatients with systemic hypertension and 18% inpatients with congestive heart failure. When sub-groups of patients were analyzed, cough developedin 10 of 56 patients with COPD and 5 patients(9.0%) discontinued the drug. In nine patients withasthma, cough developed in only one patient (11%),and drug discontinuance was not required. Broncho-spasm developed in no patients with COPD orasthma. This study was not blinded, but clinicallysignificant cough occurred in patients with conges-tive heart failure more frequently than in patientswith systemic hypertension. In many patients, coughsubsequently regressed and even disappeared with-out discontinuance of angiotensin-converting en-zyme inhibitor therapy. Patients with bronchopul-monary disease did not have a higher incidence of

angiotensin-converting enzyme inhibitor-associatedcough than those patients without bronchopulmo-nary disease. However, the use of bronchodilatorsand inhaled steroids was not mentioned.

Angiotensin II Receptor Antagonists: Drugs thatprevent angiotensin II binding to the angiotensin IIreceptors do not affect the kinase functions ofangiotensin-converting enzyme because they actmore distally in the renin-angiotensin cascade. Theaccumulation of bronchoirritants, such as the brady-kinins and substance P, does not occur with thesedrugs. In patients with pulmonary disease or patientswith congestive heart failure intolerant of cough, anangiotensin II receptor blocker would be the theo-retically preferred choice. Two studies115,116 com-pared the incidence of cough in patients with sys-temic hypertension and a previous history ofangiotensin-converting enzyme inhibitor-associatedcough who were now receiving the angiotensin IIreceptor blockers losartan or valsartan. These ran-domized double-blind studies compared the inci-dence of cough between valsartan or losartan vslisinopril and hydrochlorothiazide or metolazone.Patients in the valsartan study were treated for 6weeks, while patients in the losartan study weretreated for 10 weeks. The incidence of cough in thelosartan-treated patients was similar to that of meto-lazone-treated patients (18% vs 21%, p � not signif-icant) and significantly less than that of lisinopril-treated patients (97%, p � 0.001). Similar resultswere reported in the valsartan study. The overallincidence of adverse events was highest for lisinopril(86.7%), compared to valsartan (57.1%, p � 0.001)and hydrochlorothiazide (61.9%, p � 0.001). Al-though patients with a history of pulmonary diseasewere excluded in these studies, the authors suggestthat the use of an angiotensin II receptor antagonistcould be an alternate choice in patients with a historyof intolerant cough associated with angiotensin-converting enzyme inhibitors, pulmonary disease,bronchoreactivity, and congestive heart failure.

There are presently no large randomized con-trolled trials showing that patients with broncho-pulmonary disease have an increased risk of angio-tensin-converting enzyme inhibitor-associated coughor bronchospasm. However, studies do suggest thatbronchoreactivity as a result of angiotensin-converting enzyme inhibitor therapy has no greaterincidence in patients with bronchopulmonary dis-ease than in the general population. These studieslack statistical power, used the administered drugover a short time period, and did not control forother drugs that affect pulmonary function, and thuscould mask events induced by angiotensin-convert-ing enzyme inhibitor. Controlled longitudinal studies

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in patients with pulmonary disease might not bepossible because of the nature of the disease. Pa-tients with congestive heart failure might be atincreased risk of cough when treated with angio-tensin-converting enzyme inhibitors.

In patients with pulmonary disease where there isa concern about a possible adverse respiratory eventassociated with angiotensin-converting enzyme in-hibitor, or in patients with congestive heart failurewho acquire cough, the use of an angiotensin IIreceptor antagonist may be considered, althoughthere are no data from controlled studies (level C).

�-Adrenergic Blocking Agents: The �-blockers area major class of antihypertensive medications. Theiruse is generally avoided in patients with COPD.�2-Receptor activation promotes bronchodilationand blockade of these receptors increases airwayresistance. �1-Receptor activation may contribute tobronchodilation as well, although this is less clear. Itis, therefore, not surprising that �-adrenergic block-ing agents may have adverse clinical effects in pa-tients susceptible to bronchoconstriction.

The effects of propranolol on the ventilatory func-tion of asthmatic patients was reported by McNeill in1964.117 In this study, patients received 5 to 10 mg ofIV propranolol and measurements of FEV1 weremade prior to and 1 h after treatment. Four of 10patients demonstrated a profound sudden decreasein FEV1.

