Download Angiotensin-Converting Enzyme Inhibitor-Induced

Angiotensin-Converting Enzyme
Inhibitor-Induced Cough
ACCP Evidence-Based Clinical Practice Guidelines
Peter V. Dicpinigaitis, MD, FCCP
Background: A dry, persistent cough is a well-described class effect of the angiotensin-converting
enzyme (ACE) inhibitor medications. The mechanism of ACE inhibitor-induced cough remains
unresolved, but likely involves the protussive mediators bradykinin and substance P, agents that
are degraded by ACE and therefore accumulate in the upper respiratory tract or lung when the
enzyme is inhibited, and prostaglandins, the production of which may be stimulated by
bradykinin.
Methods: Data for this review were obtained from a National Library of Medicine (PubMed)
search, which was performed in May 2004, of the literature published in the English language
from 1985 to 2004, using the search terms “angiotensin-converting enzyme,” “angiotensin
converting enzyme inhibitors,” and “cough.”
Results: The incidence of ACE inhibitor-induced cough has been reported to be in the range
of 5 to 35% among patients treated with these agents. However, a much lower incidence has
been described in studies of patients presenting for the evaluation of chronic cough. The
onset of ACE inhibitor-induced cough ranges from within hours of the first dose to months
after the initiation of therapy. Resolution typically occurs within 1 to 4 weeks after the
cessation of therapy, but cough may linger for up to 3 months. The only uniformly effective
treatment for ACE inhibitor-induced cough is the cessation of treatment with the offending
agent. The incidence of cough associated with therapy with angiotensin-receptor blockers
appears to be similar to that of the control drug. In a minority of patients, cough will not recur
after the reintroduction of ACE inhibitor therapy.
Conclusions: In a patient with chronic cough, ACE inhibitors should be considered as wholly
or partially causative, regardless of the temporal relation between the initiation of ACE
inhibitor therapy and the onset of cough. Although the cessation of therapy is the only
uniformly effective treatment for ACE inhibitor-induced cough, some pharmacologic agents
have been shown to attenuate the cough.
(CHEST 2006; 129:169S–173S)
Key words: angiotensin-converting enzyme; angiotensin-converting enzyme inhibitors; angiotensin receptor
blockers; bradykinin; capsaicin; cough; prostaglandins; substance P
Abbreviations: ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker
hronic cough is a well-described class effect of
C the
angiotensin-converting enzyme (ACE) inhibitors.1 The cough is typically dry and is associated with a tickling or scratching sensation in the
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Peter Dicpinigaitis, MD, FCCP, Einstein
Division/Montefiore Medical Center, 1825 Eastchester Rd, Bronx,
NY 10461; e-mail: [email protected]
www.chestjournal.org
throat. The incidence of ACE inhibitor-induced
cough has been reported1,2 to be in the range of 5
to 35% among patients who have been treated
with these agents. However, in prospective, descriptive studies3–5 that evaluated the etiology of
chronic cough in patients presenting for evaluation
of this symptom, ACE inhibitors were determined
to be responsible in 0 to 3% of cases. ACE
inhibitor-induced cough is not dose-dependent.1
Patients treated with ACE inhibitors for congesCHEST / 129 / 1 / JANUARY, 2006 SUPPLEMENT
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tive heart failure cough more frequently than
those treated with these agents for hypertension.2
Cough due to ACE inhibitors occurs more commonly in women,6 –9 nonsmokers,1,8 and persons of
Chinese origin.10,11
Cough may occur within hours of the first dose of
medication, or its onset can be delayed for weeks to
months after the initiation of therapy. Treatment
with ACE inhibitors may sensitize the cough reflex,
thereby potentiating other causes of chronic cough.12
Although cough usually resolves within 1 to 4 weeks
of the cessation of therapy with the offending drug,
in a subgroup of individuals cough may linger for up
to 3 months.1,13
Although the etiology of ACE inhibitor-induced
cough remains an unresolved issue, new developments since the publication of the first American
College of Chest Physician consensus panel report
include studies implicating the bradykinin receptor
as relevant to ACE inhibitor function as well as the
cough associated with these medications. Several
new therapeutic agents have been added to the list of
drugs that may attenuate ACE inhibitor-induced
cough in some patients. Furthermore, an accumulating body of evidence supports the concept that the
angiotensin receptor blockers (ARBs) do not cause
cough, including in those patients with a history of
ACE inhibitor-induced cough. Data for this review
were obtained from a National Library of Medicine
(PubMed) search, which was performed in May
2004, of the literature published in the English
language from 1985 to 2004, using the search terms
“angiotensin-converting enzyme,” “angiotensin-converting enzyme inhibitors,” and “cough.”
