What are the best treatment combinations for hypertension?

Best Hypertension Treatment Combinations

For most patients with confirmed hypertension (BP ≥140/90 mmHg), combination therapy with a RAS blocker (ACE inhibitor or ARB) plus either a dihydropyridine calcium channel blocker (CCB) or thiazide/thiazide-like diuretic is recommended as initial therapy, preferably as a single-pill combination. 1

First-Line Combination Therapy

• Combination therapy is more effective than monotherapy for blood pressure control in most hypertensive patients 1
• The preferred initial combinations are:
  • ACE inhibitor + dihydropyridine CCB 1
  • ACE inhibitor + thiazide/thiazide-like diuretic 1
  • ARB + dihydropyridine CCB 1
  • ARB + thiazide/thiazide-like diuretic 1
• Fixed-dose single-pill combinations are strongly recommended to improve adherence 1

Treatment Algorithm

Step 1: Initial Therapy

• For most patients with confirmed hypertension (BP ≥140/90 mmHg): Start with a two-drug combination of a RAS blocker (ACE inhibitor or ARB) with either a dihydropyridine CCB or thiazide/thiazide-like diuretic 1
• Exceptions where monotherapy may be considered:
  • Patients aged ≥85 years 1
  • Patients with symptomatic orthostatic hypotension 1
  • Patients with moderate-to-severe frailty 1
  • Patients with elevated BP (systolic BP 120-139 mmHg) who have other indications for treatment 1

Step 2: Inadequate BP Control

• If BP remains uncontrolled on a two-drug combination, increase to a three-drug combination: RAS blocker + dihydropyridine CCB + thiazide/thiazide-like diuretic, preferably as a single-pill combination 1

Step 3: Resistant Hypertension

• If BP remains uncontrolled on maximally tolerated triple therapy (after confirming adherence), add spironolactone 1
• If spironolactone is not tolerated, consider:
  • Eplerenone or other mineralocorticoid receptor antagonist 1
  • Beta-blocker (if not already indicated) 1
  • Alpha-blocker (such as doxazosin) 1
  • Other potassium-sparing diuretic 1

Important Combinations to Avoid

• Combining two RAS blockers (ACE inhibitor and ARB) is not recommended due to increased risk of adverse effects without additional benefit 1
• The combination of a thiazide diuretic and a beta-blocker may have adverse metabolic effects and should be avoided in patients with metabolic syndrome or high risk of diabetes 1

Special Populations

Coronary Artery Disease

• For patients with stable angina and hypertension, a regimen including a beta-blocker with either an ACE inhibitor/ARB, CCB, or thiazide diuretic is recommended 1
• If angina persists, a long-acting dihydropyridine CCB can be added to the basic regimen 1

Heart Failure

• For patients with heart failure with reduced ejection fraction (HFrEF), treatment should include an ACE inhibitor/ARB, beta-blocker, diuretic, and/or mineralocorticoid receptor antagonist 1
• For patients with HFrEF/HFmrEF, treatments with BP-lowering effects should include ACE inhibitors/ARBs or ARNI, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors 1

Chronic Kidney Disease

• RAS blockers are more effective at reducing albuminuria and are recommended as part of the treatment strategy in hypertensive patients with microalbuminuria or proteinuria 1
• In patients with moderate-to-severe CKD (eGFR >30 mL/min/1.73 m²), target systolic BP should be 120-129 mmHg 1

Different Ethnic Groups

• In Black patients, initial antihypertensive treatment should include a diuretic or a CCB, either alone or in combination with a RAS blocker 1
• In Black patients from Sub-Saharan Africa, combination therapy including a CCB with either a thiazide diuretic or a RAS blocker is recommended 1

Benefits of Single-Pill Combinations

• Improve adherence by reducing pill burden 1
• Allow for lower doses of individual components, potentially reducing side effects 1
• Provide more rapid blood pressure control 1
• Associated with better cardiovascular outcomes in observational studies 1

Target Blood Pressure

• For most adults, target systolic BP should be 120-129 mmHg, provided treatment is well tolerated 1
• If BP-lowering treatment is poorly tolerated, target a systolic BP level that is "as low as reasonably achievable" (ALARA principle) 1

Emerging Combination Therapies

• SGLT2 inhibitors have shown modest BP-lowering effects and favorable cardiovascular outcomes 1
• Novel agents being investigated include GLP-1 agonists, non-steroidal mineralocorticoid receptor antagonists (e.g., finerenone), and aldosterone synthase inhibitors 1