Case reports have brought attention to the abilityof �-adrenergic blocking agents to cause broncho-spasm. In 1981 Raine et al96 described a 23-year-oldwoman who was prescribed nadolol for the treat-ment of hypertension. The patient had a history ofasthma without recent exacerbation and used abronchodilator aerosol to control exercise-inducedwheezing. She suffered a respiratory arrest soonafter receiving nadolol and received mechanical ven-tilation for several days before she recovered. Ander-son et al94 described two patients with a history ofmild asthma who had bronchospasm that persistedfor months after discontinuance of a �-adrenergicblocker.

Despite the known association between �-adrenergic blocker use and bronchospasm in patientswith asthma, these medications have, albeit infre-quently, been prescribed for asthmatics. Graft etal109 in 1992 reported that 3,170 patients in a healthmaintenance organization were identified as havingasthma. Of these patients, 1.4% received a �-adren-ergic blocking drug. Use varied with age and wasmore common in older patients (8.9%) vs youngerpatients (� 1.0%). Two asthmatic patients who re-ceived �-adrenergic blocking agents were hospital-ized for asthma. Both patients recovered after

several days of treatment with IV steroids, amino-phylline, and bronchodilator aerosol. In 61% of thecases where �-adrenergic blocking agents were pre-scribed to asthmatic patients, multiple physicianswere involved in patient management.

With a number of classes of drugs available to treatsystemic hypertension, is it ever necessary to use�-adrenergic blocking agents to treat hypertension inan asthmatic patient? Are any subclasses or specific�-adrenergic blocking agents safe for use in theasthmatic patient? Do �-adrenergic blocking agentscause complications in patients with lung diseasesother than COPD and asthma? What type of medicalhistory prompts caution in the use of a �-adrenergicblocking agent? For example, should a single episodeof bronchospasm associated with an upper respira-tory infection contraindicate the use of a �-adrenergicblocking agent 40 years later?

Clinical trials done to evaluate the effect of various�-adrenergic blocking agents on parameters of pul-monary function are presented in Tables 1, 4. How-ever, these studies have involved small numbers ofpatients over short periods of time. Atenolol, biso-prolol, celiprolol, metoprolol, and pindolol are the�-adrenergic blocking agents used most frequentlyin these clinical trials.89–93,95,97–108,110

Based on an understanding of �-adrenergic recep-tor antagonism, a cardioselective �-adrenergic re-ceptor blocker would be expected to have an advan-tage over a nonselective blocker in patients withasthma. Six studies evaluated the differential effectsof a cardioselective and a nonselective �-adrenergicblocker on parameters of pulmonary function inpatients with asthma or COPD.89,93,97–99,107 Atenolol,bisoprolol, celiprolol, and metoprolol are the fourcardioselective agents used most frequently in theclinical trials.

Fogari et al,107 using a single-blind, randomized,crossover design, treated patients with COPD for1 week with propranolol, 80 mg/d; oxprenolol, 80mg/d; atenolol, 100 mg/d; and celiprolol, 200 mg/d.Propranolol decreased FEV1 by 16.4% (p � 0.05),whereas atenolol and celiprolol minimally decreasedFEV1 and FVC (not significant) and permitted thebronchodilator response of salbutamol. In anothertrial, Lawrence et al98 treated hypertensive asthmat-ics in serial fashion with propranolol, atenolol, andmetoprolol using a randomized, single-blind, cross-over design. Treatment was continued for 3 weekswith each medication. The authors found that pro-pranolol decreased FEV1 compared to atenolol andmetoprolol, and also decreased the bronchodilatorresponse to salbutamol in comparison with atenololand metoprolol. Atenolol and metoprolol decreasedFEV1, FVC, and peak expiratory flow rate (PEFR)when compared to placebo, but they did not de-

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crease responsiveness to salbutamol. Nonetheless,the response to atenolol and metoprolol was superiorto propranolol.

Formgren90 reported that the cardioselectivity ofcertain �-adrenergic blockers can be lost at thehigher dosage range. Seventeen hypertensive asth-matics were treated with two doses of the cardiose-lective �-adrenergic blockers, metoprolol and prac-tolol. A single-blind, crossover design was used, andtreatment was continued for 17 days after a 14-dayplacebo run-in phase. Lower doses of practolol(200 mg/d) and metoprolol (100 mg/d) produced noeffect on FEV1. At higher doses (practolol, 400 mg/d;metoprolol, 200 mg/d) both �-blockers reduced theFEV1. Four patients experienced a worsening ofasthma during treatment at higher doses of bothmedications.

