Adverse Effects of ACE Inhibitors

Introduction to ACE Inhibitor-Induced Cough

• ACE inhibitors cause dry cough in approximately 5-35% of patients overall, according to the American Thoracic Society and the American College of Chest Physicians 1
• The mechanism of ACE inhibitor-induced cough involves the blockade of angiotensin I to angiotensin II conversion and the inhibition of bradykinin and substance P degradation, which can trigger cough, as recommended by the American College of Chest Physicians 1
• The incidence of cough is significantly higher in ACEIs (62-69%) compared to angiotensin II receptor blockers (ARBs) (17-29%) 2
• Cough induced by ACEIs occurs in approximately 5-10% of Caucasian patients and up to 50% in Chinese patients, generally appearing in the first months of treatment, due to the accumulation of bradykinin and substance P in the respiratory tract, as noted by the American College of Cardiology and the European Society of Cardiology 3, 2

Diagnosis and Confirmation of ACE Inhibitor-Induced Cough

• A dry, persistent, nonproductive cough with an annoying "tickle" in the throat typically appears within the first months of ACEI therapy and disappears within 1-2 weeks after discontinuation, according to the American Heart Association 4
• The European Society of Cardiology recommends confirming that the cough is caused by the ACEI, characterized by a dry, persistent, and bothersome cough that appears in the first months of treatment and disappears 1-2 weeks after discontinuing the medication, while excluding other causes of cough (pulmonary congestion, respiratory disease) 2

Alternative Therapies to ACE Inhibitors

• ARBs, such as Valsartan, Losartan, and Candesartan, provide similar cardiovascular benefits to ACEIs but with a significantly lower incidence of cough, as recommended by the American College of Cardiology 4
• The initial doses and maximum doses of ARBs are as follows:

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• The American College of Chest Physicians (ACCP) recommends switching to an ARB such as losartan 50 mg daily or valsartan 80 mg daily with a Grade A recommendation, as ARBs do not inhibit ACE and therefore do not increase bradykinin levels that cause cough 1

Management and Monitoring of ARB Therapy

• While rare, angioedema can occur with ARBs, so use extreme caution if the patient has a history of ACEI-induced angioedema, as warned by the American Heart Association 4, 5
• ARBs can cause hypotension, worsening renal function, and hyperkalemia similar to ACEIs, with a strength of evidence based on clinical trials 4
• Monitor potassium levels closely when using ARBs with spironolactone, as both can increase potassium levels, and check renal function and potassium levels within 1-2 weeks of starting the ARB, according to the American College of Cardiology 6
• Avoid using another ACE inhibitor due to nearly 100% cross-reactivity for cough, and do not combine ARBs with ACE inhibitors, as this increases cardiovascular and renal risk without additional benefit, as stated by the American College of Cardiology 1, 6
• The European Society of Cardiology advises monitoring renal function and potassium levels 1-2 weeks after initiating ARB treatment, as well as blood pressure to ensure adequate control, with follow-up every 3-6 months 2

Pharmacologic Therapy to Suppress Cough

• Do not suppress the cough with medications while continuing ACE inhibitors unless there is an absolute indication for ACE inhibitor therapy, due to the potential for increased risk of adverse effects 1
• If there is a compelling reason to use an ACE inhibitor, consider a trial of pharmacologic therapy to suppress cough while continuing ACE inhibitor, such as sodium cromoglycate, theophylline, amlodipine, or nifedipine 1, 7
• The following medications can be considered as alternatives or for pharmacologic therapy to suppress cough: