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Treatment of Systemic Hypertension in Patients With Pulmonary Disease: COPD and Asthma

Richard A. Dart, Steve Gollub, Jason Lazar, Chandra Nair, David Schroeder and Steven H. Woolf Chest 2003;123;222-243 DOI 10.1378/chest.123.1.222

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

CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 2007 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder (http://www.chestjournal.org/misc/reprints.shtml). ISSN: 0012-3692.

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special reports
Treatment of Systemic Hypertension in Patients 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 for systemic high BP in patients with pulmonary diseases. Part I examines the literature pertaining to the use of antihypertensive drugs in patients with systemic hypertension and coexisting pulmonary conditions, especially COPD and asthma. Part II of the series reviews studies assessing the relationship between sleep-disordered breathing (including the role of the sympathetic nervous system) and systemic hypertension, and presents an approach to the management of these patients. It is the aim of both parts of this review to make qualified conclusions and recommendations applying a methodologic critique to assess the current literature. In the first part of this series, we review the demographics of hypertension in patients with COPD. This is followed by an extensive review of the use of specific classes of antihypertensive drug therapies in patients with pulmonary disease. The antihypertensive agents reviewed include diuretics, calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists, -adrenergic blocking agents, and - -blockers and other non- -blocker classes. Additionally, the renin angiotensin system is briefly reviewed, with a discussion of how angiotensin-converting enzyme inhibitors induce cough, especially in pulmonary and congestive heart failure patients. (CHEST 2003; 123:222243)
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 and Treatment of High BP; PEFR peak expiratory flow rate; SDB sleep-disordered breathing

hypertension T reatment of patients with systemiccoexistence of is frequently complicated by the

chronic pulmonary disease and sleep-disordered breathing (SDB). The latter can itself exacerbate systemic hypertension, and certain antihypertensive drugs can affect pulmonary function. Such patients

*From the Department of Nephrology and Hypertension (Dr. Dart), Marshfield Clinic, Marshfield, WI; Kansas University Medical Center (Dr. Gollub), Kansas City, KS; Winthrop University Hospital (Dr. Lazar), Mineola, NY; Cardiac Center (Dr. Nair), Creighton University School of Medicine and Pharmacy, Omaha, NE; Asheville Cardiology Associates, P.A. (Dr. Schroeder), Asheville, NC; and Virginia Commonwealth University (Dr. Woolf), Fairfax, VA. Manuscript received November 19, 2001; revision accepted July 10, 2002. Correspondence to: Richard Dart, MD, FCCP, Department of Nephrology, Marshfield Clinic, 1000 North Oak Ave, Marshfield, WI 54449-9916; e-mail: dart.richard@marshfieldclinic.org.
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present diagnostic and therapeutic challenges. A wide variety of antihypertensive drugs are now available with different mechanisms of action. This raises questions, such as whether agents that induce bronchospasm should ever be used to treat hypertension in patients with asthma or SDB. What is the physiology behind the drug effects? What alternative classes of drugs have been tested in clinical settings and should be considered under specific circumstances? What type of medical history prompts caution in the use of these agents? The American College of Chest Physicians charged this panel to conduct a systematic and critical review of the literature and summarize relevant recommendations and conclusions regarding the following: (1) antihypertensive drug therapy in patients with chronic
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pulmonary disease, and (2) SDB as a causative or contributory factor in systemic hypertension. In the first part of this series, we review the demographics of hypertension in patients with COPD. This is followed by an extensive review of the use of specific classes of antihypertensive drug therapies in patients with pulmonary disease. The antihypertensive agents reviewed include diuretics, calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists, -adrenergic blocking agents, and - -blockers and other non- -blocker classes. Additionally, the renin angiotensin system is briefly reviewed, with a discussion of how angiotensin-converting enzyme inhibitors induce cough, especially in pulmonary and congestive heart failure patients. Findings and recommendations are presented. Patient evaluation and diagnosis were not a part of this review. SDB issues will be covered in Part II of this series. Materials and Methods
The rationale used for searching the literature, selecting relevant articles, and grading evidence for this article are described in the Appendix. Database Searches For this review, the PubMed database was systematically searched for articles published between 1972 and 2000, using key words and the medical subject heading terms to identify studies. Such studies were considered relevant if they addressed asthma, COPD, lung diseases, pulmonary disease, hypertension, arterial hypertension, and/or systemic hypertension. Both medical subject headings and keywords were used in searches, due to concerns about potential accuracy of National Library of Medicine indexing. Additional comodifying terms included names of classes of antihypertensive drugs and various permutations on class names: -adrenergic receptor blockers, -blockers, 1blockers, 2-blockers, -adrenergic antagonists, sympathetic inhibitors, adrenergic antagonists, -receptor antagonists, central -adrenergic blockers, calcium channel blockers, acetylcholinesterase inhibitors, and - -blockers. Inclusion/Exclusion Criteria Only randomized or nonrandomized control trials, observational, control cohort (longitudinal), case control, cross sectional, uncontrolled case series/cohort, time series, cross-cultural, ecologic, descriptive epidemiologic, and case reports were included. The literature search excluded pulmonary hypertension, editorials, position papers, editorial opinions, abstracts, and letters to the editor. Exceptions to this rule were editorials, position papers, editorial opinions or letters to the editor that provided additional references thought to be of relevance and not found in the original search. We also chose not to review unpublished evidence. All English-language articles identified in these searches and fitting these criteria were included for review. There is a statistically significant publication bias: investigators tend only to publish significant results.1 Thus, our review of the literature should be viewed in that context (see Appendix).
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Tabulated Study Grade Assessments Criteria for judging the retrieved articles was internally developed and uses the following scheme: level 1, randomized (controlled trials) or nonrandomized controlled trials; level 2, observational studies, control cohort (longitudinal), case control including prospective and retrospective, cross-sectional, uncontrolled case series/cohort, time-series, cross-cultural, ecologic, and descriptive epidemiologic studies; and level 3, case reports. A quality judgment was also added based on attributes of sample size, appropriate subjects, methods, outcome measures, statistical analysis, and confounding variables. This judgment was expressed in 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 within each level: level A, evidence provided by well-designed, wellconducted, controlled trials (randomized and nonrandomized) with statistically significant results to support the recommendation (A-1 all studies meet level A criteria, A-2 some studies meet level A criteria, A-3 a few studies meet level A criteria); level B, evidence provided by observational studies or by controlled trials with less consistent results to support the recommendation, or by well-designed trials that are conflicting (B1 all studies meet level B criteria, B-2 some studies meet level B criteria; B-3 a few studies meet level B criteria); and level C, expert opinion that supports the recommendation because the available scientific evidence did not present consistent results, or controlled trials are lacking.

Results and Discussion Demographic Overview: Hypertension in Patients With COPD Approximately 31% of the US adult population50 million persons has elevated systemic hypertension according to estimates based on the third National Health and Nutrition Examination Survey.2 Prevalence of arterial hypertension varies with cutoff values for systolic/diastolic pressure.3 At values of systolic BP 140 mm Hg or diastolic BP 90 mm Hg, 24% of the adult US population had high BP in 1991 according to third National Health and Nutrition Examination Survey estimates.2 The estimated 1996 cost of hypertension was $23.74 billion, including medical expenditures and lost wages.4 Systemic hypertension is a relatively frequent comorbidity with chronic lung diseases. In 1993, the National Health Interview Survey reported the incidence of COPD in the United States to be 6.2%, which broke down to 13.8 million persons with chronic bronchitis and 2.0 million persons with emphysema.5 The incidence of COPD may be higher than 6.2%, as 50% of patients with airflow limitation are asymptomatic and thus not detected in a survey.6
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Although the prevalence of asthma is difficult to ascertain due to lack of a standardized definition, the National Health Interview Survey identified 13.5 million cases of asthma in 199394 for a prevalence of 5.4% in the general population.7 During the same period, asthma accounted for 1.6% of ambulatory visits and 1.6% of emergency department visits.8,9 The incidence and mortality rate of asthma has risen steadily over the past 3 decades.10 12 The prevalence of COPD in patients with systemic hypertension was reported by the Medical Outcomes Study.13 This survey evaluated the functioning and well-being of 9,385 adult outpatients and found 37.3% to have systemic hypertension as diagnosed by their physicians. The prevalence of COPD and asthma was 7.4% in the patients with diagnosed systemic hypertension, and 7.8% in the entire study group. These data suggest that the prevalence of COPD in adults with systemic hypertension is similar to that in the general population. Although chronic bronchitis is a more frequent cause of COPD than emphysema (50.5 cases/1,000 persons vs 6.6 cases/1,000 persons),14 the relative prevalence of chronic bronchitis and emphysema in the hypertensive population is not known. The prevalence of unspecified obstructive lung disease was somewhat lower (3.4%) in the Hypertension Optimal Treatment study,15 which randomized 19,196 patients aged 50 to 80 years with diastolic BPs of 100 to 115 mm Hg to different target BPs. Tobacco smoking is an etiologic factor in both COPD and systemic hypertension. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High BP (JNC VI) emphasized the importance of risk stratification for patients with hypertension according to other risk factors for cardiovascular disease, including smoking and the presence of target organ damage.16 Various antihypertensive drug efficacy studies have found 25 to 43% of hypertensive patients to be present or former smokers.17,18 Smoking is known to increase the impact of hypertension as a risk factor for cardiovascular disease,19 and epidemiologic studies have shown airflow limitation to be an independent predictor of future cardiovascular events in patients with various cardiovascular risk factors.20,21 No study has addressed the incremental risks posed by airflow limitation in hypertensive subjects. Comorbid systemic hypertension and COPD can be expected to increase in incidence as the US baby boom generation ages. In particular, isolated systolic hypertension and emphysema may more frequently occur together, as both conditions are strongly related to advancing age.5 Given estimates that 50 million US adults have systemic hypertension, and approximately 5% of
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those also have COPD (defined as bronchitis and emphysema), there are at least 2.5 million adults in the United States with COPD who merit special consideration for treatment to lower high BP. The prevalence of COPD and asthma in patients with diagnosed systemic hypertension has been found to be similar to the incidence of COPD in the general population. Review of Specific Classes of Antihypertensive Drug Therapies In treating the hypertensive patient with pulmonary complications, a wide variety of drug classes are available in the pharmacopoeia, each of which needs to be understood in terms of its pulmonary side effects. Diuretics: The JNC VI16 recommends diuretics as a first-line choice of drug therapy in the treatment of systemic hypertension. Despite being advocated as front-line therapy, there is paucity of outcome data from randomized controlled trials designed to evaluate the effects of diuretics in the treatment of hypertension in patients with lung disease. There are theoretical benefits derived from using this class of drugs. Peripheral edema is common in this group of patients and may be related to multiple factors, including right heart failure, venous insufficiency, and malnutrition, etc. There may be favorable effects on pulmonary vascular remodeling as well as theoretical risks, including alkalemia (acetazolamide increased minute ventilation in patients with COPD),22 increased hematocrit, and hemodynamic embarrassment in patients who are preload dependent in the setting of right-heart failure. In the rabbit model, low-dose acetazolamide treatment impairs respiratory muscle function23 and magnesium depletion.24 Furthermore, the inhaled administration of nebulized amiloride does not improve pulmonary function in cystic fibrosis,25 and inhaled furosemide is not useful as adjuvant therapy to salbutamol in patients with acute or chronic asthma.26 In conclusion, the JNC VI has recommended the use of diuretics in uncomplicated hypertensive patients as a first-line therapy. However, there have been no direct studies of the use of these agents in the case of hypertensive COPD or asthma patients. Beneficial or deleterious side effects in these patients may only be presumed based on theoretical considerations, indirect animal studies, and potentially relevant observations in patients treated for other conditions. Use of diuretics in hypertensive patients with pulmonary disease is currently untested, and therefore alternatives should be considered (levels B-2, C).
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Table 1Abbreviations Used in Tables