Celiprolol and bisoprolol are cardioselective�-blockers that may have the least effect on pulmo-nary function in patients with COPD. Van Zyl et al106

treated 12 asthmatic patients with mild-to-moderatehypertension receiving atenolol, 100 mg/d, and celi-prolol, 400 mg/d. The study design involved a single-blind, 2-week, placebo run-in period followed by adouble-blind, randomized crossover phase using4-week treatment periods for each medication. Pa-rameters of pulmonary function were measured atpredetermined intervals following administration ofmedication, and response to salbutamol was mea-sured. The FEV1, FVC, and PEFR fell progressivelyover 3 h in patients receiving atenolol, but not thosereceiving celiprolol. Bronchodilator response wasmaintained after treatment with both drugs. Dailycontrol of asthma was no different during treatmentwith atenolol or celiprolol vs placebo. Cough, asthmasymptom scores, daily peak flow measurements, andbronchodilator use did not differ from placebo.

Two studies compared the cardioselective�-blockers, atenolol and bisoprolol, in patientswith reversible airways disease.100,101 Chatterjee100

treated 12 asthmatics with mild-to-moderate hyper-tension with placebo; atenolol, 100 mg/d; and twodoses of bisoprolol daily. The study design wasrandomized and double blind, and involved a four-way crossover protocol. Pulmonary function wasmeasured after a single dose of medication. Atenololand bisoprolol produced small decreases in PEFR,FEV1, and FVC that were not statistically significant.Atenolol increased airway resistance vs placebo(p � 0.05), while bisoprolol did not. None of thepatients had an adverse clinical event. In a random-ized, placebo-controlled crossover trial of 12 COPDpatients with angina, Dorow et al101 found thatatenolol treatment similarly increased airway resis-tance in comparison to bisoprolol and placebo.

The literature supports the concept that cardiose-

lective �-adrenergic blocking agents exert less effectthan nonselective agents in patients with reversibleairways disease. Cardioselectivity may be lost withcertain agents at higher doses. Most of the literaturethat reports adverse effects when �-adrenergicblockers are used in patients with lung diseaseinvolves patients with reversible airways disease:asthma or COPD. The question of whether it is everadvisable to use a cardioselective �-adrenergicblocker in patients with asthma or established COPDbecomes a question of benefit and risk.

The literature is limited in identifying other pul-monary diseases that may be exacerbated with theuse of �-adrenergic blockers. There is also insuffi-cient literature to indicate whether a hypertensivepatient with a remote history of asthma should beexcluded from a trial of a �-adrenergic blockingagent. The case histories of refractory bronchospasmin two patients indicate that �-adrenergic blockerscan produce adverse effects even in patients withmild disease. It is possible that patients with aremote history of asthma may tolerate �-adrenergicblocking agents with a low probability of developingbronchospasm.

Considering the wide range and availability ofother classes of antihypertensive drugs, �-adrenergicblockers should be avoided in patients with a historyof asthma, except in individual cases where cost/benefit analysis suggests otherwise (levels A-2, B-1).If a patient with asthma and severe systemic hyper-tension is unable to tolerate other classes of antihy-pertensive medications, a trial of a cardioselective�-adrenergic blocker could be attempted whilemaintaining optimal treatment with bronchodilators.However, the likelihood of a patient having adversereactions to all other classes of antihypertensivedrugs and requiring a �-blocker should be extremelylow (levels B-1, C).

The benefit-to-risk ratio for using a �-adrenergicblocker in a patient with mild asthma would behigher in a patient with severe angina whose diseaseis not amenable to surgery or angioplasty. Whilecalcium channel antagonists and nitrates could beused in such a patient, there might be a role for a�-adrenergic blocker (levels B-1, C).

�-�-Blockers and Other Non-�-Blocker Classes ofDrugs: �-Adrenoreceptor antagonists (�-blockers)reduce both systolic and diastolic pressure by ap-proximately 15% and are similar to thiazide diureticsin their antihypertensive effectiveness. However,they tend to worsen pulmonary function in patientswith COPD. In contrast, a class of �-blockers thatalso block �-adrenergic receptors does not inducebronchoconstriction and has been found to be effec-tive in the treatment of hypertension in patients with

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236 Special Reports

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Page 17: Treatment of Systemic Hypertension in Patients With Pulmonary Disease

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COPD and asthma. This class of drugs includesatenolol, labetalol, nebivolol, and doxazosin.

