Switching from Perindopril to ARB for ACE Inhibitor-Induced Cough

Rationale for Switching to an ARB

• ACE inhibitor-induced cough is a well-documented class effect occurring in 5-35% of patients taking medications like perindopril, according to the American Thoracic Society 1
• The cough is typically dry and associated with a tickling sensation in the throat due to accumulation of bradykinin and substance P, as reported by the American College of Chest Physicians 1, 2
• ARBs are the preferred alternative for patients with ACE inhibitor-induced cough as they do not inhibit ACE and therefore don't cause bradykinin accumulation, as recommended by the American Heart Association 3, 4
• Clinical guidelines strongly recommend (Grade A recommendation) switching to an ARB when ACE inhibitor-induced cough occurs, according to the American College of Cardiology 3, 5

Specific ARB Recommendation: Losartan

• Losartan is the most studied ARB for patients with ACE inhibitor-induced cough, with a starting dose of 25mg once daily, as recommended by the American Heart Association 5
• The initial dose of losartan can be titrated to 50mg once daily if needed for blood pressure control, as suggested by the American College of Cardiology 6

Dosing and Monitoring Considerations

• Begin with losartan 25mg once daily as an appropriate starting dose for an elderly patient, as recommended by the American Geriatrics Society 6
• Monitor blood pressure, renal function, and potassium within 1-2 weeks after initiation, as suggested by the National Kidney Foundation 6
• Pay particular attention to postural blood pressure changes in elderly patients, as recommended by the American Geriatrics Society 6

Important Precautions

• Although rare, angioedema has been reported with ARBs in patients who previously experienced angioedema with ACE inhibitors; use caution during initial treatment, as warned by the FDA 6
• Assess renal function and potassium levels regularly, as ARBs can cause hyperkalemia and worsening renal function similar to ACE inhibitors, as recommended by the National Kidney Foundation 6

Alternative ARBs if Losartan is Not Tolerated

• Candesartan 4-8mg once daily (initial dose) up to 32mg once daily (maximum dose) can be considered as an alternative, as suggested by the American College of Cardiology 6
• Valsartan 20-40mg twice daily (initial dose) up to 160mg twice daily (maximum dose) can also be considered as an alternative, as recommended by the American Heart Association 6

ARB-Related Cough Incidence

Evidence from Guidelines and Clinical Trials

• ARBs as a class have cough rates similar to placebo or hydrochlorothiazide, and dramatically lower than ACE inhibitors, due to their mechanism of not inhibiting ACE and therefore not causing accumulation of bradykinin and substance P, the mediators responsible for ACE inhibitor-induced cough 7, 8
• The American College of Chest Physicians notes that no head-to-head trials have compared cough rates between different ARBs, and the 2022 guidelines note "no sex-specific differences in cough" between ARBs 7, 8, 9

Clinical Recommendation

• When switching from an ACE inhibitor due to cough, any ARB is appropriate, and the choice should be based on comorbidities, dosing convenience, and cost and availability, rather than cough profile 7, 9
• The choice of ARB should consider once-daily formulations to improve adherence, and all ARBs have equivalent cough profiles 9

Practical Algorithm for ARB Selection

• Cough should resolve within 1-4 weeks after switching to an ARB, though may take up to 3 months in some patients 7

Management of ACE Inhibitor-Induced Cough

Diagnostic Confirmation

• The American College of Chest Physicians recommends discontinuing the ACE inhibitor regardless of when the cough started relative to when the medication was initiated, with cough resolution expected within 1-4 weeks after stopping the medication 10
• The diagnosis is confirmed only when the cough resolves after discontinuation of the ACE inhibitor, as recommended by the American College of Chest Physicians 10

Primary Management Strategy: Switch to an ARB

• The American College of Chest Physicians recommends switching to an angiotensin receptor blocker (ARB) as the Grade A recommendation when persistent or intolerable ACE inhibitor-induced cough occurs, with ARBs having a dramatically lower incidence of cough (similar to placebo) while maintaining equivalent cardiovascular benefits 10
• ARBs have a cough incidence similar to placebo (approximately 2-3%) compared to ACE inhibitors (7.9%), according to the American College of Chest Physicians 10