Abbreviation a ACE AE AHI AP ASYM AT BB BC BD C CO CS D DB DBP DBRCT DBPCS E EIB F Fnc F/u GXT HC HCTZ HMO HPLC HR HTN Hx ISA L LLD M MC MCDBRCT MD ME meds MEV MMEF n N NA NS NT OSA p PC PCC PCS Definition before angiotensin-converting enzyme adverse effects apnea/hypopnea index apnea asymptomatic atenolol -blockers bronchoconstriction bronchodilation captopril cross-over cardioselective diltiazem double blind diastolic BP double-blind randomized control trial double-blind placebo-controlled study enalapril exercise-induced bronchoconstriction female function follow-up treadmill test histamine challenge hydrochlorothiazide health maintenance organization high pressure liquid chromatography heart rate hypertensives history intrinsic sympathomimetic activity lisinopril lipid-lowering drugs male methacholine challenge multicenter, double-blind randomized control trial medical doctor metoprolol medicines maximum expiratory volume mid-maximal expiratory flow number of subjects nifedipine not applicable no significant nitrendipine obstructive sleep apnea after placebo controlled prospective case control prospective case study Abbreviation PEF PFT PI PL PR PRC PRED Pts QOL RCR RPCCT RX Rxns SAL SB SDB sl SR sx THEO V VC y/o Design flaws/limits 1: patient characteristics 1a 1b 1c Definition peak expiratory flow rate pulmonary function test pindolol placebo propranolol prospective randomized control predicted patients quality of life retrospective chart review randomized placebo-controlled crossover trial use of antihypertensive drugs reactions salbutamol single blind sleep-disordered breathing sublingual slow release symptom theophylline verapamil vital capacity year old

small population in study groups excessive loss to follow-up varying patient characteristics during followup 1d skewed study group (selection bias) 1e low body mass index 1f failure to control for confounding factors 1g errors in group classification 1h variable duration of sleep disorder 1i measured parameters not well-defined 1j excessive exclusions 1k variable duration of hypertension 2: treatment characteristics 2a variable treatment duration 2b inconsistent documentation/control of hypertension 2c poorly characterized/no intervention 2d not well controlled 2e short treatment duration 3: measurement characteristics 3a inconsistent measurements 3b systolic BP not considered 3c measurement bias (eg, self-administered questionnaire) 3d no dose-response measurement 4: study design limitations 4a short-term study

Calcium Antagonists: A systematic literature search was unable to find outcome data from randomized controlled trials designed to evaluate the effects of calcium antagonists in the treatment of systemic hypertension in patients with COPD (Tables 1, 2).27 42
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Calcium antagonists have long been established to lower BP and regress the left ventricular hypertrophy that may be a sequela of arterial hypertension (Tables 1, 3).42 49 As compared to angiotensinconverting enzyme inhibitors, the calcium antagonist verapamil was found less effective in lowering sysCHEST / 123 / 1 / JANUARY, 2003

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Table 2Calcium Channel Blocker Studies


Study Study Population Design
PRC PCC PRC PCS PCS PCS

Source

Intervention
N 20 mg vs PL N sl vs PL N 20 mg po vs PL

Methods
GXT, HC, PEF

Duration
30 min

Design Flaws/ Limits


1a, 2e, 4a 1a, 2e, 4a 1a, 2e, 4a 1a, 2e, 4a

Results
N prevented EIB N prevented EIB N prevented HC N and V without effect on FEV1 or BC No AE; N improved FEV1 Inhaled V was best at reducing bronchoconstriction

Grade
1b 2bc 1b 2bc 2a 2bc

Barnes et al,27 1981 Asthma with positive skin test (n 8) Mild asthma (n 20) Cerrina et al,28 1981 Williams et al,29 Asthma (n 10) 1981 Asthma with positive So et al,30 1982 skin test (n 8) Nair et al,31 1984 Asthma, COPD, angina (n 60) Ahmed et al,32 1985 ASYM asthma; ragweed hypersensitivity (n 10) Russi et al,33 1985 ASYM asthma; ragweed hypersensitivity (n 12) ASYM asthma Ballester et al,34 1986 (n 13)

Bicycle ergometry; 60 min flow-volume curves HC, FEV1, VC, MMEF 1 h 30 min

V 24 mg inhaled Bronchial provocation vs N 20 mg sl with allergen N 20 mg; short-term Spirometry and long-term safety V 160 mg po vs V 20 Spirometry, airway mg inhaled resistance

2 h; 2 wk 1a, 2e, 4a 45 min 1a, 2e, 4a

PCS

N, V

Ragweed provocation; airway conductance

4d

1a, 1e, 2e, 4a N variably blocked BC in 8/12 pts, V effective in 2 1a, 2e, 4a N reduced airway reactivity but lowered post-methacholine Pao2 N did not affect THEO levels N increased FEV1 but less than albuterol No change in PEF or symptoms; decrease in serum THEO THEO half-life increased by V and D, not N NT without effect Metoprolol increased and isradipine decreased OSA N lowered BP, no effect on FEV1, lower serum THEO at 45 d No AE

2bc

RPCCT N vs PL

MC; FEV1, Pao2

7d

1bc

Jackson et al,35 1986 Schwartzstein and Fanta,36 1986 Smith et al,37 1987

Healthy controls (n 8) Angina, COPD (n 10) Asthma (n 10)

PCS

N SR 20 mg

N levels (HPLC) Spirometry PEF; symptom score

5d 2h 2 wk

1a 1a, 2e, 4a 1a, 2e, 4a

2bc 1b 1b

RPCCT N 20 mg, albuterol, PL RPCCT N SR 20 mg vs PL RPCCT N, V, D

Sirmans et al,38 1988

Healthy controls (n 12) 8)

Serum THEO

8d

1a

1b

Mulloy et al,39 1990 Asthma (n Kantola et al,40 1991

HTN snorers; 12 M

RPCCT nt 20 mg vs PL PCS Isradipine vs metoprolol PCS N 10 po bid

HC, PEF, oximetry Ballistocardiogram, respiratory movement Serum THEO; BP; FEV1; PEF

23 h 8 wk

1a, 4a 1a, 2e, 4a

1bc 2ab

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

45 d

1a

2a

Lin et al,42 1996

HTN and COPD (n 66)

PRC

Diuretics with or BP control; cough without N, lisinopril reporting

1 yr

1a, 2e, 4a

1bc

tolic BP in patients with hypertension and asthma,50 whereas nifedipine was found equally effective as diuretics and angiotensin-converting enzyme inhibitors in lowering systolic and diastolic BP in patients with COPD.42 The JNC VI advocates the use of long-acting dihydropyridine calcium antagonists as second-line therapy for older persons with isolated systolic hypertension.16 This new recommendation was based on the results of the Systolic Hypertension in Europe trial, which randomized 4,695 patients 60 years old with isolated systolic hypertension (systolic BP 160 mm Hg and diastolic BP 95 mm Hg) to nitrendipine or placebo.17 After 2 years,
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there was a 42% reduction in total stroke and 26% reduction in all cardiac end points, a trend toward a 27% reduction in cardiovascular mortality, and no significant change in all-cause mortality. There were no comments about the presence of COPD in the Systolic Hypertension in Europe trial population. Thus, no specific comments regarding any benefits of long-acting dihydropyridine in patients with mildto-moderate lung disease can be made. African Americans as a group are more responsive to calcium antagonists than to -blockers or angiotensin-converting enzyme inhibitors, except with the addition of diuretics that have been shown to imSpecial Reports

