Is it reasonable to start hypertension treatment with a combination of an Angiotensin-Converting Enzyme (ACE) inhibitor and a thiazide diuretic?

Starting Treatment with an ACE Inhibitor and Thiazide Diuretic Combination for Hypertension

Starting treatment with a combination of an ACE inhibitor and a thiazide diuretic is an effective and recommended approach for hypertension management, especially in patients with stage 2 hypertension or those at higher cardiovascular risk. 1

When to Consider Combination Therapy

• Initial monotherapy vs. combination therapy:

  • For mild hypertension (stage 1) with low/moderate cardiovascular risk: Start with monotherapy
  • For stage 2 hypertension (≥160/100 mmHg): Start with combination therapy 1
  • For patients at high/very high cardiovascular risk: Start with combination therapy 1

• Benefits of starting with combination therapy:

  1. Achieves blood pressure targets more rapidly 1
  2. Higher probability of controlling BP with fewer medication adjustments
  3. Allows use of lower doses of each agent, potentially reducing side effects
  4. Blocks different complementary mechanisms of hypertension 1

Evidence Supporting ACE Inhibitor + Thiazide Combination

The ACE inhibitor and thiazide diuretic combination is specifically listed as an effective and well-tolerated two-drug combination by the European Society of Hypertension/European Society of Cardiology guidelines 1. This combination offers several advantages:

• Complementary mechanisms of action: ACE inhibitors block the renin-angiotensin system while thiazides promote sodium excretion 2
• Counterbalancing effects on potassium: ACE inhibitors tend to increase serum potassium while thiazides tend to decrease it 3, 4
• Metabolic effects: ACE inhibitors may help offset some of the adverse metabolic effects of thiazides 2
• Outcome benefits: The ADVANCE trial demonstrated that routine administration of a fixed combination of an ACE inhibitor (perindopril) and a thiazide-type diuretic (indapamide) significantly reduced combined microvascular and macrovascular outcomes, as well as cardiovascular mortality 1

Practical Considerations

• Dosing strategy: Start with low doses of both medications, which can be given as a fixed-dose combination tablet to improve adherence 1

• Monitoring:

  • Blood pressure response
  • Serum potassium (the combination tends to balance potassium effects) 3, 4
  • Renal function, particularly in high-risk patients 3

• Specific agent selection:

  • ACE inhibitors: lisinopril, perindopril, or benazepril have evidence supporting their use in combination therapy 1, 2
  • Thiazide diuretics: chlorthalidone has stronger outcome evidence than hydrochlorothiazide, particularly in advanced CKD 1, 5

Special Populations

• Diabetes: The combination of an ACE inhibitor and thiazide diuretic has shown benefits in reducing cardiovascular events and mortality in patients with diabetes 1
• Chronic kidney disease: Chlorthalidone may be effective even in advanced CKD (eGFR <30 mL/min/1.73m²) 1
• Elderly patients: Start with lower doses and titrate more gradually, but the combination remains effective 1

Cautions and Contraindications

• Avoid in pregnancy due to risks associated with ACE inhibitors 6
• Monitor for hypotension, especially in volume-depleted patients 3
• Do not combine an ACE inhibitor with an ARB due to increased risk of hyperkalemia and acute kidney injury 1
• Use caution in patients at high risk for developing diabetes, though the addition of an ACE inhibitor may mitigate some of the diabetogenic effects of thiazides 7

In conclusion, the combination of an ACE inhibitor and a thiazide diuretic represents a rational, evidence-based approach to hypertension management, particularly for patients with stage 2 hypertension or those at higher cardiovascular risk who need more prompt blood pressure control.