What alternative antihypertensive therapy can be considered for a patient with hypertension who is not tolerating perindopril (Angiotensin-Converting Enzyme inhibitor) due to cough?

Switch to an Angiotensin Receptor Blocker (ARB)

For a patient with hypertension experiencing cough from perindopril, immediately discontinue the ACE inhibitor and switch to an ARB such as losartan, valsartan, or candesartan, as ARBs provide equivalent blood pressure control and cardiovascular benefits without causing cough. 1, 2

Why ARBs Are the Preferred Alternative

• ARBs do not cause cough because they do not inhibit bradykinin accumulation, which is the mechanism responsible for ACE inhibitor-induced cough 1, 3
• The incidence of cough with ARBs is significantly lower than with ACE inhibitors—studies show cough rates of 17-29% with losartan versus 62-69% with lisinopril, with ARB rates similar to placebo 4
• ARBs provide equivalent cardiovascular benefits to ACE inhibitors for hypertension management, making them an appropriate substitute 1, 3
• The 2022 AHA/ACC/HFSA guidelines give a Class 1, Level A recommendation (highest level) for using ARBs in patients intolerant to ACE inhibitors due to cough 1, 2

Specific ARB Options and Dosing

Start with one of these evidence-based regimens 1, 3:

• Candesartan: Start 4-8 mg once daily, titrate to target dose of 32 mg once daily 1
• Valsartan: Start 40 mg twice daily (or 80 mg once daily), titrate to target dose of 160 mg twice daily 1, 3
• Losartan: Start 50 mg once daily, titrate to target dose of 100 mg once daily 3, 4

Implementation Strategy

Discontinue perindopril immediately, as this is the only uniformly effective treatment for ACE inhibitor-induced cough 2, 3

• The cough typically resolves within 1-4 weeks after stopping the ACE inhibitor, though it may take up to 3 months in some patients 2, 3
• Do not try switching to another ACE inhibitor (such as lisinopril or enalapril), as cough is a class effect and will recur with any ACE inhibitor 2
• Do not reduce the perindopril dose, as the cough is not dose-dependent and will persist at any dosage 2, 5

Monitoring After Starting ARB

Check baseline renal function and potassium before initiating ARB therapy 1, 3:

• Reassess blood pressure, renal function, and potassium within 1-2 weeks after starting the ARB 1, 3
• Recheck these parameters 1 and 4 weeks after any dose increase 1
• Monitor at 1,3, and 6 months after achieving maintenance dose, then every 6 months thereafter 1

Acceptable laboratory changes include 3:

• Creatinine increases up to 50% above baseline or 266 μmol/L (3 mg/dL), whichever is smaller
• Potassium levels up to 5.5 mmol/L

If potassium rises above 5.5 mmol/L, halve the ARB dose and recheck within 1-2 weeks; seek specialist advice if potassium exceeds 6.0 mmol/L 3

Dose Titration Strategy

• Double the ARB dose every 2-4 weeks if blood pressure remains ≥140/90 mm Hg and the medication is well-tolerated 3
• Aim for evidence-based target doses shown to reduce cardiovascular events in clinical trials 1, 3
• If target doses are not tolerated, accept intermediate doses, as some ARB therapy is better than none 3

Critical Safety Consideration: Angioedema Risk

Although rare (<1%), angioedema can occur with ARBs in patients who previously experienced angioedema with ACE inhibitors 1, 3, 6:

• If the patient has a history of ACE inhibitor-induced angioedema (not just cough), use extreme caution when prescribing an ARB 3, 6
• A mandatory 6-week washout period is required before starting an ARB in patients with prior ACE inhibitor-induced angioedema 6
• If angioedema occurs with an ARB, discontinue immediately and avoid all ARBs for the patient's lifetime 3
• In patients with any history of angioedema, neprilysin inhibitors (ARNIs like sacubitril-valsartan) are absolutely contraindicated 6

Common Pitfalls to Avoid

• Do not assume all cough is ACE inhibitor-related—exclude pulmonary edema and other respiratory causes before attributing cough solely to perindopril 3
• Do not combine ARBs with both ACE inhibitors and aldosterone antagonists, as this increases the risk of hyperkalemia and renal dysfunction 3
• Asymptomatic hypotension does not require dose adjustment, but symptomatic hypotension requires reconsideration of other vasodilators and possible diuretic dose reduction 3
• Do not abruptly withdraw renin-angiotensin system inhibition, as clinical deterioration is likely 3

Alternative if ARB Not Tolerated

If the patient cannot tolerate an ARB (extremely rare scenario), consider 1:

• Hydralazine plus isosorbide dinitrate (H-ISDN): Start hydralazine 37.5 mg and ISDN 20 mg three times daily, titrate to target doses of hydralazine 75 mg and ISDN 40 mg three times daily 1
• However, many patients experience headaches or gastrointestinal distress with these direct-acting vasodilators, which can prevent long-term treatment 1