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Table 3Angiotensin-Converting Enzyme Inhibitor Studies

prove response.16 It is unknown whether these results may be extrapolated to the African-American patient with COPD. Although the oral and sublingual administration of calcium antagonists does not affect resting bronchial tone, the drugs sometimes attenuate bronchospasm induced by exercise, methacholine, and antigen.2734,36,39 However, single-dose effect, use of short-acting preparations, and lack of BP data limit the applicability of these data. The beneficial effects of calcium antagonists in reducing airway reactivity appear to be offset by worsening of ventilationperfusion mismatch.34 Short-acting preparations of verapamil and nifedipine do not worsen pulmonary symptoms after up to 1 year of treatment.42,50 With regard to drug interactions, calcium antagonists lower serum theophylline levels by a small and insignificant extent.35,37,38,41 In the management of hypertension associated with sleep apnea, one study found dihydropyridine calcium antagonist to cause fewer obstructive breathing patterns as compared to -blocker.40 However, neither drug had a significant effect on BP values. At present, there are insufficient data on which to base any specific recommendations about the use of calcium antagonists in the management of systemic hypertension in patients with concomitant COPD or sleep apnea syndrome. Most studies to date have demonstrated calcium antagonists modestly decrease bronchial reactivity. Additional studies are needed to investigate the clinical outcomes of patients with COPD using calcium antagonists to lower arterial BP. While there may be some benefit in the reduction of bronchial reactivity, the use of calcium antagonists in hypertensive patients with pulmonary disease cannot yet be advocated, and alternatives should be considered (level B-2). Angiotensin-Converting Enzyme Inhibitors: Angiotensin-converting enzyme inhibitors have been successfully used in the treatment of systemic hypertension, congestive heart failure, and more recently in treating diabetic nephropathy. Angiotensinconverting enzyme inhibitors are recognized as firstline agents in the JNC VI report.16 However, adverse drug reactions considered a class effect have been reported, including hypotension, cough, hyperkalemia, renal failure, fetal anomalies, angioedema, and dysgeusia. Other adverse reactions, not believed to be a class effect but related to the presence of a sulfhydryl group, include rash, neutropenia, and a nephrotic type proteinuria. Of the associated side effects, cough is the most common and widely reported class effect of the angiotensin-converting enzyme inhibitors.51 Havelka et al52 first reported cough as a captopril-related
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Grade

2b 2b 1b 2c

2b

2b

No change in BC No effect on FEV1, PEF No change in FEV1, PEF, or cough No change in BC or cough during E; no change in substance P levels No change in spirometry, MC

8890% AE were cough; 10% were asthma, dyspnea, or BC

2a

Design Flaws/Limits

4a 4a 4a 4a

1a, 1a, 1a, 1a,

1a, 1f; 2d

2e, 2e, 2e, 2e,

19811992 1d

Duration

4 wk 60 d 8 wk 24 wk

35 yr

12 wk

3c

MC; serum substance P FEV1, PEF BP, FEV1, PEF, symptoms MC; serum substance P

Occurrence of asthma, dyspnea in pts. on ACE inhibitors C, E, L vs benzafibrate Questionnaire

Intervention

Spirometry, MC

11 different ACE inhibitors

Study Design

PCS PCS RPCCT PCS

C C C, V E

Asthma, allergic rhinitis PCS (n 21) Population base RCS receiving ACE inhibitors (n 9,309) HTN with history of BC RCC (n 4,646) Kaufman et al,47 1992 Lunde et al,48 1994 Wood,49 1995

E vs spirapril

Study Population

12)

Sala et al,43 1986 Asthma (n 16) Schalekamp et al,44 1986 COPD (n 19) HTN, asthma (n Riska et al,45 1987 Asthma (n 6) Mue et al,46 1990

Lin et al,42 1996

Source

HTN and COPD (n 66)

PRC

Diuretics with or without N, L

BP control; cough reporting

Methods

1 yr

1a

Cough 12% in ACE inhibitors, 2.7% in LLD; no effect of prior Hx of BC No AE; 3/22 in L group had cough

Results

1c

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adverse reaction 15 years ago. Unfortunately, the association between cough and angiotensinconverting enzyme inhibitors was not widely accepted until several years later.53,54 Cough associated with angiotensin-converting enzyme inhibitors is more of a nuisance than a hazard in the general population of hypertensive patients receiving the drugs. Studies estimate the incidence of angiotensin-converting enzyme inhibitor-induced cough ranges from 10 to 20%.55,56 Most of these reports were from patients without comorbid diseases. In patients with sensitive airway disease or decreased pulmonary function, cough could be a serious adverse reaction to this class of drugs. Cough and possible bronchospasm may also be an important determinant regarding compliance. With regard to the angiotensin-converting enzyme and the renin-angiotensin system, the renin-angiotensin system/kallikrein-kinin system plays an important role in BP regulation. Two key elements in the system are angiotensin II and bradykinin. Angiotensin II is a potent smooth-muscle vasoconstrictor.57 It causes sodium retention through aldosterone release, increased vascular tone through sympathetic activation,58 and increased fluid retention through increased antidiuretic hormone.59,60 Bradykinin, however, is a potent vasodilator whose effects are mediated through the 2 receptor.61 Many of its effects are through the production of arachidonic acid, nitric oxide, endothelium-derived hyperpolarizing factor, and natriuresis.62,63 Bradykinin increases vascular permeability, mucus secretion, and C-fiber stimulation. This molecule also causes smoothmuscle contractions in specific organs, such as the small intestine and uterus.64 Angiotensin-converting enzyme or kininase II regulates the balance between angiotensin II and bradykinin. The enzyme is found in several locations, a soluble form present in blood and a membranebound form located in epithelial cells and brain tissue.65 Although the clinical significance has not been established, several studies have shown a better correlation between tissue angiotensin-converting enzyme and systemic hypertension than circulating angiotensin-converting enzyme.52,66 The hemodynamic effects of bradykinin and angiotensin II are such that, with increased bradykinin levels blood volume is decreased and BP reduced, while with increased levels of angiotensin II blood volume and BP are increased. With regard to the cough mechanism, a number of hypotheses have been put forward to explain the causes of angiotensin-converting enzyme inhibitorinduced cough. For example, it is believed that when angiotensin-converting enzyme is inhibited, kinin levels are increased in lung tissue. In addition to
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converting angiotensin I to angiotensin II, angiotensin-converting enzyme is also a kininase enzyme that reduces the levels of several inflammatory compounds such as bradykinin, substance P, and neurokinin A. These kinins can stimulate phospholipase A2, causing an increase in the prostanoid synthesis of prostaglandins I2 and E2. Rapidly adapting stretch receptors and C fibers are stimulated directly by bradykinins, prostaglandin I2 and prostaglandin E2, both of which are involved with the vagal afferent limb of the cough reflex.66 Other irritants or proinflammatory agents that are released or formed are leukotrienes and histamines from mast cells.67,68 Bradykinin and substance P activate mast cells, causing histamine release. Histamines are chemotactic agents inducing an inflammatory response and cellular migration of eosinophils and neutrophils.69 When kinins accumulate in lung tissue, cough and bronchospasm might occur, causing a serious adverse event in susceptible patients with certain disease states.70 72 Prostaglandin and leukotrienes are formed through the direct stimulation of phospholipase A2 and the arachidonic acid pathway.73 Inhibition of prostaglandin formation appears to attenuate the cough reflex. Malini et al74 reported a reduction in angiotensin-converting enzyme inhibitor-induced cough by using the thromboxane antagonist picotamide. Picotamide is a potent platelet antiaggregant that acts by inhibiting thromboxane synthesis and is a thromboxane receptor antagonist. Picotamide was effective in stopping cough in eight of nine patients who had cough as a result of taking enalapril. The cough was suppressed up to 6 months. Ozagrel, a thromboxane A2 inhibitor, also reduced or eliminated cough in patients receiving an angiotensinconverting enzyme inhibitor.75 Other drugs affecting prostanoid synthesis have not been shown to be as effective. Two different studies using the nonsteroidal anti-inflammatory drugs, sulindac or indomethacin, showed efficacy in approximately 50% of patients studied.76,77 One possible explanation could be an incomplete inhibition of the cyclo-oxygenase pathway leading to thromboxane A2 synthesis. Substance P, a potent bronchoconstrictor, is also degraded by angiotensin-converting enzyme. It is the proposed neurochemical mediator of the cough reflex.78 Baclofen, an agent used to treat muscle spasticity, has been shown to suppress the release of substance P in an animal model.79 The drug also has been shown to be effective in reducing bronchial hyperresponsiveness in patients with spinal cord injury.80 In an open-label clinical trial, baclofen reduced the severity of cough in patients with severe angiotensin-converting enzyme inhibitor-induced
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cough. Subjects continued to demonstrate cough suppression 25 to 74 days after discontinuation of baclofen therapy.81 With regard to special populations, pulmonary patients, it is very probable that several mechanisms are involved in the increased incidence of cough and increased airway sensitivity associated with angiotensin-converting enzyme inhibitors. Therefore, concerns arise regarding potential risk in patients with COPD and asthma who are administered angiotensin-converting enzyme inhibitors to lower BP. Semple and Herd82 described an asthmatic patient who experienced worsening dyspnea and wheezing after receiving enalapril for hypertension. Popa83 reported a patient with no previous history of asthma, hay fever, or allergies who had a severe asthma attack after receiving captopril. The reported effects of angiotensin-converting enzyme inhibitors on lung function in patients with COPD or asthma are from individual case reports and a limited number of small clinical trials. As is the case with many small studies, statistical power is lacking and results are conflicting. In some of the studies, no negative effects were observed. Many of these studies were uncontrolled and of short duration, and the patients were stable as defined by no recent exacerbation of their disease. In many of the earlier studies, a drug was administered for a very short period of time, and sometimes only a single dose was administered, making it difficult to draw any valid conclusions.43 45,84 86 While some of the studies showed no effect, two uncontrolled case studies did report immediate deterioration of lung function in asthmatics after receiving an angiotensinconverting enzyme inhibitor.83,87 The longitudinal assessment of asthmatic patients is difficult even in a controlled trial. Most of the studies retrieved for review excluded unstable patients. Continued use of inhaled glucocorticoids and bronchodilators may have masked the effects of angiotensin-converting enzyme inhibitors in some studies. There is also reason to believe that an increase in cough or bronchoreactivity might require several weeks or months of angiotensin-converting enzyme inhibitor therapy before effects are observed.88 In a MEDLINE search of English-language literature from 1985 to 2000, only a limited number of clinical studies were found to have investigated bronchial reactivity and cough in patients with COPD or asthma (Tables 1, 4).89 110 Evaluation of the studies was conducted as described in the Materials and Methods section. In one of the earlier studies, Sala et al43 reported no difference in bronchial responsiveness in 16 asthmatic patients before and after a 4-week treatwww.chestjournal.org

