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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
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
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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: dart.richard@marshfieldclinic.org.
special reports
222 Special Reports
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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).
224 Special Reports
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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
Tab
le3—
Ang
iote
nsin
-Con
vert
ing
Enz
yme
Inhi
bit
orSt
udi
es
Sour
ceSt
udy
Popu
latio
nSt
udy
Des
ign
Inte
rven
tion
Met
hods
Dur
atio
nD
esig
nF
law
s/L
imits
Res
ults
Gra
de
Sala
etal
,4319
86A
sthm
a(n
�16
)PC
SC
MC
;ser
umsu
bsta
nce
P4
wk
1a,2
e,4a
No
chan
gein
BC
2bSc
hale
kam
pet
al,44
1986
CO
PD(n
�19
)PC
SC
FE
V1,
PEF
60d
1a,2
e,4a
No
effe
cton
FE
V1,
PEF
2bR
iska
etal
,4519
87H
TN
,ast
hma
(n�
12)
RPC
CT
C,V
BP,
FE
V1,
PEF
,sym
ptom
s8
wk
1a,2
e,4a
No
chan
gein
FE
V1,
PEF
,or
coug
h1b
Mue
etal
,4619
90A
sthm
a(n
�6)
PCS
EM
C;s
erum
subs
tanc
eP
2–4
wk
1a,2
e,4a
No
chan
gein
BC
orco
ugh
duri
ngE
;no
chan
gein
subs
tanc
eP
leve
ls2c
Kau
fman
etal
,4719
92A
sthm
a,al
lerg
icrh
initi
s(n
�21
)PC
SE
vssp
irap
ril
Spir
omet
ry,M
C12
wk
1a,1
f;2d
No
chan
gein
spir
omet
ry,M
C2b
Lun
deet
al,48
1994
Popu
latio
nba
sere
ceiv
ing
AC
Ein
hibi
tors
(n�
9,30
9)
RC
S11
diff
eren
tA
CE
inhi
bito
rsO
ccur
renc
eof
asth
ma,
dysp
nea
inpt
s.on
AC
Ein
hibi
tors
1981
–199
21d
88–9
0%A
Ew
ere
coug
h;10
%w
ere
asth
ma,
dysp
nea,
orB
C2a
Woo
d,49
1995
HT
Nw
ithhi
stor
yof
BC
(n�
4,64
6)R
CC
C,E
,Lvs
benz
afib
rate
Que
stio
nnai
re3–
5yr
3cC
ough
�12
%in
AC
Ein
hibi
tors
,2.
7%in
LL
D;n
oef
fect
ofpr
ior
Hx
ofB
C
2b
Lin
etal
,4219
96H
TN
and
CO
PD(n
�66
)PR
CD
iure
tics
with
orw
ithou
tN
,LB
Pco
ntro
l;co
ugh
repo
rtin
g1
yr1a
No
AE
;3/2
2in
Lgr
oup
had
coug
h1c
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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
Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.orgDownloaded from
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
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
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
ring
145,
199
pts
inan
HM
O
duri
ng19
89
RC
RN
one
Cha
rtau
dit
tove
rify
diag
nosi
s
and
med
s
NA
3cPr
eval
ence
ofas
thm
a�
2.2%
;
1.4%
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www.chestjournal.org CHEST / 123 / 1 / JANUARY, 2003 231
Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.orgDownloaded from
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
232 Special Reports
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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
www.chestjournal.org CHEST / 123 / 1 / JANUARY, 2003 233
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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-
234 Special Reports
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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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Tab
le5—
�-�
Blo
cker
Stu
dies
Sour
ceSt
udy
Popu
latio
nSt
udy
Des
ign
Inte
rven
tion
Met
hods
Dur
atio
nD
esig
nF
law
s/L
imits
Res
ults
Com
men
tsG
rade
Ana
veka
ret
al,1
1819
829
pts;
HT
Nfo
r2–
18yr
plus
CO
PDfo
r8–
22yr
;FE
V1
�30
–60%
FV
C
DB
RC
T4
wk
basa
l,2
wk
plac
ebo,
6w
kve
rapa
mil
160
mg
bid
orla
beta
lol2
00m
gbi
d,2
wk
plac
ebo,
6w
kla
beta
lolo
rve
rapa
mil
HR
,BP,
and
FE
V1,F
VC
aan
dp
salb
utam
ol20
wk
1a,1
d,2e
,4a
Lab
etal
olsi
gnifi
cant
lyre
duce
sF
EV
1an
dF
VC
;ver
apam
ilha
sno
effe
ct;n
eith
erca
uses
side
effe
cts
No
adva
ntag
eat
dose
sus
ed;s
mal
lsel
ectio
nbi
asof
fset
byre
prod
ucib
ility
ofth
est
udy
1b
Lig
htet
al,1
1919
8320
pts;
HT
Npl
usC
OPD
for
2m
oor
mor
e;95
�D
BP
�12
0m
mH
g;0.