As reviewed earlier, other alternatives to the�-blockers are also now available and include thecalcium channel blockers, angiotensin-convertingenzyme inhibitors, and angiotensin receptor block-ers. Calcium blockers, such as verapamil, nifedipine,nitrendipine, and amlodipine, have antihypertensiveactivity with no effect on respiratory function. Theangiotensin-converting enzyme inhibitors captopril,enalapril, spirapril, candesartan, and cilexetil havealso been found useful in the treatment of hyperten-sive asthmatics (Tables 1, 5).39,41,50,118–131

Almost all studies demonstrate that the newerclass of �-�-blockers with �-blocking activity, cal-cium blockers, and angiotensin-converting enzymeinhibitors effectively treat hypertension without ex-acerbating already compromised pulmonary function(asthma, COPD, or obstructive sleep apnea). Mostfindings are based on well-designed, double-blind,randomized control studies of a limited number ofpatients. Larger studies are needed. Consistent studyoutcomes warrant the application of these drugs inhypertensive patients with compromised pulmonaryfunction (level A-2).

Final Summary of Recommendations

Within the population of approximately 50 millionUS adults with systemic hypertension, a subpopula-tion of several million with comorbid chronic pul-monary disease merits special consideration of BP-lowering treatment that takes the comorbidpulmonary disease into account.

Diuretics

Use of diuretics in hypertensive patients withpulmonary disease is currently untested, and there-fore alternatives should be considered (levels B-2, C).

Calcium Antagonists

There are insufficient data for making a recom-mendation regarding use of calcium antagonists inthe management of systemic hypertension in pa-tients with concomitant COPD or SDB. Most studiesto date have shown calcium antagonists to modestlydecrease bronchial reactivity (level B-2).

Angiotensin-Converting Enzyme Inhibitors

Cough associated with angiotensin-converting en-zyme inhibitors could be a moderate-to-serious ad-verse reaction to this class of drugs in patients withsensitive airway disease, decreased pulmonary func-

tion, or congestive heart failure. Cough and possiblebronchospasm could be an important factor in pa-tient noncompliance (level C).

Studies to date indicate the incidence of angio-tensin-converting enzyme inhibitor-associated coughto be 10 to 20%. There are no large randomizedcontrolled trials to indicate any higher incidence ofcough or bronchospasm in patients with bronchopul-monary disease (levels A-2, B-1).

Angiotensin II Receptor Antagonists

The use of an angiotensin II receptor antagonistmay be considered when angiotensin-converting en-zyme inhibitor-associated cough is a concern inpatients with congestive heart failure or pulmonarydisease (level C).

�-Adrenergic Blocking Agents

�-Adrenergic blocking agents increase airway re-sistance and should not be administered to patientswith asthma or other reversible airways disease. Onlyin selected instances of coexisting cardiac conditions,may �-adrenergic blocking agents be considered fortrial (levels B-1, C).

Some studies support the concept that cardiose-lective �-adrenergic blocking agents exert less effectthan nonselective agents on pulmonary function inpatients with reversible airways disease. If an asth-matic patient with severe systemic hypertension isunable to tolerate other classes of antihypertensivemedications, a trial of a cardioselective �-adrenergicblocker could be attempted while maintaining opti-mal treatment with bronchodilators. Cardioselectiv-ity may be lost at higher doses of these agents (levelsB-1, C).

�-�-Blockers and Other Alternatives to �-Blockers

Based on well-designed, double-blind, random-ized control studies of a limited number of patients,the application of the newer class of �-�-blockerswith �-blocking activity, calcium blockers, and an-giotensin-converting enzyme inhibitors in hyperten-sive patients with compromised pulmonary functionis warranted (level A-2).

ACKNOWLEDGMENTS: We owe a debt of gratitude tothe American College of Chest Physicians, who encouraged theinitiation of this review. We would also like to acknowledge thetechnical writing assistance of James Breeling, Alice Stargardt,and Graig Eldred, and the assistance in literature research byBarbara Bartkowiak and Rose Sterzinger-Johnson. We furtherthank Richard Wurdeman and Sungyong Choi of CreightonUniversity, School of Pharmacy, for their contribution of review-ing and drafting a section of this article.

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Appendix: Rationale of the MethodologicApproach

Selection of Studies for Review

The starting point for a systematic review, as was conducted forthis work, is to ensure that relevant evidence is reviewedcomprehensively and objectively. Searches based on selectiveretrieval of studies are vulnerable to biases and imbalancedperspectives on extant data. Systematic reviews define admissibleevidence by specifying the diagnosis, patients, interventions, andoutcomes of interest, relevant study designs, and exclusioncriteria.

