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Angiotensin-Converting Enzyme Inhibitor-Induced Cough : ACCP Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Peter V. Dicpinigaitis, MD, FCCP
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Correspondence to: Peter Dicpinigaitis, MD, FCCP, Einstein Division/Montefiore Medical Center, 1825 Eastchester Rd, Bronx, NY 10461; e-mail: pdicpinigaitis@pol.net



Chest. 2006;129(1_suppl):169S-173S. doi:10.1378/chest.129.1_suppl.169S
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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.

Chronic cough is a well-described class effect of the angiotensin-converting enzyme (ACE) inhibitors.1 The cough is typically dry and is associated with a tickling or scratching sensation in the throat. The incidence of ACE inhibitor-induced cough has been reported12 to be in the range of 5 to 35% among patients who have been treated with these agents. However, in prospective, descriptive studies35 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.1Patients treated with ACE inhibitors for congestive heart failure cough more frequently than those treated with these agents for hypertension.2 Cough due to ACE inhibitors occurs more commonly in women,69 nonsmokers,1,8 and persons of Chinese origin.1011

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.”

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

The mechanism of ACE inhibitor-induced cough remains unclear. Possible protussive mediators include 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 inhibitor-induced cough.14Some evidence has suggested that the therapeutic effect of ACE inhibitors may involve the activation of bradykinin receptors,15and that bradykinin receptor gene polymorphism is associated with the cough that is related to ACE inhibitors.16The 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

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,19theophylline,20sulindac,21indomethacin,22 the calcium-channel antagonists amlodipine and nifedipine,22ferrous sulfate,23and the thromboxane receptor antagonist picotamide (not available in the United States).24In open-label, uncontrolled studies, agents shown to suppress ACE inhibitor-induced cough include the γ-aminobutyric acid agonist baclofen,25the thromboxane synthetase inhibitor ozagrel,26and 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.

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

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 history of ACE inhibitor-induced cough.13 Numerous comparative trials2829 have subsequently been performed, demonstrating the lower incidence of cough associated with several ARBs compared to that with ACE inhibitors.

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

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

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

Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker

Table Graphic Jump Location
Table 1. Drugs Shown to Attenuate Cough Due to ACE Inhibitors
* 

Values are given as mean ± SD or range.

Israili, ZH, Hall, WD (1992) Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.Ann Intern Med117,234-242
 
Ravid, D, Lishner, M, Lang, R, et al Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and in congestive heart failure.J Clin Pharmacol1994;34,1116-1120
 
Mello, CJ, Irwin, RS, Curley, FJ The predictive values of the character, timing, and complications of chronic cough in diagnosing its cause.Arch Intern Med1996;156,997-1003
 
Irwin, RS, Curley, FJ, French, CL Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outline of specific therapy.Am Rev Respir Dis1990;141,640-647
 
Smyrnios, NA, Irwin, RS, Curley, FJ Chronic cough with a history of excessive sputum production: the spectrum and frequency of causes and key components of the diagnostic evaluation, and outcome of specific therapy.Chest1995;108,991-997
 
Os, I, Bratland, B, Dahlof, B, et al Female preponderance for lisinopril-induced cough in hypertension.Am J Hypertens1994;7,1012-1015
 
Coulter, DM, Edwards, IR Cough associated with captopril and enalapril.BMJ1987;294,1521-1523
 
Strocchi, E, Malini, PL, Valtancoli, G, et al Cough during treatment with angiotensin converting enzyme inhibitors: analysis of predisposing factors.Drug Invest1992;4,69-72
 
Gibson, GR Enalapril-induced cough.Arch Intern Med1989;149,2701-2703
 
Woo, J, Chan, TYK A high incidence of cough associated with combination therapy of hypertension with isradipine and lisinopril in Chinese subjects.Br J Clin Pract1991;45,178-180
 
Woo, KS, Nicholls, MG High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese.Br J Clin Pharmacol1995;40,141-144
 