Alternative Approach: Pharmacologic Cough Suppression

• The American College of Chest Physicians recommends attempting pharmacologic cough suppression with medications such as amlodipine or nifedipine (calcium channel blockers), which have shown ability to suppress ACE inhibitor-induced cough in controlled trials, as a Grade B recommendation 10
• Sodium cromoglycate (cromolyn) 1.6 mg via MDI 4 times daily or 20 mg capsules 4 times daily has shown efficacy in case reports, as noted by the American College of Chest Physicians 10
• Other options include theophylline, sulindac, indomethacin, ferrous sulfate, or picotamide, although these suppressive therapies have only fair quality evidence and intermediate benefit, according to the American College of Chest Physicians 10

Management of ACE Inhibitor-Induced Cough

Immediate Management and Alternative Therapies

• Discontinuing the ACE inhibitor immediately is the only uniformly effective treatment for ACE inhibitor-induced cough, with cough resolution expected within 1-4 weeks after stopping the medication, though it may take up to 3 months in some patients 11
• Amlodipine 5 mg once daily has demonstrated the ability to attenuate ACE inhibitor-induced cough in randomized controlled trials, with 61% of patients showing significant cough reduction 11
• Nifedipine 30 mg daily is another option, showing cough elimination or significant reduction in 51% of patients 11
• Sodium cromoglycate, 10 mg inhaled four times daily for 14 days, showed reduction in 9/10 patients 11
• Indomethacin, 50 mg twice daily for 14 days, eliminated cough in 27% and significantly reduced in 69% of patients 11
• Ferrous sulfate, 256 mg once daily for 28 days, resulted in a 45% reduction in mean cough score 11

Considerations for ACE Inhibitor Rechallenge

• Approximately 30% of patients with confirmed ACE inhibitor-induced cough who were challenged and dechallenged twice did not develop cough after a third trial of ACE inhibitor therapy, suggesting a repeat trial of ACE inhibitor therapy may be attempted in patients with compelling indications after cough resolution 11

Management of ACE‑Inhibitor–Induced Cough

Diagnostic Confirmation

• Exclude alternative etiologies such as pulmonary congestion, respiratory infections, lung disease, and post‑nasal drip before attributing cough to an ACE inhibitor. American College of Cardiology and American Heart Association recommendations. [12][13]
• Typical ACE‑inhibitor cough is dry, non‑productive, and described as a persistent tickle at the back of the throat. American College of Cardiology and American Heart Association observations. [12][13]
• Confirm diagnosis by demonstrating cough resolution after ACE‑inhibitor discontinuation and recurrence within days after re‑exposure to another ACE inhibitor. American College of Cardiology and American Heart Association criteria. [12][13]

Severity Assessment and Initial Decision

• Mild cough: Continue ACE inhibitor because of its proven long‑term cardiovascular benefit, provided the cough is not severe. American College of Cardiology and American Heart Association guidance. [12][13]
• Persistent or bothersome cough: Discontinue the ACE inhibitor. American College of Cardiology and American Heart Association algorithm. [12][13]

Substitution After Discontinuation

• Angiotensin‑II receptor blockers (ARBs) are first‑line alternatives after stopping an ACE inhibitor. American College of Cardiology and American Heart Association recommendation. [12][13]

Dosing regimens are endorsed by the American College of Cardiology and the American Heart Association. [12][13]

Timeline for Cough Resolution

• Typical resolution occurs within 1–2 weeks after ACE‑inhibitor cessation. American College of Cardiology and American Heart Association data. [12][13]
• Extended resolution may require up to 3 months in some patients. Chest publication. 14
• Re‑challenge effect: Cough reappears within days after exposure to another ACE inhibitor. American College of Cardiology and American Heart Association findings. [12][13]

