What are the first-line and second-line treatment options for managing hypertension, including the selection of anti-hypertensive medications such as Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin II Receptor Blockers (ARBs), Calcium Channel Blockers (CCBs), and diuretics?

First-Line and Second-Line Antihypertensive Medications

For most patients with hypertension, first-line treatment should include a thiazide-like diuretic, ACE inhibitor, ARB, or calcium channel blocker (CCB), with specific selection based on patient characteristics and comorbidities. 1, 2

First-Line Antihypertensive Selection

General Population

• Thiazide-like diuretics (especially chlorthalidone) are often preferred as initial therapy due to their proven efficacy in reducing cardiovascular events 1, 3
• ACE inhibitors, ARBs, and CCBs are equally effective first-line options for most patients 4
• For stage 2 hypertension (BP ≥140/90 mmHg) or when BP is >20/10 mmHg above target, initiation with two first-line agents of different classes is recommended 4, 2

Special Populations

• For Black patients: Initial therapy should include a thiazide diuretic or CCB, as these are more effective than ACE inhibitors or ARBs in this population 4, 1, 2
• For patients with diabetes: All first-line classes (diuretics, ACE inhibitors, ARBs, and CCBs) are effective, but ACE inhibitors or ARBs are preferred, especially with albuminuria 4, 1
• For patients with chronic kidney disease and albuminuria: ACE inhibitors or ARBs are recommended as first-line therapy 1, 2
• For patients with coronary artery disease: ACE inhibitors or ARBs are suggested as first-line agents 1, 2

Combination Therapy Approach

• Preferred combinations include:

  • ACE inhibitor or ARB + CCB 1, 2, 5
  • ACE inhibitor or ARB + thiazide diuretic 1, 2, 6
  • CCB + thiazide diuretic 2

• Combinations to avoid:

  • ACE inhibitor + ARB (increases risk of hyperkalemia without additional benefit) 1, 2

• For patients not achieving BP control with a two-drug combination, add a third agent from a different class, preferably as a single-pill combination to improve adherence 2, 6

Second-Line Options

• If initial therapy fails to achieve target BP, add a second agent from a complementary class rather than maximizing the dose of a single agent 1, 2
• For patients not responding to ACE inhibitor/ARB + CCB, add a thiazide diuretic 2, 6
• For patients not responding to ACE inhibitor/ARB + thiazide diuretic, add a CCB 2, 6
• For patients not controlled on three classes of medications, consider adding a mineralocorticoid receptor antagonist like spironolactone 2

Specific Drug Considerations

ACE Inhibitors

• Effective in reducing all-cause mortality in hypertensive patients 3
• May cause dry cough in approximately 5-20% of patients 7
• Contraindicated in pregnancy 1

ARBs

• Similar benefits to ACE inhibitors with fewer side effects (particularly cough) 1, 8
• Effective for patients with left ventricular hypertrophy 8
• Losartan has been shown to reduce stroke risk by 25% compared to atenolol 8

Calcium Channel Blockers

• Particularly effective in older patients and Black patients 1, 9
• Dihydropyridine CCBs (like amlodipine) have minimal effects on heart rate 9
• In the CAMELOT study, amlodipine reduced cardiovascular events by 31% compared to placebo 9

Thiazide Diuretics

• Proven to reduce cardiovascular events and mortality 3
• May cause metabolic side effects (hyperglycemia, hyperuricemia) but this doesn't reduce their efficacy in preventing cardiovascular events 3
• Chlorthalidone has stronger evidence for cardiovascular risk reduction than hydrochlorothiazide 3

Common Pitfalls to Avoid

• Underdosing medications before adding additional agents 1
• Failing to consider ethnicity in medication selection (ACE inhibitors and ARBs are less effective in Black patients) 1, 2
• Using ACE inhibitor + ARB combinations (increases adverse effects without additional benefit) 1, 2
• Overlooking the need for more aggressive initial therapy in patients with markedly elevated blood pressure 1, 2
• Not monitoring serum creatinine, eGFR, and potassium when using ACE inhibitors, ARBs, or diuretics 1, 2

Monitoring and Follow-up

• Monitor BP monthly after initiation or change in medication until target is reached 2
• For patients on ACE inhibitors, ARBs, or diuretics, monitor serum creatinine/eGFR and potassium within 7-14 days of initiation and at least annually thereafter 1, 2
• Follow up every 3-5 months for patients with controlled BP 2