55�
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V1/F
VC
�0.
70;C
OPD
reve
rsib
lep
isop
rote
reno
l:F
EV
1
�15
%or
MM
EF
�25
–75%
DB
RC
T4
wk
plac
ebo,
4w
kla
beta
lol1
00–4
00m
gtid
orhy
droc
hlor
othi
azid
e25
–50
mg
tid,1
wk
plac
ebo
FE
V1,F
VC
,HR
,BP
mea
sure
da
and
pm
edic
atio
n
9w
k1a
,2e,
4aD
iure
ticde
crea
sed
BP
asm
uch
asla
beta
lol
Smal
lstu
dy,s
hort
dura
tion;
emph
asis
onsa
fety
ofla
beta
lol;
little
onH
CT
Z
1b
Fal
liers
etal
,120
1985
52as
thm
atic
pts
(35
qual
ified
bypr
opra
nolo
lstr
ess
test
);95
�D
BP
�11
5m
mH
g
DB
RC
T2–
4w
kpl
aceb
o,4
wk
labe
talo
l(10
0–60
0m
gbi
d)or
HC
TZ
(25–
50m
gbi
d)
FE
V1,F
VC
,aan
dp
prop
rano
lol,
BP,
HR
6–8
wk
1a,2
e,4a
Bot
heq
ually
effe
ctiv
e,no
adve
rse
side
effe
cts,
both
decr
ease
dB
Pab
out
the
sam
e
1b
Geo
rge
etal
,121
1985
41pt
s;H
TN
plus
asth
ma
(mild
tom
oder
ate)
DB
RC
T2–
4w
kpl
aceb
o,4
wk
labe
talo
l(10
0–60
0m
gbi
d)or
HC
TZ
(25–
50m
gbi
d)
FE
V1
aan
dp
prop
rano
lol
6–8
wk
1a,1
d,2e
,4a
Bot
hre
duce
dF
EV
1,
labe
talo
lmor
eth
anH
CT
Z,bu
tba
rely
Prim
ary
focu
son
labe
talo
lsa
fety
;sm
alls
tudy
ofsh
ort
dura
tion
1b
Ana
veka
ran
dD
oyle
,122
1986
1)17
pts
with
HT
N;
2)9
pts
with
HT
Npl
usC
OPD
DB
RC
T1)
vera
pam
il(1
20m
gtid
)or
pind
olol
(7.5
mg
bid)
;2)
vera
pam
il(1
60m
gtid
)or
labe
talo
l(7
.5m
gbi
d)
1)he
mod
ynam
ican
dca
rdia
cF
ncan
dbi
oche
m;2
)H
R,B
P,F
EV
1,F
VC
w/s
albu
tam
olch
alle
nge
20w
k1a
,1d,
2e,4
a1)
BP
fell
equa
lly;
vera
pam
ilha
dno
effe
cton
plas
ma
reni
nco
ncen
trat
ion
2)la
beta
lolr
educ
edF
EV
1an
dF
VC
,ve
rapa
mil
did
not
Bot
hst
udie
sw
ere
smal
lin
No.
1b
Ris
kaet
al,1
2319
868
pts;
asth
ma
plus
HT
ND
BR
CT
Cap
topr
il(5
0–10
0m
g)or
vera
pam
il(1
60–2
40m
g)
BP;
PEF
;ast
hma
sym
ptom
s4
wk
1a,2
e,4a
Bot
hdr
ugs
redu
ced
BP
with
few
eror
thos
tatic
chan
ges
with
capt
opri
l;no
effe
cton
PEF
oras
thm
asy
mpt
oms
Ver
yfe
wpa
tient
san
dsh
ort
dura
tion;
allw
ere
onhy
droc
hlor
othi
azid
ean
dbr
onch
odila
tors
thro
ugho
ut
1b
Cla
uzel
etal
,124
1988
9pt
s;M
ildH
TN
plus
asth
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236 Special Reports
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www.chestjournal.org CHEST / 123 / 1 / JANUARY, 2003 237
Copyright © 2003 by American College of Chest Physicians on February 14, 2008 chestjournal.orgDownloaded from
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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