Morice, AH, Lowry, R, Brown, MJ, et al Angiotensin-converting enzyme and the cough reflex.Lancet1987;2,1116-1118
 
Lacourciere, Y, Brunner, H, Irwin, RS, et al Effects of modulators of the renin-angiotensin-aldosterone system on cough.J Hypertens1994;12,1387-1393
 
Fox, AJ, Lalloo, UG, Belvisi, MG, et al Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough.Nat Med1996;2,814-817
 
Ignjatovic, T, Tan, F, Brovkovych, V, et al Novel mode of action of angiotensin I converting enzyme inhibitors.J Biol Chem2002;277,16847-16852
 
Mukae, S, Aoki, S, Itoh, S, et al Bradykinin B2receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitor-related cough.Hypertension2000;36,127-131
 
Dicpinigaitis, PV, Dobkin, JB Effect of angiotensin-converting enzyme inhibition on bronchial responsiveness.J Clin Pharmacol1996;36,361-364
 
O’Connell, F, Thomas, VE, Pride, NB, et al Capsaicin cough sensitivity decreases with successful treatment of chronic cough.Am J Respir Crit Care Med1994;150,374-380
 
Hargreaves, MR, Benson, MK Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough.Lancet1995;345,13-16
 
Cazolla, M, Matera, MG, Liccardi, G, et al Theophylline in the inhibition of angiotensin-converting enzyme inhibitor-induced cough.Respiration1993;60,212-215
 
McEwan, JR, Choudry, NB, Fuller, RW The effect of sulindac on the abnormal cough reflex associated with dry cough.J Pharmacol Exp Ther1990;255,161-164
 
Fogari, R, Zoppi, A, Mugellini, A, et al Effects of amlodipine, nifedipine GITS, and indomethacin on angiotensin-converting enzyme inhibitor-induced cough: a randomized, placebo-controlled, double-masked, crossover study.Curr Ther Res1999;60,121-128
 
Lee, S-C, Park, SW, Kim, D-K, et al Iron supplementation inhibits cough associated with ACE inhibitors.Hypertension2001;38,166-170
 
Malini, PL, Strocchi, E, Zanardi, M, et al Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor.Lancet1997;350,15-18
 
Dicpinigaitis, PV Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors.Ann Pharmacother1996;30,1242-1245
 
Umemura, K, Nakashima, M, Saruta, T Thromboxane A2synthetase inhibitor suppresses cough induced by angiotensin converting enzyme inhibitors.Life Sci1997;60,1583-1588
 
Tenenbaum, A, Grossman, E, Shemesh, J, et al Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough.Am J Hypertens2000;13,776-782
 
Pylypchuk, GB ACE inhibitor- versus angiotensin II blocker-induced cough and angioedema.Ann Pharmacother1998;32,1060-1066
 
Hernandez-Hernandez, R, Sosa-Canache, B, Velasco, M, et al Angiotensin II receptor antagonists role in arterial hypertension.J Hum Hypertens2002;16(suppl),S93-S99
 

Figures

Tables

Table Graphic Jump Location
Table 1. Drugs Shown to Attenuate Cough Due to ACE Inhibitors
* 

Values are given as mean ± SD or range.

References

Israili, ZH, Hall, WD (1992) Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.Ann Intern Med117,234-242
 
Ravid, D, Lishner, M, Lang, R, et al Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and in congestive heart failure.J Clin Pharmacol1994;34,1116-1120
 
Mello, CJ, Irwin, RS, Curley, FJ The predictive values of the character, timing, and complications of chronic cough in diagnosing its cause.Arch Intern Med1996;156,997-1003
 
Irwin, RS, Curley, FJ, French, CL Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outline of specific therapy.Am Rev Respir Dis1990;141,640-647
 
Smyrnios, NA, Irwin, RS, Curley, FJ Chronic cough with a history of excessive sputum production: the spectrum and frequency of causes and key components of the diagnostic evaluation, and outcome of specific therapy.Chest1995;108,991-997
 
