When should combination therapy be used in arterial hypertension?

Combination therapy should be considered when blood pressure is significantly above target, when monotherapy is insufficient or when greater efficacy is desired with lower doses of complementary drugs.

What are the preferred combinations of antihypertensive drugs?

Preferred combinations generally include an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker combined with a calcium-channel blocker or a thiazide or thiazide-like diuretic.

Which combination between ACE inhibitors and ARBs should be avoided?

The combination of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker should be avoided because of the increased risk of hyperkalaemia, hypotension and deterioration of renal function.

What is the usual triple therapy?

Usual triple therapy combines an ACE inhibitor or ARB, a calcium-channel blocker and a thiazide or thiazide-like diuretic, with doses and drugs adjusted to the patient’s clinical profile.

What should be done in resistant hypertension?

In resistant hypertension, adherence, measurement technique, white-coat effect, salt intake, interfering drugs and secondary causes should be confirmed or excluded, and additional therapy such as an aldosterone antagonist may be considered.

When should an aldosterone antagonist be added?

An aldosterone antagonist may be considered in resistant hypertension, especially after optimised triple therapy, provided renal function and potassium allow safe use.

What monitoring is required with combination therapy?

Blood pressure, symptoms of hypotension, renal function, potassium, sodium, heart rate and class-specific adverse effects should be monitored.

Are fixed-dose combinations useful?

Fixed-dose combinations may improve adherence, simplify the dosing regimen and facilitate blood pressure control, provided they allow appropriate adjustment to individual needs.

Antihypertensive drugs: pharmacological combinations and clinical indications

Pharmacological combinations in arterial hypertension are essential to achieve blood pressure control in most patients, particularly from stage 2 hypertension onwards or in the presence of resistant hypertension. Rational drug combination makes it possible to enhance the antihypertensive effect, reduce dose-dependent adverse effects and improve adherence, especially when fixed-dose combinations are used.
This table summarises preferred combinations, conditional alternatives and combinations to avoid, organised according to the first drug selected.

Podcast transcript

General principles

Antihypertensive combinations are an effective strategy for achieving blood pressure control, improving therapeutic adherence and reducing adverse effects. They combine drugs from different classes, with complementary mechanisms, allowing blood pressure targets to be reached with lower doses of each component.

Types of combination

Combinations may be dual, two pharmacological classes, or triple, three classes with synergistic action. Dual combinations are the basis of combined treatment, whereas triple combinations are reserved for patients with resistant or difficult-to-control hypertension.

Combinations with ACE inhibitors

The combination of an angiotensin-converting enzyme inhibitor, ACE inhibitor, with a thiazide diuretic is one of the most widely used — examples include perindopril + indapamide, enalapril + hydrochlorothiazide and ramipril + HCT.

This combination simultaneously reduces vascular resistance and intravascular volume, enhancing the antihypertensive effect.

Another frequent combination is between an ACE inhibitor and a calcium-channel blocker, CCB, such as perindopril + amlodipine or ramipril + felodipine, combining arterial vasodilation with modulation of the renin–angiotensin–aldosterone system.

Combinations with angiotensin II receptor blockers, ARBs

ARBs may be combined with a thiazide diuretic — for example losartan + HCT, valsartan + HCT, olmesartan + HCT — or with a CCB, such as olmesartan + amlodipine, telmisartan + amlodipine and valsartan + amlodipine.

There are also triple formulations, which include ARB + CCB + diuretic, such as olmesartan + amlodipine + HCT or telmisartan + amlodipine + HCT.

Combinations with beta-blockers and diuretics

The combination of a beta-blocker with a thiazide diuretic, for example atenolol + HCT or bisoprolol + HCT, is traditional and effective, particularly in patients with coronary artery disease, heart failure or arrhythmias.

Combinations of a thiazide diuretic with a potassium-sparing diuretic, for example HCT + amiloride or HCT + spironolactone, are also used to prevent hypokalaemia.

Less common combinations

Combinations with alpha-blockers, central vasodilators or direct renin inhibitors, for example HCT + aliskiren, are less frequent and should be reserved for specific situations under strict clinical monitoring.

