How to manage an Angiotensin-Converting Enzyme (ACE) inhibitor-induced cough?

Management of ACE Inhibitor-Induced Cough

The only uniformly effective treatment for ACE inhibitor-induced cough is discontinuation of the offending agent, regardless of the temporal relationship between cough onset and medication initiation. 1, 2

Diagnosis and Prevalence

• ACE inhibitor-induced cough occurs in approximately 5-35% of patients treated with these medications 1, 2
• The cough is typically dry and associated with a tickling or scratching sensation in the throat 1
• Cough may develop within hours of the first dose or be delayed for weeks to months after starting therapy 1
• ACE inhibitor-induced cough occurs more frequently in women, nonsmokers, and persons of Chinese origin 1, 3

Pathophysiology

• The mechanism involves accumulation of bradykinin and substance P in the upper airway, along with prostaglandins stimulated by bradykinin 1
• Bradykinin-induced sensitization of airway sensory nerves has been proposed as a potential mechanism 1
• Subjects with ACE inhibitor-induced cough demonstrate increased cough reflex sensitivity to experimental stimulation with capsaicin 1

Management Algorithm

First-Line Approach

• Discontinue the ACE inhibitor - this is the only uniformly effective intervention 1, 2
• Diagnosis is confirmed by resolution of cough, usually within 1-4 weeks of cessation, though it may take up to 3 months in some patients 1, 2

Alternative Antihypertensive Options

• Switch to an angiotensin receptor blocker (ARB) as first-line alternative - ARBs do not affect bradykinin metabolism and typically do not cause cough 2, 3
• If ARBs are contraindicated or not tolerated, consider a calcium channel blocker (CCB) 2, 3
• Thiazide-like diuretics can also be considered if CCBs are not suitable 2

Pharmacologic Interventions to Suppress Cough (if ACE inhibitor must be continued)

• Several agents have demonstrated the ability to attenuate ACE inhibitor-induced cough in randomized, double-blind, placebo-controlled trials:
  • Inhaled sodium cromoglycate 1, 3
  • Theophylline 1, 3
  • Calcium channel antagonists (amlodipine, nifedipine) 1, 2
  • NSAIDs (sulindac, indomethacin) - use with caution in elderly patients 1, 3
  • Ferrous sulfate 1, 3

Special Considerations

• In approximately 30% of patients with ACE inhibitor-induced cough who have been challenged and dechallenged twice, cough may not recur after a third trial of ACE inhibitor therapy 1
• For patients with compelling indications for ACE inhibitor therapy, a repeat trial may be attempted if the cough resolves after initial discontinuation 1
• Concomitant use of calcium antagonists or diuretics with ACE inhibitors may reduce the frequency of cough compared to ACE inhibitor monotherapy 4
• Taking the medication at bedtime may reduce the frequency of cough as an adverse reaction 4

Monitoring After Medication Change

• After switching from an ACE inhibitor to an alternative medication, monitor blood pressure closely to ensure adequate control 2
• If blood pressure is not adequately controlled on monotherapy, combination therapy may be necessary 2

Pitfalls and Caveats

• Cough may resolve spontaneously in some patients despite continuing ACE inhibitor treatment 5, 4
• Switching between different ACE inhibitors is generally not recommended as cough is considered a class effect 6
• Rare cases of cough with ARBs have been reported, though the incidence is similar to placebo 7
• Always exclude other common causes of cough (respiratory infections, heart failure, pulmonary disease, post-nasal drip) before attributing it to ACE inhibitors 3