Recommendation
1. In patients presenting with chronic cough,
in order to determine that the ACE inhibitor is
the cause of the cough, therapy with ACE
inhibitors should be discontinued regardless of
the temporal relation between the onset of
cough and the initiation of ACE inhibitor therapy. The diagnosis is confirmed by the resolution of cough, usually within 1 to 4 weeks of the
cessation of the offending agent; however, the
resolution of cough may be delayed in a subgroup of patients for up to 3 months. Quality of
evidence, low; net benefit, substantial; grade of
recommendation, B
clude bradykinin and substance P, which are degraded by ACE and therefore accumulate in the
upper airway or lung when the enzyme is inhibited;
and prostaglandins, the production of which may be
stimulated by bradykinin.1,14 Bradykinin-induced
sensitization of airway sensory nerves has been proposed as a potential mechanism of ACE inhibitorinduced cough.14 Some evidence has suggested that
the therapeutic effect of ACE inhibitors may involve
the activation of bradykinin receptors,15 and that
bradykinin receptor gene polymorphism is associated
with the cough that is related to ACE inhibitors.16
The enhancement of bronchial responsiveness does
not appear to be a relevant mechanism.17 Subjects
with ACE inhibitor-induced cough demonstrate increased cough reflex sensitivity to experimental stimulation with capsaicin,12 which resolves after the
discontinuation of therapy with the inciting drug.18
Treatment
The only uniformly effective intervention for ACE
inhibitor-induced cough is the cessation of therapy
with the offending agent. Numerous small studies
have evaluated various drugs as potential therapies
(Table 1). Agents demonstrating the ability to attenuate cough due to ACE inhibitors in randomized,
double-blind, placebo-controlled trials include inhaled sodium cromoglycate,19 theophylline,20 sulindac,21 indomethacin,22 the calcium-channel antagonists amlodipine and nifedipine,22 ferrous sulfate,23
and the thromboxane receptor antagonist picotamide
(not available in the United States).24 In open-label,
uncontrolled studies, agents shown to suppress ACE
inhibitor-induced cough include the ␥-aminobutyric
acid agonist baclofen,25 the thromboxane synthetase
inhibitor ozagrel,26 and aspirin, 500 mg/d (low-dose
therapy with aspirin was found to be ineffective).27
One randomized, double-blind, parallel-group,
controlled trial13 demonstrated that about 30% of
patients with ACE inhibitor-induced cough who had
been challenged and dechallenged twice did not
develop cough after a third trial of ACE inhibitor
therapy.13 Therefore, in patients whose cough resolves after the cessation of ACE inhibition therapy
and for whom there is a compelling reason to treat
with these agents, a repeat trial of ACE inhibitor
therapy may be attempted.
Pathogenesis
Recommendations
The mechanism of ACE inhibitor-induced cough
remains unclear. Possible protussive mediators in-
2. In patients presenting with chronic ACE
inhibitor-induced cough, discontinue therapy
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Diagnosis and Management of Cough: ACCP Guidelines
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Table 1—Drugs Shown to Attenuate Cough Due to ACE Inhibitors
Patients,
No.