ment using captopril. FEV1 and a dose-response curve with methacholine were measured before and after treatment. The incidence of cough was not reported. Schalekamp et al44 reported a similar lack of differences in a group of patients with COPD and systemic or pulmonary hypertension treated with captopril. Nine patients with COPD and pulmonary hypertension were treated with a single dose, while 10 patients were treated for 60 days. Mean pulmonary wedge pressure, mean pulmonary artery pressure, and total pulmonary arterial resistance were significantly decreased after the single dose in patients with pulmonary hypertension. In patients with COPD and essential hypertension treated for 60 days, no airflow differences were observed before and after treatment. No side effects were observed and no bronchospasms occurred, even in those patients responsive to bronchodilator treatments. This study did not report incidence of cough and wheezing. The authors concluded that angiotensinconverting enzyme inhibitors are safe and effective in patients with COPD and systemic hypertension. In one of the few prospective, double-blind crossover studies, Riska et al50 reported no differences in FEV1 values in patients receiving captopril or verapamil before and after treatment. These results were based on a total of 17 patients. Patients were treated for 4 weeks in each arm of the study and allowed to continue using steroids and bronchodilators, possibly masking effects of the angiotensin-converting enzyme inhibitors. There were no differences in increased use of steroids and 2-sympathomimetic bronchodilators between the two groups during the trial. The incidence of increased cough during active drug treatment or placebo phase was similar for the two medications. In a double-blind study, Kaufman et al47 evaluated pulmonary function in 21 patients receiving two different angiotensin-converting enzyme inhibitors (14 patients with asthma, and 7 patients with allergic rhinitis). After a washout period, baseline FVC, FEV1/FVC ratio, and provocative dose of methacholine causing a 20% fall in FEV1 were measured. Patients were then started on either spirapril or enalapril for a period of 3 weeks, after which time the pulmonary function tests and methacholine challenge were repeated. The authors reported no significant change in spirometric measurements or methacholine challenge test before or after treatment. Unfortunately, this study also allowed patients to continue asthmatic medications, such as theophylline preparations and oral or inhaled -agonists, until 36 h prior to spirometry and methacholine provocation. Increased use of inhalers was not reported. This study lacked an active control and combined asthmatics with patients having allergic
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Table 4 -Adrenergic Receptor Blocker Studies

Source
PCC propranolol 0.21.0 mg IV on day 2 Practolol 100, 200 mg bid; ME FEV1 31 d 4a only at higher dose; in 4 pts asthma increased, 2 severely AT 100 mg, practolol 300 mg response to isoprenaline RPCCT PI RPCCT acebutalol 300 mg, PR 100 mg, oxprenolol 100 mg, PI 5 mg, and timolol 10 mg RCR other oxprenolol 240 mg qd RPCCT FVC, response to terbutaline RCR PRC PI 5, 20 mg RPCCT ME 100 mg bid, AT 100 mg qd PFT HC, GXT, inhaled fenoterol 3 wk PR 40, 160 mg; AT 50, 200 mg; HR, FEV1, MMEF, tremor, 6d Nadolol Symptoms 1 wk 1a 1a, 2e, 3d, 4a 1a, 2e, 3d, 4a First 4 wk SB placebo, then DB, PC, CO; 4 wk RX periods; PFTs a and p each Rx period RPCCT 20 mg, PL AT 100 mg qd, bisoprolol 10, FEV1, VC, PEF, airway resistance p SAL 1 mo 1a, 2e, 3d, 4a AT increased airway resistance; NS change in PEF, FEV1, VC with either; response to SAL preserved RPCCT PL, AT 100 mg, bisoprolol 20 mg FEV1, airway resistance, response to SAL 24 h 1a, 2e, 3d Bisoprolol has greater
1

Study Population
Atenolol 79 mg IV on day 1, meds 1a, 1d, 2e, FEV1 dropped with both meds with PR p PR Airway conductance a and p 1d 1a Airway conductance decreased

Study Design

Intervention

Methods

Duration

Design Flaws/ Limits Results Comments


2 pts had increased symptoms

Grade
2c

Astrom,89

1975

Mild-to-moderate asthma

(n

5)

Formgren,90 1976 50, 100 mg bid

Asthma plus HTN, 12 M, 5 F; PRC

Most on long-term steroids

1a

13 on long-term steroids; all

on oral terbutaline plus PFTs, bicycle ergometry, effect on BD 1d 1d 1a, 2e, 4a 1a, 2e, 4a SAL increased FEV1 p PL, not PFT; response to SAL FEV1 1d 1a Practolol decreased PFTs; no

aerosol BD Atenolol more cardioselective than practolol PI Rx was associated with asthma (n 1) 1b 1b 1c

Vilsvik and PI 5 mg vs PL PL, AT 100 mg, ME 100 mg,

Asthma (n

12); 9 on steroids PRC

Schaanning,91 1976

Christensen et al,92

Asthma (n

20); no HTN

1978

Decalmer et al,93

Asthma (n

10)

All meds decreased FEV1 except ISA was not asthma protective AT; only CS BB permitted BD, only AT allowed normal BD to isoprenaline

1978

Anderson et al,94 One pt on ME 100 mg bid, the Symptoms PL ME 100 mg, AT 100 mg 4a HR, BP, ECG, tremor, FEV1, 1d 1a, 2e, 3d, 18 mo f/u 1a

2 patients with mild asthma

Both developed severe prolonged asthma AT and ME decreased HR and FEV1 and reduced response to terbutaline 23 y/o developed respiratory arrest p drug PI caused the least, PR the greatest decrease in PFTs vs placebo Propranolol decreased FEV1 and response to salbutamol vs atenolol or metoprolol

Asthma persisted months p stopping BB Differences in cardioselectivity between AT and ME could not be shown Near-fatal bronchospasm after oral nadolol Sensitivity to histamine did not predict reduction in PFTs p therapy Atenolol superior to metoprolol in asthmatic attacks, asthmafree days, PFT

3b 1b

1979

Lofdahl and

Asthma (n

8); 2050%

Svedmyr,95 1981

reversibility with terbutaline

Raine et al,96 1981

1 patient with asthma

3b 1b

Ruffin et al,97 1982

Mild-to-moderate asthma

(n

12)

Lawrence et al,98

Asthma plus HTN (n

14)

1a

1983 PI 10 mg bid, ME 100 mg bid FEV1, FVC, PEF, BP 4 wk

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1a, 1d FEV1 decreased with ME but not PI; inhalation of terbutaline produced small increase in large airway function p placebo and ME but not p PI bisoprolol and placebo

Lammers et al,99

Asthma (n

1); chronic

Other expiratory flow parameters did not change with therapy

1b

1985

bronchitis (n

7); DBP

95 mm Hg

Chatterjee,100 1986

12 pts; mean FEV1

1.74,

1b selectivity than atenolol

FEV1 increases by

15%

with SAL, mild-to-moderate

HTN

Dorow et al,101 1986

COPD plus angina (n

12)

AT increased airway resistance vs Bisoprolol safe in pts with HTN and/or angina & COPD

Special Reports

1b

Dorow et al,102 1986 PRC vs celiprolol 200, 400, 600 mg qd; dose titration to BP RPCCT mg, 600 mg MMEF vs PL; BD response to albuterol best with celiprolol RPCCT 400 mg greater recovery from MC with celiprolol than ME RPCCT 200 mg AT than ME 4 wk RX periods 1a FEV1, FVC, PEF reduced with AT not celiprolol; response to SAL retained with both; cough, asthma sx score, PEF and BD use was no different with meds vs placebo PR 80 mg qd, oxprenolol 80 mg qd, AT 100 mg qd, and celiprolol 200 mg qd a and p salbutamol 4a FEV1, FVC, HR, BP measured 1 wk 1a, 1d, 2e, PR, oxprenolol decreased FEV1 by 14%, p 0.05; AT and celiprolol only minimally decreased PFTs (NS) and permitted BD PRC 2.5 mg qd RCR and meds None Chart audit to verify diagnosis NA 3c Prevalence of asthma prescribed BB; 2 pts hospitalized with asthma, one taking atenolol and one labetalol RPCCT ME, AT 100 mg qd, PL FEV1, airways conductance, finger tremor, HR, BP 7d 1a, 1j, 2e, 4a AT caused
2

Asthma plus HTN (n 4a both meds vs placebo run-in Serial PFT; response to SAL bronchosparing 1d 1a AT decreased FEV1 and Celiprolol found to be symptoms decreased with with asthma and HTN

66)

Chlorthalidone 12.5, 25, 37.5 mg Serial PFT

12 wk

1a, 2d, 2e,

PFTs similar for both meds;

No AEs from celiprolol in pts.

