What are common combination antihypertensives for managing hypertension?

Common Combination Antihypertensives for Managing Hypertension

For most hypertensive patients, a two-drug combination of a RAS blocker (ACE inhibitor or ARB) with either a dihydropyridine calcium channel blocker or thiazide/thiazide-like diuretic is recommended as initial therapy, preferably as a single-pill combination. 1

First-Line Combination Therapies

• The most effective and well-tolerated two-drug combinations for hypertension management include:

  • Thiazide diuretic and ACE inhibitor 2
  • Thiazide diuretic and angiotensin receptor antagonist (ARB) 2
  • Calcium antagonist and ACE inhibitor 2
  • Calcium antagonist and ARB 2
  • Calcium antagonist and thiazide diuretic 2
  • β-blocker and dihydropyridine calcium antagonist 2

• Fixed-dose single-pill combinations significantly improve adherence by reducing pill burden and simplifying treatment regimens 2, 1

• Combination therapy is more effective than monotherapy because:

  • It targets multiple pathophysiological pathways contributing to hypertension 2
  • Lower doses of individual components can be used, potentially reducing side effects 2
  • Blood pressure targets can be reached more quickly 2, 1
  • It avoids the frustration of repeatedly searching for effective monotherapies 2

Treatment Algorithm

1. Initial therapy for 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 2, 1
   • Use low doses initially, preferably as a single-pill combination 2, 1

2. If BP remains uncontrolled:

   • Increase to a three-drug combination: RAS blocker + dihydropyridine CCB + thiazide/thiazide-like diuretic 2, 1
   • Preferably as a single-pill combination when available 1

3. For resistant hypertension (uncontrolled on triple therapy):

   • Add spironolactone as fourth-line therapy 2, 1
   • If spironolactone is not tolerated, consider eplerenone or beta-blockers 2
   • Only thereafter consider hydralazine, other potassium-sparing diuretics, centrally acting medications, or alpha-blockers 2

Specific Combination Examples

• ARB + Thiazide diuretic: Combinations such as losartan/hydrochlorothiazide provide complementary mechanisms of action 3, 4

  • Addition of low-dose hydrochlorothiazide (12.5 mg) to losartan 50 mg results in placebo-adjusted BP reductions of 15.5/9.2 mmHg 3
  • ARBs attenuate the hydrochlorothiazide-associated decrease in serum potassium 5

• ACE inhibitor + Thiazide diuretic: Both drug classes have been shown to reduce all-cause mortality in hypertensive patients when compared to placebo 6

• Thiazide diuretic + Potassium-sparing diuretic: This combination has been widely used to prevent potassium loss associated with thiazide administration 2

  • May reduce the incidence of sudden death and decrease diabetes risk associated with thiazide-induced hypokalemia 2

Important Considerations

• The combination of a thiazide diuretic and a beta-blocker should be avoided in patients with metabolic syndrome or high risk of diabetes due to potential dysmetabolic effects 2

• Chlorthalidone (25 mg) appears more potent than hydrochlorothiazide (50 mg), particularly for overnight blood pressure reduction 7

• Certain patient populations (blacks, elderly, diabetics, those with metabolic syndrome) may be more responsive to thiazide-type diuretic therapy 7

• The combination of two RAS blockers (ACE inhibitor + ARB) is not recommended due to increased adverse effects without additional benefit 2

• Fixed-dose combinations allow for easier dose adjustments and improved compliance compared to separate pill regimens 2

Special Populations

• For patients with stable angina and hypertension, consider a regimen including a beta-blocker with either an ACE inhibitor/ARB, CCB, or thiazide diuretic 1

• For patients with heart failure with reduced ejection fraction, treatment should include an ACE inhibitor/ARB, beta-blocker, diuretic, and/or mineralocorticoid receptor antagonist 1

• RAS blockers are particularly beneficial for hypertensive patients with microalbuminuria or proteinuria 1