Os, I, Bratland, B, Dahlof, B, et al Female preponderance for lisinopril-induced cough in hypertension.Am J Hypertens1994;7,1012-1015
 
Coulter, DM, Edwards, IR Cough associated with captopril and enalapril.BMJ1987;294,1521-1523
 
Strocchi, E, Malini, PL, Valtancoli, G, et al Cough during treatment with angiotensin converting enzyme inhibitors: analysis of predisposing factors.Drug Invest1992;4,69-72
 
Gibson, GR Enalapril-induced cough.Arch Intern Med1989;149,2701-2703
 
Woo, J, Chan, TYK A high incidence of cough associated with combination therapy of hypertension with isradipine and lisinopril in Chinese subjects.Br J Clin Pract1991;45,178-180
 
Woo, KS, Nicholls, MG High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese.Br J Clin Pharmacol1995;40,141-144
 
Morice, AH, Lowry, R, Brown, MJ, et al Angiotensin-converting enzyme and the cough reflex.Lancet1987;2,1116-1118
 
Lacourciere, Y, Brunner, H, Irwin, RS, et al Effects of modulators of the renin-angiotensin-aldosterone system on cough.J Hypertens1994;12,1387-1393
 
Fox, AJ, Lalloo, UG, Belvisi, MG, et al Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough.Nat Med1996;2,814-817
 
Ignjatovic, T, Tan, F, Brovkovych, V, et al Novel mode of action of angiotensin I converting enzyme inhibitors.J Biol Chem2002;277,16847-16852
 
Mukae, S, Aoki, S, Itoh, S, et al Bradykinin B2receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitor-related cough.Hypertension2000;36,127-131
 
Dicpinigaitis, PV, Dobkin, JB Effect of angiotensin-converting enzyme inhibition on bronchial responsiveness.J Clin Pharmacol1996;36,361-364
 
O’Connell, F, Thomas, VE, Pride, NB, et al Capsaicin cough sensitivity decreases with successful treatment of chronic cough.Am J Respir Crit Care Med1994;150,374-380
 
Hargreaves, MR, Benson, MK Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough.Lancet1995;345,13-16
 
Cazolla, M, Matera, MG, Liccardi, G, et al Theophylline in the inhibition of angiotensin-converting enzyme inhibitor-induced cough.Respiration1993;60,212-215
 
McEwan, JR, Choudry, NB, Fuller, RW The effect of sulindac on the abnormal cough reflex associated with dry cough.J Pharmacol Exp Ther1990;255,161-164
 
Fogari, R, Zoppi, A, Mugellini, A, et al Effects of amlodipine, nifedipine GITS, and indomethacin on angiotensin-converting enzyme inhibitor-induced cough: a randomized, placebo-controlled, double-masked, crossover study.Curr Ther Res1999;60,121-128
 
Lee, S-C, Park, SW, Kim, D-K, et al Iron supplementation inhibits cough associated with ACE inhibitors.Hypertension2001;38,166-170
 
Malini, PL, Strocchi, E, Zanardi, M, et al Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor.Lancet1997;350,15-18
 
Dicpinigaitis, PV Use of baclofen to suppress cough induced by angiotensin-converting enzyme inhibitors.Ann Pharmacother1996;30,1242-1245
 
Umemura, K, Nakashima, M, Saruta, T Thromboxane A2synthetase inhibitor suppresses cough induced by angiotensin converting enzyme inhibitors.Life Sci1997;60,1583-1588
 
Tenenbaum, A, Grossman, E, Shemesh, J, et al Intermediate but not low doses of aspirin can suppress angiotensin-converting enzyme inhibitor-induced cough.Am J Hypertens2000;13,776-782
 
Pylypchuk, GB ACE inhibitor- versus angiotensin II blocker-induced cough and angioedema.Ann Pharmacother1998;32,1060-1066
 
Hernandez-Hernandez, R, Sosa-Canache, B, Velasco, M, et al Angiotensin II receptor antagonists role in arterial hypertension.J Hum Hypertens2002;16(suppl),S93-S99
 
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