1b

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PL, AT 100 mg, celiprolol 400 1b PL, ME 100 mg, celiprolol p MC & SAL FEV1; increased resistance; FEV1 and airway resistance 3h 1a, 2e ME, not celiprolol reduced Bronchial asthma, but normal ventilatory function 1b PL, AT 100 mg, ME SR 100, terbutaline FEV1, FVC, PEF p SAL AT 100 mg qd, celiprolol 400 mg qd Serial PFTs with response to 1d 1a FEV1 p terbutaline lower with Controlled release metoprolol has fewer AEs than atenolol Day-to-day asthma control interpreted from patient recordings of peak flow, inhaler use, and symptom scores No clinical deterioration; 1b
1

Doshan et al,103 1986

Asthma (n

16)

Bruschi et al,104 1988

Asthma, 8 M, 2 F; FEV1

80% PRED

Lofdahl et al,105 1988 Asthma (n RPCCT

10)

1b 1a

van Zyl et al,106 1989

12 pts; 95

DBP

115 mm

Hg; FEV1

85% PRED;

FEV1 increases by 15% p

salbutamol

Fogari et al,107 1990

10 M; 95

DBP

115 mm Hg; RPCCT

FEV1

70% PRED and

selectivity more important than ISA in pts with asthma

increases by 20% p

salbutamol ME 100 mg qd, cilazapril Sleep studies 8d 1a, 2e, 4a

Weichler et al,108

OSA (n

24);

10 AP/h; DBP

AHI decreased with both meds 2.2%; 1.4% of asthmatics were

Sleep apnea study For 60.5% asthmatics prescribed BB, the prescribing MD was different from the MD treating asthma bronchial blockade, ME did not 10 pts excluded; 2 pts developed asthma during washout periods

1b 2a

1991

95 mm Hg

Graft et al,109 1992

Claims-based surveillance

system for monitoring

145,199 pts in an HMO

during 1989

Bauer et al,110 1994

Stable asthma; n

28; FEV1

1b

50% PRED; FEV1

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increases 15% p salbutamol;