In performing a critical review of the literature, one caution iswarranted. Deriving evidence solely from studies in the literatureexcludes unpublished data and may generate an unbalanced viewof the evidence. There exists a statistically significant publicationbias: investigators tend only to publish significant results.1 Ourreview of the literature should be viewed in that context.

Nonetheless, we chose not to include unpublished findings inour analyses. To do so would require review of conferenceabstracts, databases, and laborious inquiries at academic depart-ments, journals, and other settings. Moreover, studies are oftenunpublished because of serious methodologic problems anddesign flaws, and can be unreliable sources of evidence.

Evaluating the Quality of Individual Studies

A distinction must be drawn between evaluating individualstudies and weighing the evidence as a whole. The overallevidence for the health benefits of a treatment involves multiplelinkages in the causal pathway that links intervention to healthoutcomes. To infer that lowering dietary fat intake is beneficial inpreventing heart disease, for example, one must consider theevidence relating dietary fat intake to serum lipid levels, the linkbetween serum lipids and atherosclerosis, and the relationshipbetween fat intake, lipid levels, and the incidence of heartdisease. For each of these linkages, the quality of the evidencemust be examined carefully, with attention not only to individualstudies, but to the consistency and strength of the evidence as awhole.

Study Design Categories

The persuasiveness of a study is influenced in large measure byits overall design structure, eg, randomized controlled trial,cohort study, etc. The vulnerability of research findings to biasand measurement error depends on how subjects were selected,how outcomes were measured, the inclusion of a comparison(control) group, whether the analysis was prospective or retro-spective, and a variety of other important methodologic consid-erations. Certain archetypal study designs—randomized con-trolled trials—are considered more persuasive than others becausethey are inherently less vulnerable to bias and confounding.

However, randomized controlled trials are typically expensiveand time-consuming, and thus are characteristically fewer innumber than other types of studies of a given subject matter.While nonrandomized controlled trials are not as rigorous asrandomized controlled trials, they nonetheless rank highly ascompared to other study designs reported in this review. Due tothe paucity of both randomized and nonrandomized controlledstudies available for analysis, we have chosen to combine the twotypes into the level 1 evidence category. Other types of studiesthat may provide evidence for analysis range from the case report(may highlight interesting findings but does not provide adenominator for calculating the frequency of observed effects or

the strength of associations), to observational studies in which thedecision as to whether the subjects will or will not receive atreatment is not made by the investigators.

Whether a study is a randomized controlled trial or a case-control study is often less important than how well it wasconducted: the clarity of the design, sample size, definition ofinterventions and outcomes, and statistical methods. The qualityof the research methods can affect both internal validity (theextent to which the study results are applicable to the populationand setting described in the study) and external validity (thegeneralizability of the results to the “real world” outside thestudy). Issues affecting internal validity include sample size andstatistical power, selection of subjects and control subjects,definition of intervention, definition/measurement of health,intermediate and surrogate outcomes, confounding variables andmeasurement biases, attrition and follow-up, and statistical meth-ods. Issues affecting external validity include the generalizabilityof the study population, intervention, and setting to the situationof interest.

The strength of evidence that a treatment is associated with ahealth outcome depends not only on the quality of individualstudies, but on the overall grade of the evidence taken together,the number of studies, the consistency of results, and themagnitude of effects. Moreover, evidence of an association doesnot infer causality. An association or correlation of variablesmeans only that they occur together, not that one causes theother. To invoke causality one must also demonstrate certainwell-established patterns such as biological plausibility, consis-tency of association, dose-response relationship, and specificity.

The final judgment of the quality of the evidence is oftensubjective. Although checklists can be helpful in ensuring thatthese determinants of quality are considered, the integration ofeach element into an overall rating of “good,” “fair,” or “poor”often culminates in a subjective judgment. What qualifies as“insufficient evidence” can mean that no studies have beenperformed, that studies have not been performed that proveineffectiveness, or that extant studies are of poor quality, incon-sistent, or too few in number to allow definitive conclusions.Reviewers with different methodologic expectations about goodscience, preconceptions, biases, and conflicts of interest reachdifferent conclusions about when the evidence is “good enough.”

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DOI 10.1378/chest.123.1.222 2003;123;222-243 Chest

and Steven H. Woolf Richard A. Dart, Steve Gollub, Jason Lazar, Chandra Nair, David Schroeder

Disease: COPD and AsthmaTreatment of Systemic Hypertension in Patients With Pulmonary

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