Combination Antihypertensive Therapy

Combination antihypertensive therapy uses two or more drugs from different classes, because most people need two or three drugs to reach target and low-dose combinations lower pressure more than doubling a single drug while causing fewer adverse effects. A single-pill combination improves adherence and is preferred. Combination therapy is the usual start when pressure is 20/10 mmHg or more over target.

Pharmacology. Calcium channel blockers cause vasodilatation and ankle oedema, which an ACE inhibitor or angiotensin receptor blocker reduces. Thiazide-like diuretics activate the renin axis, which an ACE inhibitor or angiotensin receptor blocker blunts.

Preferred pairs. An ACE inhibitor or angiotensin receptor blocker with a dihydropyridine calcium channel blocker or with a thiazide-like diuretic. In people of African ancestry, a calcium channel blocker with a thiazide-like diuretic works well.

Step 2. Ramipril 2.5 to 5 mg orally once daily with amlodipine 5 mg once daily. Alternatively, losartan 50 mg once daily with amlodipine 5 mg once daily, or losartan 50 mg with hydrochlorothiazide 12.5 mg once daily.

Step 3. An ACE inhibitor or angiotensin receptor blocker, amlodipine 5 to 10 mg once daily and indapamide modified-release 1.5 mg once daily (or chlorthalidone 12.5 to 25 mg once daily), at maximum tolerated doses.

Do not combine. An ACE inhibitor with an angiotensin receptor blocker, because of hyperkalaemia and kidney injury without added benefit. Avoid a beta blocker with verapamil or diltiazem, which risks heart block.

Beta blockers. Add bisoprolol 2.5 mg orally once daily, maximum 10 mg, only for angina, previous myocardial infarction, heart failure with reduced ejection fraction or rate control.

Special groups. In pregnancy use labetalol, nifedipine modified-release or methyldopa. In older adults use half doses and check for postural hypotension. In creatinine clearance under 30 mL/min, indapamide is less effective, so chlorthalidone or a loop diuretic is preferred. In hepatic impairment avoid labetalol and use amlodipine 2.5 mg as a start.

Titration. Move to full doses of two drugs before adding a third, and leave 4 weeks between steps.

Monitoring. Creatinine, potassium and sodium 1 to 2 weeks after any new combination, then at 3 months and each year. Measure standing blood pressure in older adults and people with diabetes.

Sick day rule. During vomiting, diarrhoea or poor intake, withhold ACE inhibitors, angiotensin receptor blockers and diuretics, and restart after 24 to 48 hours of normal drinking.

Stopping. If pressure falls under target, remove the drug with the most adverse effects first. Taper beta blockers over 1 to 2 weeks rather than stopping suddenly.

Common errors. Adding a third drug before the first two reach full dose, using two drugs of the same class, and forgetting that a single-pill product contains a diuretic when adding another.

Referral and escalation. Refer when pressure remains over target on three drugs, including a diuretic, at full doses.