Safety and Special Considerations

• Do not substitute another ACE inhibitor; the cough is a class effect and will almost invariably recur. American College of Cardiology and American Heart Association warning. [12][13]
• Rare angio‑edema risk with ARBs in patients who previously experienced ACE‑inhibitor‑related angio‑edema. American College of Cardiology and American Heart Association caution. [12][13]
• Higher susceptibility to ACE‑inhibitor cough is observed in women, non‑smokers, and individuals of Chinese ancestry, with incidence reported up to 50% in the latter group. American College of Cardiology and American Heart Association epidemiology. [12][13]

Management of ACE Inhibitor‑Induced Cough

Confirming the Diagnosis

• Discontinuing the ACE inhibitor is recommended regardless of the interval between drug initiation and cough onset, because a temporal relationship does not exclude the medication as the cause. 15
• In most patients, cough resolves within 1–4 weeks after stopping the ACE inhibitor; a minority may require up to 3 months for complete resolution. 15
• Resolution of cough after drug withdrawal serves as the definitive diagnostic criterion for ACE‑inhibitor‑induced cough. 15

Primary Management: Switch to an Angiotensin Receptor Blocker (ARB)

• The American College of Chest Physicians gives a Grade A recommendation to discontinue the ACE inhibitor immediately and replace it with an ARB, the only uniformly effective intervention. 15
• ARBs have cough incidence comparable to placebo (approximately 2–3 %) and markedly lower than ACE inhibitors (≈ 8 %). 15
• After switching, blood pressure, renal function, and serum potassium should be monitored within 1–2 weeks to ensure safety and efficacy. 15

Alternative Pharmacologic Cough Suppression (When ACE Inhibitor Must Be Continued)

• Calcium‑channel blockers demonstrated cough improvement: amlodipine 5 mg daily achieved a 61 % response rate, and nifedipine 30 mg daily achieved a 51 % response rate. 15
• Inhaled sodium cromoglycate (20 mg four times daily) reduced cough in roughly 90 % of treated patients. 15
• Ferrous sulfate 256 mg daily for 28 days lowered cough scores by about 45 %. 15
• Intermediate‑dose aspirin (500 mg daily) suppressed cough in 93 % of patients, though caution is advised in elderly individuals. 15
• Non‑steroidal anti‑inflammatory drugs (e.g., indomethacin 50 mg twice daily or sulindac) showed efficacy but require careful risk assessment for cardiovascular and renal adverse effects. 15
• Theophylline was effective in reducing cough, but therapeutic drug monitoring is necessary to avoid toxicity. 15

Important Clinical Considerations

• Switching to another ACE inhibitor is ineffective because cough is a class effect and will recur with any ACE inhibitor. 15
• Populations at higher risk for ACE‑inhibitor‑induced cough include women, nonsmokers, and individuals of Chinese ancestry, with incidence reported up to 50 % in the latter group. 15
• Patients with a prior ACE‑inhibitor‑related angioedema have a rare but possible risk of angioedema when treated with an ARB; close monitoring during the initial treatment period is advised. 15
• Rechallenge after confirmed cough may be considered in select cases: approximately 30 % of patients who underwent two cycles of dechallenge and rechallenge did not develop cough on a third trial, suggesting feasibility when therapeutic indications are compelling. 15

Mechanistic Insight

• ACE inhibition leads to accumulation of bradykinin and substance P in the airways, as ACE normally degrades these mediators, contributing to cough generation. 15
• Elevated bradykinin stimulates prostaglandin production, further sensitizing the cough reflex. 15
• The cough is not dose‑dependent; reducing the ACE‑inhibitor dose does not alleviate the symptom. 15

Monitoring After Switching to an ARB

• Cough should resolve within 1–4 weeks after the transition to an ARB, confirming that the original ACE inhibitor was the cause. 15
• Persistent cough beyond 3 months warrants evaluation for alternative etiologies such as pulmonary congestion, respiratory infection, chronic lung disease, or post‑nasal drip. 15
• Adequate blood pressure control should be reassessed after the switch; additional antihypertensive agents may be required if monotherapy is insufficient. 15