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DBP

95 mm Hg

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rhinitis who had no clinical signs of asthma. Compared to baseline, coughing and wheezing did increase in the two groups, but not more than reported in the general population (14% cough, 5% wheeze). Mue et al46 reported a similar lack of differences in a small group of patients with stable asthma (n 6) treated with enalapril for 2 to 4 weeks. Serum levels of substance P and bronchoreactivity were measured before and after drug treatment. There were no differences in bronchoreactivity as measured by the methacholine challenge test, or differences in measured serum substance P values before or after treatment. There were no treatment-associated changes in the frequency of cough or asthmatic attacks. Patients in this study were also allowed to continue on their asthmatic medications, which included theophylline and occasional -adrenomimetic drugs via a metered-dose inhaler. Associated antiasthmatic medication did not increase. A summary of drug-related adverse respiratory events reported to both the World Health Organization (up to 1992) and the Swedish Adverse Drug Reaction Advisory Committee (from 1981 to 1991) revealed a large number of adverse reactions.48 A total of 1,215 adverse reactions to angiotensinconverting enzyme inhibitors was reported to the Swedish Adverse Drug Reaction Advisory Committee. Of these, 424 reactions (34.9%) were adverse respiratory reactions. Cough accounted for the largest number (n 374) of adverse respiratory reactions. The remaining 50 reactions were dyspnea (n 19), aggravated asthma (n 11), bronchospasm (n 6), rhinitis (n 5), laryngeal edema (n 4), nasal congestion (n 3), interstitial pneumonia (n 1), and pleuritis (n 1). Of the reported events, 36 patients had dyspnea, aggravated asthma, or bronchospasm, representing 8.2% of the total adverse events. When extrapolated back to the number of prescriptions sold, a risk of one event per 6,200 new prescriptions could be calculated. Reports to the World Health Organization showed a total of 8,094 respiratory reactions, of which cough accounted for 89.7%, and asthma, bronchospasm, or dyspnea accounted for 10.3%. What percentage of total prescriptions this represented was not calculated. Cough was reported 8 to 10 times more often than wheezing or dyspnea. More than one half of the patients (53%) with wheezing and dyspnea acquired signs within the first 2 weeks of treatment. Several patients in the Swedish database had serious respiratory adverse events requiring hospitalization and bronchodilator treatment. Of the total reported adverse respiratory events, the incidence of dyspnea, aggravated asthma, or bronchospasm was similar for the two reports: 8.2% and 10.3%. The authors summarized that the adverse respiratory symptoms
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of dyspnea, asthma, or bronchospasm associated with angiotensin-converting enzyme inhibitor therapy are rare, but should be recognized as serious adverse reactions. In a controlled postmarketing study, Wood49 compared the occurrence of cough and bronchospasm in patients receiving an angiotensin-converting enzyme inhibitor or the lipid-lowering drug, benzafibrate. Cohorts of patients were compared for the occurrence of cough, new bronchospasm, or a relapse of a previous cough or bronchospasm. The study randomized 6,000 patients from the New Zealand Intensive Medicine Monitoring Program. Data on each patient were obtained from a physician questionnaire. Of the 6,000 patients randomized, data were obtained on 1,013 patients receiving angiotensinconverting enzyme inhibitors and 1,017 patients receiving benzafibrate. Patients receiving angiotensin-converting enzyme inhibitors had a higher incidence of cough (12.3% vs 2.7%, p 0.0001). Although patients receiving angiotensin-converting enzyme inhibitors reported a higher frequency of cough and bronchospasm, those patients with a prior history of asthma or bronchospasm did not report a higher incidence of respiratory adverse reactions (16%) than those patients receiving an angiotensinconverting enzyme inhibitor without a prior history of bronchospasm (13%, p 0.447), suggesting that patients with a history of asthma were not at increased risk of bronchospasm or cough. This study evaluated patients over a period of 3 to 5 years. Of the 6,000 patients randomized, only data for 2,030 patients were available for analysis due to poor physician response or grossly inadequate information supplied. Also, patients with a history of asthma would be expected to continue their antiasthmatic medications. In a prospective, randomized study comparing three different antihypertensive therapies in patients with COPD, Lin et al42 reported overall side effects were similar in patients receiving lisinopril with or without diuretics (16 of 22 patients) compared to nifedipine with or without diuretics (17 of 22 patients), or diuretics with or without vasodilators (19 of 22 patients). The primary objective in this study was BP control in patients with COPD. The study was conducted over a 1-year period. Bronchoreactivity or pulmonary function tests were not done. Only the incidence of cough was reported higher in the lisinopril group than in the other two cohorts (significance not reported).42 With regard to congestive heart failure, angiotensin-converting enzyme inhibitors favorably alter cardiac function in patients with left ventricular systolic dysfunction. Since 1987, several large, prospective, randomized, placebo-controlled trials have
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demonstrated that angiotensin-converting enzyme inhibitors can favorably affect mortality and morbidity in patients with congestive heart failure and left ventricular systolic dysfunction.111113 These studies have had a major impact on the management of congestive heart failure. Unfortunately, as cough is the major side effect, data are somewhat limited on the incidence of cough and the cause for angiotensin-converting enzyme inhibitor withdrawal in the congestive heart failure patients. This is in contrast to the abundant literature on angiotensinconverting enzyme inhibitor-induced cough in patients with systemic hypertension. In the angiotensin-converting enzyme inhibitor mortality trials, cough was not a major reported side effect.42,48 Only in the Veterans Administration Cooperative Vasodilator-Heart Failure Trial, comparing enalapril to hydralazine plus isosorbide dinitrate, did patients receiving an angiotensin-converting enzyme inhibitor report a significantly higher incidence of cough than the hydralazine plus isosorbide dinitrate group (37% vs 29%, p 0.05).42 There were no significant differences in withdrawal rates or incidence of bronchospasm between the two groups. In a later study, Ravid et al114 did show significant differences in the development of cough between patients receiving an angiotensin-converting enzyme inhibitor for systemic hypertension (n 164), and patients receiving an angiotensin-converting enzyme inhibitor for congestive heart failure (n 104). Cough developed in 50 patients (18.6%) receiving an angiotensin-converting enzyme inhibitor. Cough developed in 23 patients (14%) with systemic hypertension at 24.7 17.1 weeks, and cough developed in 27 patients (26%) with congestive heart failure at 12.3 12 weeks. In the 50 patients in whom cough developed, 25 patients (50%) had treatment permanently discontinued. These differences accounted for an incidence of intolerable angiotensin-converting enzyme inhibitor-induced cough of 4.0% in patients with systemic hypertension and 18% in patients with congestive heart failure. When subgroups of patients were analyzed, cough developed in 10 of 56 patients with COPD and 5 patients (9.0%) discontinued the drug. In nine patients with asthma, cough developed in only one patient (11%), and drug discontinuance was not required. Bronchospasm developed in no patients with COPD or asthma. This study was not blinded, but clinically significant cough occurred in patients with congestive heart failure more frequently than in patients with systemic hypertension. In many patients, cough subsequently regressed and even disappeared without discontinuance of angiotensin-converting enzyme inhibitor therapy. Patients with bronchopulmonary disease did not have a higher incidence of
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angiotensin-converting enzyme inhibitor-associated cough than those patients without bronchopulmonary disease. However, the use of bronchodilators and inhaled steroids was not mentioned. Angiotensin II Receptor Antagonists: Drugs that prevent angiotensin II binding to the angiotensin II receptors do not affect the kinase functions of angiotensin-converting enzyme because they act more distally in the renin-angiotensin cascade. The accumulation of bronchoirritants, such as the bradykinins and substance P, does not occur with these drugs. In patients with pulmonary disease or patients with congestive heart failure intolerant of cough, an angiotensin II receptor blocker would be the theoretically preferred choice. Two studies115,116 compared the incidence of cough in patients with systemic hypertension and a previous history of angiotensin-converting enzyme inhibitor-associated cough who were now receiving the angiotensin II receptor blockers losartan or valsartan. These randomized double-blind studies compared the incidence of cough between valsartan or losartan vs lisinopril and hydrochlorothiazide or metolazone. Patients in the valsartan study were treated for 6 weeks, while patients in the losartan study were treated for 10 weeks. The incidence of cough in the losartan-treated patients was similar to that of metolazone-treated patients (18% vs 21%, p not significant) and significantly less than that of lisinopriltreated patients (97%, p 0.001). Similar results were reported in the valsartan study. The overall incidence of adverse events was highest for lisinopril (86.7%), compared to valsartan (57.1%, p 0.001) and hydrochlorothiazide (61.9%, p 0.001). Although patients with a history of pulmonary disease were excluded in these studies, the authors suggest that the use of an angiotensin II receptor antagonist could be an alternate choice in patients with a history of intolerant cough associated with angiotensinconverting enzyme inhibitors, pulmonary disease, bronchoreactivity, and congestive heart failure. There are presently no large randomized controlled trials showing that patients with bronchopulmonary disease have an increased risk of angiotensin-converting enzyme inhibitor-associated cough or bronchospasm. However, studies do suggest that bronchoreactivity as a result of angiotensinconverting enzyme inhibitor therapy has no greater incidence in patients with bronchopulmonary disease than in the general population. These studies lack statistical power, used the administered drug over a short time period, and did not control for other drugs that affect pulmonary function, and thus could mask events induced by angiotensin-converting enzyme inhibitor. Controlled longitudinal studies
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in patients with pulmonary disease might not be possible because of the nature of the disease. Patients with congestive heart failure might be at increased risk of cough when treated with angiotensin-converting enzyme inhibitors. In patients with pulmonary disease where there is a concern about a possible adverse respiratory event associated with angiotensin-converting enzyme inhibitor, or in patients with congestive heart failure who acquire cough, the use of an angiotensin II receptor antagonist may be considered, although there are no data from controlled studies (level C). -Adrenergic Blocking Agents: The -blockers are a major class of antihypertensive medications. Their use is generally avoided in patients with COPD. 2-Receptor activation promotes bronchodilation and blockade of these receptors increases airway resistance. 1-Receptor activation may contribute to bronchodilation as well, although this is less clear. It is, therefore, not surprising that -adrenergic blocking agents may have adverse clinical effects in patients susceptible to bronchoconstriction. The effects of propranolol on the ventilatory function of asthmatic patients was reported by McNeill in 1964.117 In this study, patients received 5 to 10 mg of IV propranolol and measurements of FEV1 were made prior to and 1 h after treatment. Four of 10 patients demonstrated a profound sudden decrease in FEV1. Case reports have brought attention to the ability of -adrenergic blocking agents to cause bronchospasm. In 1981 Raine et al96 described a 23-year-old woman who was prescribed nadolol for the treatment of hypertension. The patient had a history of asthma without recent exacerbation and used a bronchodilator aerosol to control exercise-induced wheezing. She suffered a respiratory arrest soon after receiving nadolol and received mechanical ventilation for several days before she recovered. Anderson et al94 described two patients with a history of mild asthma who had bronchospasm that persisted for months after discontinuance of a -adrenergic blocker. Despite the known association between adrenergic blocker use and bronchospasm in patients with asthma, these medications have, albeit infrequently, been prescribed for asthmatics. Graft et al109 in 1992 reported that 3,170 patients in a health maintenance organization were identified as having asthma. Of these patients, 1.4% received a -adrenergic blocking drug. Use varied with age and was more common in older patients (8.9%) vs younger patients ( 1.0%). Two asthmatic patients who received -adrenergic blocking agents were hospitalized for asthma. Both patients recovered after
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several days of treatment with IV steroids, aminophylline, and bronchodilator aerosol. In 61% of the cases where -adrenergic blocking agents were prescribed to asthmatic patients, multiple physicians were involved in patient management. With a number of classes of drugs available to treat systemic hypertension, is it ever necessary to use -adrenergic blocking agents to treat hypertension in an asthmatic patient? Are any subclasses or specific -adrenergic blocking agents safe for use in the asthmatic patient? Do -adrenergic blocking agents cause complications in patients with lung diseases other than COPD and asthma? What type of medical history prompts caution in the use of a -adrenergic blocking agent? For example, should a single episode of bronchospasm associated with an upper respiratory infection contraindicate the use of a -adrenergic blocking agent 40 years later? Clinical trials done to evaluate the effect of various -adrenergic blocking agents on parameters of pulmonary function are presented in Tables 1, 4. However, these studies have involved small numbers of patients over short periods of time. Atenolol, bisoprolol, celiprolol, metoprolol, and pindolol are the -adrenergic blocking agents used most frequently in these clinical trials.89 93,95,97108,110 Based on an understanding of -adrenergic receptor antagonism, a cardioselective -adrenergic receptor blocker would be expected to have an advantage over a nonselective blocker in patients with asthma. Six studies evaluated the differential effects of a cardioselective and a nonselective -adrenergic blocker on parameters of pulmonary function in patients with asthma or COPD.89,93,9799,107 Atenolol, bisoprolol, celiprolol, and metoprolol are the four cardioselective agents used most frequently in the clinical trials. Fogari et al,107 using a single-blind, randomized, crossover design, treated patients with COPD for 1 week with propranolol, 80 mg/d; oxprenolol, 80 mg/d; atenolol, 100 mg/d; and celiprolol, 200 mg/d. Propranolol decreased FEV1 by 16.4% (p 0.05), whereas atenolol and celiprolol minimally decreased FEV1 and FVC (not significant) and permitted the bronchodilator response of salbutamol. In another trial, Lawrence et al98 treated hypertensive asthmatics in serial fashion with propranolol, atenolol, and metoprolol using a randomized, single-blind, crossover design. Treatment was continued for 3 weeks with each medication. The authors found that propranolol decreased FEV1 compared to atenolol and metoprolol, and also decreased the bronchodilator response to salbutamol in comparison with atenolol and metoprolol. Atenolol and metoprolol decreased FEV1, FVC, and peak expiratory flow rate (PEFR) when compared to placebo, but they did not deSpecial Reports