Selection criteria

The choice of combination should consider the patient’s clinical profile, presence of comorbidities, for example heart failure, CKD or diabetes, global cardiovascular risk and individual tolerability.

The combined strategy allows lower doses to be used, reduces adverse effects and enhances pharmacological synergy, improving blood pressure control and cardiovascular prognosis.

Clinical cases

Clinical cases — Antihypertensive combinations

Case 1 — Uncontrolled hypertension on monotherapy

A 56-year-old man with essential hypertension diagnosed 3 years ago, treated with enalapril 20 mg/day. His average BP remains 152/92 mmHg, eGFR 78 mL/min/1.73 m², with no other comorbidities. He has good treatment adherence.
What is the best option to optimise blood pressure control?

Increase enalapril to 40 mg/day
Switch the ACE inhibitor to an ARB
Add a thiazide diuretic, for example enalapril + hydrochlorothiazide
Add a beta-blocker

See answer

c) Add a thiazide diuretic, for example enalapril + hydrochlorothiazide. Rationale: The ACE inhibitor + thiazide diuretic combination is first-line in patients without contraindications, enhancing the antihypertensive effect. The diuretic reduces intravascular volume, complementing blockade of the renin–angiotensin–aldosterone system.

Case 2 — Ankle oedema induced by a calcium-channel blocker

A 64-year-old woman treated with amlodipine 10 mg/day for hypertension. She reports bilateral ankle oedema without pain and without signs of heart failure. BP is controlled, 132/78 mmHg.
What is the most appropriate next step?

Stop amlodipine
Add a loop diuretic
Add an ACE inhibitor, for example perindopril + amlodipine
Reduce the amlodipine dose and add a beta-blocker

See answer

c) Add an ACE inhibitor, for example perindopril + amlodipine. Rationale: Peripheral oedema caused by calcium-channel blockers results from isolated arteriolar vasodilation. Combination with an ACE inhibitor promotes compensatory venous vasodilation, significantly reducing oedema without loss of antihypertensive efficacy.

Case 3 — Resistant hypertension and risk of hypokalaemia

A 70-year-old man with stage 3a CKD, eGFR 52 mL/min/1.73 m², taking losartan 100 mg and hydrochlorothiazide 25 mg/day. BP remains 154/88 mmHg and he reports nocturnal cramps. Serum K⁺ 3.3 mmol/L.
What is the most appropriate treatment adjustment?

Switch hydrochlorothiazide to furosemide
Stop losartan
Add a potassium-sparing diuretic, for example HCT + amiloride
Add a beta-blocker

See answer

c) Add a potassium-sparing diuretic, for example HCT + amiloride. Rationale: In patients with thiazide-induced hypokalaemia and preserved renal function, eGFR > 45 mL/min, adding a potassium-sparing diuretic corrects the electrolyte imbalance while maintaining the overall antihypertensive effect.

FAQ

Frequently asked questions about Antihypertensive Combinations

1) When is combination therapy indicated?

Antihypertensive combinations are indicated when monotherapy does not achieve the BP target, usually after 4–6 weeks, or in patients with initial BP ≥160/100 mmHg. They provide greater efficacy with lower doses of each drug and improve therapeutic adherence.

2) What are the first-line combinations?

The main recommended combinations are: ACE inhibitor or ARB + thiazide diuretic, for example perindopril + indapamide, losartan + HCT, and ACE inhibitor or ARB + calcium-channel blocker, for example perindopril + amlodipine, olmesartan + amlodipine. Both enhance therapeutic effects and reduce cardiovascular events.

3) When should triple combinations be considered?

They should be used in resistant hypertension or when two classes at full dose are insufficient. Examples include olmesartan + amlodipine + HCT or perindopril + amlodipine + indapamide. The third class should act through a complementary mechanism.

4) Which combinations should be avoided?

ACE inhibitor + ARB increases the risk of hyperkalaemia and renal failure without additional benefit. Combining two thiazide diuretic classes should also be avoided, as should concomitant use of aliskiren with ACE inhibitors/ARBs in patients with diabetes or CKD.

5) What are the advantages of fixed-dose formulations?

Fixed-dose combinations simplify the treatment regimen, improve adherence and reduce dosing errors. However, they limit individual dose adjustment and require monitoring for combined adverse effects.