Age,*
yr
Dosing
Results
p Value
10
49–77
10 mg inhaled qid, for 14 d
Reduction in 9/10 patients
⬍ 0.01
Theophylline
Sulindac
Hargreaves and
Benson19
Cazolla et al20
McEwan et al21
10
6
33–74
46–66
8.5 mg/kg po qd, for 14 d
200 mg po qd, 7 d
Indomethacin
Fogari et al22
33
42–65
50 mg po bid, 14 d
Amlodipine
Fogari et al22
33
42–65
5 mg po qd, 14 d
Nifedipine
Fogari et al22
33
42–65
30 mg po qd, 14 d
Ferrous sulfate
Lee et al23
19
59.9 ⫾ 12.2
256 mg po qd, 28 d
Picotamide
Malini et al24
9
39–69
600 mg po bid, 14 d
Baclofen
Dicpinigaitis25
7
43–73
5–10 mg po tid, 28 d
Ozagrel
Umemura et al26
10
60 ⫾ 11
200 mg po qd, 30–60 d
Aspirin
Tenenbaum et al27
14
63 ⫾ 11
500 mg po qd, 7 d
Remission in 8/10 patients
37% reduction in cough
score
Eliminated in 27%,
significantly reduced in
69% of patients
Eliminated in 6%,
significantly reduced in
61% of patients
Eliminated in 3%,
significantly reduced in
51% of patients
45% reduction in mean
cough score
Significant
reduction/elimination in
8/9 patients
64% reduction in mean
cough score
Reduced or eliminated in
8/10 patients
Reduced or eliminated in
8/9 patients
Treatment
Sodium cromoglycate
Study
⬍ 0.01
⬍ 0.05
⬍ 0.05
⬍ 0.01
⬍ 0.001
0.012
⬍ 0.002
*Values are given as mean ⫾ SD or range.
with the drug because it is the only uniformly
effective treatment. Quality of evidence, low; net
benefit, substantial; grade of recommendation, B
3. In patients whose cough resolves after the
cessation of therapy with ACE inhibitors, and
for whom there is a compelling reason to treat
with these agents, a repeat trial of ACE inhibitor therapy may be attempted. Quality of evidence, fair; net benefit, substantial; grade of recommendation, A
4. In patients for whom the cessation of ACE
inhibitor therapy is not an option, pharmacologic therapy, including that with sodium cromoglycate, theophylline, sulindac, indomethacin, amlodipine, nifedipine, ferrous sulfate, and
picotamide that is aimed at suppressing cough
should be attempted. Quality of evidence, fair; net
benefit, intermediate; grade of recommendation, B
Theoretically, the recently introduced ARBs
should not induce cough, because their mechanism
of action does not involve the inhibition of ACE with
the resultant elevation of tissue levels of bradykinin
and substance P. Indeed, losartan, the first ARB that
was approved for clinical use, has been associated
with a low incidence of cough, similar to that of the
diuretic hydrochlorothiazide, in patients with a hiswww.chestjournal.org
tory of ACE inhibitor-induced cough.13 Numerous
comparative trials28,29 have subsequently been performed, demonstrating the lower incidence of cough
associated with several ARBs compared to that with
ACE inhibitors.
Recommendation
5. In patients in whom persistent or intolerable ACE inhibitor-induced cough occurs, therapy should be switched, when indicated, to an
ARB, with which the incidence of associated
cough appears to be similar to that for the
control drug, or to an appropriate agent of
another drug class. Quality of evidence, good; net
benefit, substantial; grade of recommendation, A
Summary of Recommendations
1. In patients presenting with chronic
cough, in order to determine that the ACE
inhibitor is the cause of the cough, therapy
with ACE inhibitors should be discontinued
regardless of the temporal relation between
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the onset of cough and the initiation of ACE
inhibitor therapy. The diagnosis is confirmed by the resolution of cough, usually
within 1 to 4 weeks of the cessation of the
offending agent; however, the resolution of
cough may be delayed in a subgroup of
patients for up to 3 months. Quality of evidence, low; net benefit, substantial; grade of
recommendation, B
2. In patients presenting with chronic
ACE inhibitor-induced cough, discontinue
therapy with the drug because it is the only
uniformly effective treatment. Quality of evidence, low; net benefit, substantial; grade of
recommendation, B
3. In patients whose cough resolves after the cessation of therapy with ACE
inhibitors, and for whom there is a compelling reason to treat with these agents, a
repeat trial of ACE inhibitor therapy may
be attempted. Quality of evidence, fair; net
benefit, substantial; grade of recommendation,
A
4. In patients for whom the cessation of
ACE inhibitor therapy is not an option,
pharmacologic therapy, including that
with sodium cromoglycate, theophylline,
sulindac, indomethacin, amlodipine, nifedipine, ferrous sulfate, and picotamide
that is aimed at suppressing cough should
be attempted. Quality of evidence, fair; net
benefit, intermediate; grade of recommendation, B
5. In patients in whom persistent or intolerable ACE inhibitor-induced cough occurs,
therapy should be switched, when indicated, to an ARB, with which the incidence
of associated cough appears to be similar to
that for the control drug, or to an appropriate agent of another drug class. Quality of
evidence, good; net benefit, substantial; grade of
recommendation, A
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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