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crease responsiveness to salbutamol. Nonetheless, the response to atenolol and metoprolol was superior to propranolol. Formgren90 reported that the cardioselectivity of certain -adrenergic blockers can be lost at the higher dosage range. Seventeen hypertensive asthmatics were treated with two doses of the cardioselective -adrenergic blockers, metoprolol and practolol. A single-blind, crossover design was used, and treatment was continued for 17 days after a 14-day placebo run-in phase. Lower doses of practolol (200 mg/d) and metoprolol (100 mg/d) produced no effect on FEV1. At higher doses (practolol, 400 mg/d; metoprolol, 200 mg/d) both -blockers reduced the FEV1. Four patients experienced a worsening of asthma during treatment at higher doses of both medications. Celiprolol and bisoprolol are cardioselective -blockers that may have the least effect on pulmonary function in patients with COPD. Van Zyl et al106 treated 12 asthmatic patients with mild-to-moderate hypertension receiving atenolol, 100 mg/d, and celiprolol, 400 mg/d. The study design involved a singleblind, 2-week, placebo run-in period followed by a double-blind, randomized crossover phase using 4-week treatment periods for each medication. Parameters of pulmonary function were measured at predetermined intervals following administration of medication, and response to salbutamol was measured. The FEV1, FVC, and PEFR fell progressively over 3 h in patients receiving atenolol, but not those receiving celiprolol. Bronchodilator response was maintained after treatment with both drugs. Daily control of asthma was no different during treatment with atenolol or celiprolol vs placebo. Cough, asthma symptom scores, daily peak flow measurements, and bronchodilator use did not differ from placebo. Two studies compared the cardioselective -blockers, atenolol and bisoprolol, in patients with reversible airways disease.100,101 Chatterjee100 treated 12 asthmatics with mild-to-moderate hypertension with placebo; atenolol, 100 mg/d; and two doses of bisoprolol daily. The study design was randomized and double blind, and involved a fourway crossover protocol. Pulmonary function was measured after a single dose of medication. Atenolol and 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 the patients had an adverse clinical event. In a randomized, placebo-controlled crossover trial of 12 COPD patients with angina, Dorow et al101 found that atenolol treatment similarly increased airway resistance in comparison to bisoprolol and placebo. The literature supports the concept that cardiosewww.chestjournal.org

lective -adrenergic blocking agents exert less effect than nonselective agents in patients with reversible airways disease. Cardioselectivity may be lost with certain agents at higher doses. Most of the literature that reports adverse effects when -adrenergic blockers are used in patients with lung disease involves patients with reversible airways disease: asthma or COPD. The question of whether it is ever advisable to use a cardioselective -adrenergic blocker in patients with asthma or established COPD becomes a question of benefit and risk. The literature is limited in identifying other pulmonary diseases that may be exacerbated with the use of -adrenergic blockers. There is also insufficient literature to indicate whether a hypertensive patient with a remote history of asthma should be excluded from a trial of a -adrenergic blocking agent. The case histories of refractory bronchospasm in two patients indicate that -adrenergic blockers can produce adverse effects even in patients with mild disease. It is possible that patients with a remote history of asthma may tolerate -adrenergic blocking agents with a low probability of developing bronchospasm. Considering the wide range and availability of other classes of antihypertensive drugs, -adrenergic blockers should be avoided in patients with a history of asthma, except in individual cases where cost/ benefit analysis suggests otherwise (levels A-2, B-1). If a patient with asthma and severe systemic hypertension is unable to tolerate other classes of antihypertensive medications, a trial of a cardioselective -adrenergic blocker could be attempted while maintaining optimal treatment with bronchodilators. However, the likelihood of a patient having adverse reactions to all other classes of antihypertensive drugs and requiring a -blocker should be extremely low (levels B-1, C). The benefit-to-risk ratio for using a -adrenergic blocker in a patient with mild asthma would be higher in a patient with severe angina whose disease is not amenable to surgery or angioplasty. While calcium channel antagonists and nitrates could be used in such a patient, there might be a role for a -adrenergic blocker (levels B-1, C). - -Blockers and Other Non- -Blocker Classes of Drugs: -Adrenoreceptor antagonists ( -blockers) reduce both systolic and diastolic pressure by approximately 15% and are similar to thiazide diuretics in their antihypertensive effectiveness. However, they tend to worsen pulmonary function in patients with COPD. In contrast, a class of -blockers that also block -adrenergic receptors does not induce bronchoconstriction and has been found to be effective in the treatment of hypertension in patients with
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Table 5 - Blocker Studies


Study Design
DBRCT HR, BP, and FEV1, FVC a and p salbutamol 20 wk 1a, 1d, 2e, 4a Labetalol significantly reduces FEV1 and FVC; verapamil has no effect; neither causes side effects Diuretic decreased BP as much as labetalol

Source

Study Population

Intervention

Methods

Duration

Design Flaws/ Limits Results Comments

Grade
1b

Anavekar et

al,118

1982

9 pts; HTN for 218 yr plus COPD for 822 yr; FEV1 3060% FVC

No advantage at doses used; small selection bias offset by reproducibility of the study Small study, short duration; emphasis on safety of labetalol; little on HCTZ

Light et al,119 1983 DBRCT FEV1, FVC, HR, BP measured a and p medication 9 wk 1a, 2e, 4a

4 wk basal, 2 wk placebo, 6 wk verapamil 160 mg bid or labetalol 200 mg bid, 2 wk placebo, 6 wk labetalol or verapamil 4 wk placebo, 4 wk labetalol 100400 mg tid or hydrochlorothiazide 2550 mg tid, 1 wk placebo

1b

Falliers et al,120 1985 DBRCT 24 wk placebo, 4 wk labetalol (100600 mg bid) or HCTZ (2550 mg bid) FEV1 a and p propranolol 68 wk 1a, 1d, 2e, 4a FEV1, FVC, a and p propranolol, BP, HR 68 wk 1a, 2e, 4a

Both equally effective, no adverse side effects, both decreased BP about the same Both reduced FEV1, labetalol more than HCTZ, but barely Primary focus on labetalol safety; small study of short duration

1b

George et al,121 1985 DBRCT

20 pts; HTN plus COPD for 2 mo or more; 95 DBP 120 mm Hg; 0.55 FEV1/FVC 0. 70; COPD reversible p isoproterenol: FEV1 15% or MMEF 2575% 52 asthmatic pts (35 qualified by propranolol stress test); 95 DBP 115 mm Hg 41 pts; HTN plus asthma (mild to moderate)

1b

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DBRCT 24 wk placebo, 4 wk labetalol (100600 mg bid) or HCTZ (2550 mg bid) 1) verapamil (120 mg tid) or pindolol (7.5 mg bid); 2) verapamil (160 mg tid) or labetalol (7.5 mg bid) 1) hemodynamic and cardiac Fnc and biochem; 2) HR, BP, FEV1, FVC w/salbutamol challenge 20 wk 1a, 1d, 2e, 4a DBRCT Captopril (50100 mg) or verapamil (160240 mg) BP; PEF; asthma symptoms 4 wk 1a, 2e, 4a DBRCT 4 wk placebo, 3 mo celiprolol (200600 mg qd) or chlorthalidone (12.537.5 mg qd), 12 mo open-label study PEFR, FEV1, MEV at 50% VC, salbutamol response 16 mo 1a, 2e, 4a

Anavekar and Doyle,122 1986

1) 17 pts with HTN; 2) 9 pts with HTN plus COPD

Both studies were small in No.

1b

Riska et al,123 1986

8 pts; asthma plus HTN

Clauzel et al,124 1988

9 pts; Mild HTN plus asthma

1) BP fell equally; verapamil had no effect on plasma renin concentration 2) labetalol reduced FEV1 and FVC, verapamil did not Both drugs reduced BP with fewer orthostatic changes with captopril; no effect on PEF or asthma symptoms No effect on FEV1, celiprolol safe for HTN

Very few patients and short duration; all were on hydrochlorothiazide and bronchodilators throughout Very small group

1b

1b

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Dorow,125 1988 115 HR, BP, and FEV1, FVC 16 wk 1a, 2e, 4a DBRCT Small No. and short duration; possible selection bias Small No. of pts with variable study duration Small No. and short duration

30 pts; 90 mm Hg

DBP

1b

www.chestjournal.org PCS 627 wk 1a, 2e, 4a 4 wk placebo, 12 wk celiprolol (200600 mg qd) or chlorthalidone (12.537.5 mg qd) 24 wk placebo; doxazosin (116 mg qd) BP; PEF; FEV1 24 wk washout, 4 wk prazosin (110 mg bid); diuretic as needed FEV1 with histamine challenge BP; orthostatic Rxns; FEV1; FVC; PEF; asthmatic symptoms 2024 wk 1a, 2e, 4a 3h 1a, 1d, 2e, 4a BP, FVC, FEV1, PEF, pt symptom rating 68 wk 1a, 2e, 4a 1b PCS 1b DBRCT Very small No. and short duration Small No. of pts. 1b DBRCT 8 h w/o bronchodilators, 24 h without theophylline; nitrendipine (20 mg) HCTZ with captopril (25 50 mg BID) or verapamil (80120 mg bid) or placebo BP; FEV1; PEF; serum theophylline 60 d 1a, 2e, 4a 1b DBPCS Both drugs decrease BP; no change in FEV1 with either drug; no adverse side effects Doxazosin reduced BP without affecting preexisting airflow limitation Prazosin reduced hypertension but had no effect on pulmonary function Nitrepidine safely tolerated in pts with airflow obstruction Both drugs reduced BP; normal orthostatic changes; no effect on pulmonary fnc or asthma symptoms After 45 d on both drugs, serum theophylline declined; no changes in pulmonary Fnc Small No. of pts. and short duration 1a, 2e, 4a Small No. of patients, short duration; not a BP study per se; rather a nifedipine mechanism study 1b PCS 48 h Theophylline (200 mg bid) for 15 days, then theophylline plus nifedipine (10 mg bid) or placebo for 45 days Nifedipine (20 mg qd) Systemic and pulmonary hemodynamics and left and right ventricular function 2b PCS BP; FVC; FEV1; PEF 3d 1a, 2e, 4a Short-term nifedipine improves systolic Fnc by decrements in ventricular afterload and increments ventricular contractility and compliance No differences between the BP or respiratory actions of the two drugs 15 wk (6 wk each with 3 wk washout between) 1a, 2e, 4a Atenolol most effective in reducing BP; severity of SDB and daytime wellbeing not influenced by any of the drugs Small No. of patients and short duration 2b Balanced incomplete block BP; severity of SDB; daytime well-being Unusual study design 2b MCDBRCT Single oral dose of nebivolol (5 mg) or celiprolol (200 mg) or placebo Atenolol (50 mg) or amiodipine (5 mg) or enalapril (20 mg) or HCTZ (25 mg) or losartan (50 mg) qd; each pt received 2 of above in sequence Placebo washout, 8 wk; candesartan cilexetil (8 mg) or enalapril (10 mg) or placebo Incidence, frequency and severity of dry cough; QOL survey 8 wk 1a, 2e, 3c, 4a Candesartan cilexetil reduced cough to placebo levels Major clinical study 1b