6) When should potassium-sparing agents be added?

In patients with diuretic-induced hypokalaemia and preserved renal function. Examples include HCT + amiloride or HCT + spironolactone. Avoid if eGFR < 45 mL/min/1.73 m² or when combined with ACE inhibitors/ARBs without close laboratory monitoring.

7) What is the best combination in older adults?

In older adults, ACE inhibitor/ARB + CCB combinations are preferable, as they avoid diuretic-induced hyponatraemia and hypokalaemia. Example: perindopril + amlodipine. Doses should be adjusted gradually to prevent postural hypotension.

8) What about patients with diabetes or CKD?

ACE inhibitors or ARBs should be part of the combination because of their nephroprotective effect. A thiazide diuretic or CCB may be added according to the blood pressure profile and renal function. Combinations that worsen renal function or electrolytes should be avoided.

9) Are there efficacy differences between ACE inhibitors and ARBs in combinations?

Both have similar efficacy in reducing BP and preventing cardiovascular events. ARBs tend to be better tolerated, with a lower risk of cough and angioedema, and are often preferred in ACE inhibitor intolerance.

10) When should resistant hypertension be suspected?

When BP remains ≥140/90 mmHg despite the use of 3 complementary pharmacological classes, one of them a diuretic, at maximally tolerated doses and with good adherence. In these cases, secondary causes should be investigated and combination therapy optimised.

11) How should safety be monitored in combinations?

Renal function and electrolytes should be assessed periodically, especially in combinations including ACE inhibitors/ARBs and diuretics. Orthostatic blood pressure should be monitored in older adults, with dose adjustment in renal or hepatic impairment.

12) What additional benefits does combination therapy provide?

It provides a faster and more sustained reduction in BP, better circadian control, lower blood pressure variability and a reduction in the risk of stroke and major cardiovascular events.

References

Authorship and updates

Author(s): Filipe Cerca, MD

Last review: (31/12/2025) Raquel Lisboa, MD

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20/06/2026

Table of antihypertensive drug combinations

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Antihypertensive drugs: pharmacological combinations and clinical indications

General principles

Types of combination

Combinations with ACE inhibitors

Combinations with angiotensin II receptor blockers, ARBs

Combinations with beta-blockers and diuretics

Less common combinations

Selection criteria

Clinical cases — Antihypertensive combinations

Case 1 — Uncontrolled hypertension on monotherapy

Case 2 — Ankle oedema induced by a calcium-channel blocker

Case 3 — Resistant hypertension and risk of hypokalaemia

Frequently asked questions about Antihypertensive Combinations

1) When is combination therapy indicated?

2) What are the first-line combinations?

3) When should triple combinations be considered?

4) Which combinations should be avoided?

5) What are the advantages of fixed-dose formulations?

6) When should potassium-sparing agents be added?

7) What is the best combination in older adults?

8) What about patients with diabetes or CKD?

9) Are there efficacy differences between ACE inhibitors and ARBs in combinations?

10) When should resistant hypertension be suspected?

11) How should safety be monitored in combinations?

12) What additional benefits does combination therapy provide?

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Antihypertensive drugs: pharmacological combinations and clinical indications

General principles

Types of combination

Combinations with ACE inhibitors

Combinations with angiotensin II receptor blockers, ARBs

Combinations with beta-blockers and diuretics

Less common combinations

Selection criteria

Clinical cases — Antihypertensive combinations

Case 1 — Uncontrolled hypertension on monotherapy

Case 2 — Ankle oedema induced by a calcium-channel blocker

Case 3 — Resistant hypertension and risk of hypokalaemia

Frequently asked questions about Antihypertensive Combinations

1) When is combination therapy indicated?

2) What are the first-line combinations?

3) When should triple combinations be considered?

4) Which combinations should be avoided?

5) What are the advantages of fixed-dose formulations?

6) When should potassium-sparing agents be added?

7) What is the best combination in older adults?

8) What about patients with diabetes or CKD?

9) Are there efficacy differences between ACE inhibitors and ARBs in combinations?

10) When should resistant hypertension be suspected?

11) How should safety be monitored in combinations?

12) What additional benefits does combination therapy provide?

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