What are the first-line treatment options for managing hypertension with antihypertensive drugs, such as Angiotensin-Converting Enzyme (ACE) inhibitors?

First-Line Antihypertensive Treatment

For most adults with hypertension, initiate treatment with thiazide or thiazide-like diuretics (chlorthalidone or hydrochlorothiazide), ACE inhibitors, ARBs, or dihydropyridine calcium channel blockers, with the choice guided by blood pressure severity, comorbidities, and patient-specific factors. 1

Treatment Initiation Based on Blood Pressure Severity

Stage 1 Hypertension (140-159/90-99 mmHg)

• Begin with single-agent therapy in patients with blood pressure 140-159/90-99 mmHg 1
• Lifestyle modifications should be initiated simultaneously, including weight loss when indicated, DASH diet, sodium restriction (<2,300 mg/day), increased potassium intake, physical activity, and limited alcohol consumption 1, 2

Stage 2 Hypertension (≥160/100 mmHg)

• Initiate treatment with two antihypertensive medications or a single-pill combination for patients with blood pressure ≥160/100 mmHg 1
• This approach achieves blood pressure control more rapidly and effectively than sequential monotherapy 1
• The 2024 ESC guidelines recommend upfront low-dose combination therapy for most patients with confirmed hypertension, preferably as single-pill combinations 1

First-Line Medication Classes

Thiazide and Thiazide-Like Diuretics (Preferred for General Population)

• Thiazide-like diuretics, particularly chlorthalidone, represent the optimal first-line choice based on the highest-quality evidence for cardiovascular outcomes 1, 3, 4
• Chlorthalidone has demonstrated superiority over ACE inhibitors (lisinopril) for stroke prevention and over calcium channel blockers (amlodipine) for heart failure prevention in large randomized trials involving over 50,000 patients 4
• Hydrochlorothiazide is an acceptable alternative when chlorthalidone is unavailable 4
• Diuretics were significantly more effective than beta-blockers for stroke and cardiovascular event prevention in network meta-analyses 1

ACE Inhibitors and ARBs

• ACE inhibitors or ARBs are the preferred first-line agents for specific high-risk populations 1, 2:
  • Patients with diabetes and albuminuria (UACR ≥30 mg/g) 1, 2
  • Patients with established coronary artery disease 1, 2
  • Patients with chronic kidney disease and proteinuria 1, 2
• ACE inhibitors and ARBs have demonstrated reduction in all-cause mortality compared to placebo, preventing approximately 2-3 deaths per 100 patients treated for 4-5 years 4
• Critical contraindication: ACE inhibitors and ARBs are absolutely contraindicated in pregnancy and should be avoided in women of childbearing potential without reliable contraception 5

Calcium Channel Blockers

• Dihydropyridine calcium channel blockers (amlodipine, nifedipine) are recommended as first-line therapy 1, 3
• Calcium channel blockers are the preferred first-line choice for women of childbearing potential due to proven safety in pregnancy 5
• Amlodipine demonstrated significant reduction in cardiovascular events, hospitalizations for angina, and need for revascularization in patients with documented coronary artery disease 6

Special Population Considerations

Black Patients

• Initial treatment should include a thiazide diuretic or calcium channel blocker for Black adults without heart failure or chronic kidney disease 1
• ACE inhibitors and ARBs are less effective as monotherapy in Black patients (typically a low-renin population) 7, 8

Diabetic Patients

• For blood pressure 140-159/90-99 mmHg: begin with single-agent therapy 1
• For blood pressure ≥160/100 mmHg: initiate two medications or single-pill combination 1
• ACE inhibitors or ARBs at maximum tolerated dose are first-line for diabetic patients with albuminuria (UACR ≥30 mg/g) 1, 2
• For diabetic women of childbearing potential, calcium channel blockers are preferred first-line 5

Patients with Coronary Artery Disease

• ACE inhibitors or ARBs are recommended as first-line therapy for patients with diabetes and established coronary artery disease 1, 2

Combination Therapy Strategy

Recommended Combinations

• The 2024 ESC guidelines recommend starting with a single-pill combination containing two drug classes at low doses from: ACE inhibitor/ARB + calcium channel blocker, ACE inhibitor/ARB + thiazide diuretic, or calcium channel blocker + thiazide diuretic 1
• If blood pressure remains uncontrolled, escalate to triple therapy with RAS blocker + calcium channel blocker + thiazide diuretic 1

Contraindicated Combinations

• Never combine ACE inhibitors with ARBs - this increases adverse events (hyperkalemia, syncope, acute kidney injury) without additional cardiovascular benefit 1, 2
• Never combine ACE inhibitors or ARBs with direct renin inhibitors for the same reasons 1

Monitoring Requirements

• Monitor serum creatinine/eGFR and potassium levels at least annually for patients on ACE inhibitors, ARBs, or diuretics 1, 2
• More frequent monitoring (7-14 days after initiation or dose changes) is recommended 2
• Reassess blood pressure every 2-4 weeks until target achieved, then every 3 months 5

Resistant Hypertension (Fourth-Line Therapy)

• For patients not meeting blood pressure targets on three medications (including a diuretic), add a mineralocorticoid receptor antagonist (spironolactone) 1, 2
• If spironolactone is not tolerated, consider eplerenone (dosed 50-200 mg, potentially twice daily) or vasodilating beta-blockers (labetalol, carvedilol, nebivolol) 1
• Refer to a specialist with expertise in hypertension management 1, 2

Common Pitfalls to Avoid

• Do not use beta-blockers as first-line therapy for uncomplicated hypertension - they are less effective than diuretics for stroke prevention and should be reserved for patients with specific indications (prior MI, active angina, heart failure) 1, 2
• Do not delay pharmacologic therapy in patients with significantly elevated blood pressure - prompt initiation and timely titration are essential 1, 2
• Do not prescribe ACE inhibitors or ARBs to women of childbearing potential without reliable contraception - these agents cause fetal damage and are absolutely contraindicated in pregnancy 5
• Do not assume medication adherence in patients with uncontrolled hypertension - assess adherence before diagnosing resistant hypertension 1