Biernacki and Flenley,126 1989

Chodosh et al,127 1989

Mulloy et al,39 1990

19 pts; 95 DBP 114 mm Hg; FEV1 2273% of predicted 17 pts; HTN (DBP 95 mm Hg) plus COPD (7 chronic bronchitis, 10 bronchial asthma) 8 pts; chronic asthma (2 with hypertension)

Riska et al,50 1990

17 pts; asthma plus HTN

Yilmaz et al,41 1991

13 pts; HTN plus asthma; on theophylline therapy

Mols et al,128 1993

13 pts; HTN plus COPD

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Cazzola et al,129 2000

12 pts; asthma

Kraiczi et al,130 2000

40 pts; HTN plus OSA

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Tanser et al,131 2000

154 pts; HTN plus cough on enalapril (10 mg) challenge

237

COPD and asthma. This class of drugs includes atenolol, labetalol, nebivolol, and doxazosin. As reviewed earlier, other alternatives to the -blockers are also now available and include the calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Calcium blockers, such as verapamil, nifedipine, nitrendipine, and amlodipine, have antihypertensive activity with no effect on respiratory function. The angiotensin-converting enzyme inhibitors captopril, enalapril, spirapril, candesartan, and cilexetil have also been found useful in the treatment of hypertensive asthmatics (Tables 1, 5).39,41,50,118 131 Almost all studies demonstrate that the newer class of - -blockers with -blocking activity, calcium blockers, and angiotensin-converting enzyme inhibitors effectively treat hypertension without exacerbating already compromised pulmonary function (asthma, COPD, or obstructive sleep apnea). Most findings are based on well-designed, double-blind, randomized control studies of a limited number of patients. Larger studies are needed. Consistent study outcomes warrant the application of these drugs in hypertensive patients with compromised pulmonary function (level A-2).

tion, or congestive heart failure. Cough and possible bronchospasm could be an important factor in patient noncompliance (level C). Studies to date indicate the incidence of angiotensin-converting enzyme inhibitor-associated cough to be 10 to 20%. There are no large randomized controlled trials to indicate any higher incidence of cough or bronchospasm in patients with bronchopulmonary disease (levels A-2, B-1). Angiotensin II Receptor Antagonists The use of an angiotensin II receptor antagonist may be considered when angiotensin-converting enzyme inhibitor-associated cough is a concern in patients with congestive heart failure or pulmonary disease (level C). -Adrenergic Blocking Agents -Adrenergic blocking agents increase airway resistance and should not be administered to patients with asthma or other reversible airways disease. Only in selected instances of coexisting cardiac conditions, may -adrenergic blocking agents be considered for trial (levels B-1, C). Some studies support the concept that cardioselective -adrenergic blocking agents exert less effect than nonselective agents on pulmonary function in patients with reversible airways disease. If an asthmatic patient with severe systemic hypertension is unable to tolerate other classes of antihypertensive medications, a trial of a cardioselective -adrenergic blocker could be attempted while maintaining optimal treatment with bronchodilators. Cardioselectivity may be lost at higher doses of these agents (levels B-1, C). - -Blockers and Other Alternatives to -Blockers Based on well-designed, double-blind, randomized control studies of a limited number of patients, the application of the newer class of - -blockers with -blocking activity, calcium blockers, and angiotensin-converting enzyme inhibitors in hypertensive patients with compromised pulmonary function is warranted (level A-2).
ACKNOWLEDGMENTS: We owe a debt of gratitude to the American College of Chest Physicians, who encouraged the initiation of this review. We would also like to acknowledge the technical writing assistance of James Breeling, Alice Stargardt, and Graig Eldred, and the assistance in literature research by Barbara Bartkowiak and Rose Sterzinger-Johnson. We further thank Richard Wurdeman and Sungyong Choi of Creighton University, School of Pharmacy, for their contribution of reviewing and drafting a section of this article.
Special Reports

Final Summary of Recommendations Within the population of approximately 50 million US adults with systemic hypertension, a subpopulation of several million with comorbid chronic pulmonary disease merits special consideration of BPlowering treatment that takes the comorbid pulmonary disease into account. Diuretics Use of diuretics in hypertensive patients with pulmonary disease is currently untested, and therefore alternatives should be considered (levels B-2, C). Calcium Antagonists There are insufficient data for making a recommendation regarding use of calcium antagonists in the management of systemic hypertension in patients with concomitant COPD or SDB. Most studies to date have shown calcium antagonists to modestly decrease bronchial reactivity (level B-2). Angiotensin-Converting Enzyme Inhibitors Cough associated with angiotensin-converting enzyme inhibitors could be a moderate-to-serious adverse reaction to this class of drugs in patients with sensitive airway disease, decreased pulmonary func238

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Appendix: Rationale of the Methodologic Approach


Selection of Studies for Review The starting point for a systematic review, as was conducted for this work, is to ensure that relevant evidence is reviewed comprehensively and objectively. Searches based on selective retrieval of studies are vulnerable to biases and imbalanced perspectives on extant data. Systematic reviews define admissible evidence by specifying the diagnosis, patients, interventions, and outcomes of interest, relevant study designs, and exclusion criteria. In performing a critical review of the literature, one caution is warranted. Deriving evidence solely from studies in the literature excludes unpublished data and may generate an unbalanced view of the evidence. There exists a statistically significant publication bias: investigators tend only to publish significant results.1 Our review of the literature should be viewed in that context. Nonetheless, we chose not to include unpublished findings in our analyses. To do so would require review of conference abstracts, databases, and laborious inquiries at academic departments, journals, and other settings. Moreover, studies are often unpublished because of serious methodologic problems and design flaws, and can be unreliable sources of evidence. Evaluating the Quality of Individual Studies A distinction must be drawn between evaluating individual studies and weighing the evidence as a whole. The overall evidence for the health benefits of a treatment involves multiple linkages in the causal pathway that links intervention to health outcomes. To infer that lowering dietary fat intake is beneficial in preventing heart disease, for example, one must consider the evidence relating dietary fat intake to serum lipid levels, the link between serum lipids and atherosclerosis, and the relationship between fat intake, lipid levels, and the incidence of heart disease. For each of these linkages, the quality of the evidence must be examined carefully, with attention not only to individual studies, but to the consistency and strength of the evidence as a whole. Study Design Categories The persuasiveness of a study is influenced in large measure by its overall design structure, eg, randomized controlled trial, cohort study, etc. The vulnerability of research findings to bias and 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 retrospective, and a variety of other important methodologic considerations. Certain archetypal study designsrandomized controlled trialsare considered more persuasive than others because they are inherently less vulnerable to bias and confounding. However, randomized controlled trials are typically expensive and time-consuming, and thus are characteristically fewer in number than other types of studies of a given subject matter. While nonrandomized controlled trials are not as rigorous as randomized controlled trials, they nonetheless rank highly as compared to other study designs reported in this review. Due to the paucity of both randomized and nonrandomized controlled studies available for analysis, we have chosen to combine the two types into the level 1 evidence category. Other types of studies that may provide evidence for analysis range from the case report (may highlight interesting findings but does not provide a denominator for calculating the frequency of observed effects or
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the strength of associations), to observational studies in which the decision as to whether the subjects will or will not receive a treatment is not made by the investigators. Whether a study is a randomized controlled trial or a casecontrol study is often less important than how well it was conducted: the clarity of the design, sample size, definition of interventions and outcomes, and statistical methods. The quality of the research methods can affect both internal validity (the extent to which the study results are applicable to the population and setting described in the study) and external validity (the generalizability of the results to the real world outside the study). Issues affecting internal validity include sample size and statistical power, selection of subjects and control subjects, definition of intervention, definition/measurement of health, intermediate and surrogate outcomes, confounding variables and measurement biases, attrition and follow-up, and statistical methods. Issues affecting external validity include the generalizability of the study population, intervention, and setting to the situation of interest. The strength of evidence that a treatment is associated with a health outcome depends not only on the quality of individual studies, but on the overall grade of the evidence taken together, the number of studies, the consistency of results, and the magnitude of effects. Moreover, evidence of an association does not infer causality. An association or correlation of variables means only that they occur together, not that one causes the other. To invoke causality one must also demonstrate certain well-established patterns such as biological plausibility, consistency of association, dose-response relationship, and specificity. The final judgment of the quality of the evidence is often subjective. Although checklists can be helpful in ensuring that these determinants of quality are considered, the integration of each 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 been performed, that studies have not been performed that prove ineffectiveness, or that extant studies are of poor quality, inconsistent, or too few in number to allow definitive conclusions. Reviewers with different methodologic expectations about good science, preconceptions, biases, and conflicts of interest reach different conclusions about when the evidence is good enough.

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Treatment of Systemic Hypertension in Patients With Pulmonary Disease: COPD and Asthma Richard A. Dart, Steve Gollub, Jason Lazar, Chandra Nair, David Schroeder and Steven H. Woolf Chest 2003;123;222-243 DOI 10.1378/chest.123.1.222 This information is current as of February 14, 2008
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