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

First-Line Antihypertensive Drug Treatment

For most adults with hypertension, thiazide or thiazide-like diuretics (particularly chlorthalidone) should be the first-line pharmacological treatment, as they have the strongest evidence for reducing mortality, stroke, coronary heart disease, and cardiovascular events. 1, 2, 3

Blood Pressure Thresholds for Initiating Treatment

• For blood pressure 140/90-159/99 mmHg: Begin with a single antihypertensive agent alongside lifestyle modifications 1, 2
• For blood pressure ≥160/100 mmHg: Initiate treatment with two antihypertensive medications simultaneously or a single-pill combination to achieve more rapid blood pressure control 1, 2
• For blood pressure >130/80 mmHg: All patients should begin lifestyle modifications including DASH diet, sodium restriction (<2,300 mg/day), weight loss when indicated, increased physical activity, and limited alcohol consumption 1, 2

First-Line Drug Classes: General Population

Thiazide and Thiazide-Like Diuretics (Preferred)

Thiazide-type diuretics are the preferred first-line agents for most patients with uncomplicated hypertension because they reduce all-cause mortality (RR 0.89), stroke (RR 0.63), coronary heart disease (RR 0.84), and cardiovascular events (RR 0.70) 4. The 2017 ACC/AHA guidelines specifically note that chlorthalidone may provide optimal first-step therapy based on the largest comparative trials 1.

• Low-dose thiazides (chlorthalidone 12.5-25 mg daily or hydrochlorothiazide with amiloride/triamterene) are more effective than high-dose thiazides for reducing coronary heart disease 4
• Long-acting agents like chlorthalidone and indapamide are preferred over hydrochlorothiazide for cardiovascular event reduction 1
• The ALLHAT trial demonstrated thiazide diuretics were superior to calcium channel blockers for preventing heart failure and superior to ACE inhibitors for preventing stroke and heart failure 5

Alternative First-Line Options

When thiazide diuretics cannot be used, the following are acceptable alternatives 1, 2:

• ACE inhibitors (e.g., lisinopril 10-40 mg daily, enalapril): Reduce mortality (RR 0.83), stroke (RR 0.65), CHD (RR 0.81), and cardiovascular events (RR 0.76) 4
• Angiotensin receptor blockers (ARBs) (e.g., losartan 50-100 mg daily, candesartan): Similar efficacy to ACE inhibitors 1, 3
• Dihydropyridine calcium channel blockers (e.g., amlodipine 2.5-10 mg daily): Reduce stroke (RR 0.58) and cardiovascular events (RR 0.71) 4, 6

Beta-blockers are NOT recommended as first-line therapy for uncomplicated hypertension because they are less effective than thiazides for stroke prevention and overall cardiovascular outcomes 1, 4. They should be reserved for patients with specific indications such as prior myocardial infarction, active angina, or heart failure 2.

First-Line Drug Selection Based on Comorbidities

Diabetes with Albuminuria

• For UACR ≥300 mg/g: ACE inhibitors or ARBs at maximum tolerated doses are strongly recommended as first-line therapy to reduce progressive kidney disease 1, 2
• For UACR 30-299 mg/g: ACE inhibitors or ARBs are recommended as initial treatment 1, 2
• For diabetic patients without albuminuria, thiazide-like diuretics, ACE inhibitors, ARBs, or dihydropyridine calcium channel blockers are all appropriate first-line options 1

Coronary Artery Disease

• ACE inhibitors or ARBs are recommended as first-line therapy for patients with established coronary artery disease 1, 2
• The CAMELOT trial demonstrated amlodipine reduced hospitalizations for angina and revascularization procedures by 31% in patients with documented CAD 6

Chronic Kidney Disease

• ACE inhibitors or ARBs are first-line agents for patients with CKD and albuminuria to slow progression of kidney disease 1, 2

Heart Failure

• ACE inhibitors are preferred first-line agents for patients with heart failure, as they reduce mortality and hospitalizations 7, 8
• Thiazide diuretics are also beneficial for volume management 1

Combination Therapy Approach

When to Use Combination Therapy

The 2024 ESC guidelines recommend upfront low-dose combination therapy for most patients with confirmed hypertension (blood pressure ≥140/90 mmHg), preferably as single-pill combinations to improve adherence 1. This represents a shift from traditional stepped-care approaches.

• Single-pill combinations are preferred over separate pills because they improve adherence and persistence 1
• Initial combinations should include two drugs from: ACE inhibitor/ARB + calcium channel blocker, ACE inhibitor/ARB + thiazide diuretic, or calcium channel blocker + thiazide diuretic 1, 2

Prohibited Combinations

Never combine ACE inhibitors with ARBs or combine either with direct renin inhibitors, as this increases risk of hyperkalemia, syncope, and acute kidney injury without additional cardiovascular benefit 1, 2

Monitoring Requirements

• For patients on ACE inhibitors, ARBs, or diuretics: Monitor serum creatinine/eGFR and potassium levels at least annually 1, 2
• After initiation or dose changes: Recheck electrolytes and renal function within 7-14 days 2
• Blood pressure targets: <130/80 mmHg for adults <65 years; SBP <130 mmHg for adults ≥65 years 3

Resistant Hypertension (Fourth-Line Therapy)

• For blood pressure ≥140/90 mmHg despite three medications (including a diuretic at adequate doses), add a mineralocorticoid receptor antagonist such as spironolactone 1, 2
• Before diagnosing resistant hypertension, exclude medication nonadherence, white coat hypertension, and secondary causes 1
• If spironolactone is not tolerated, consider eplerenone (50-200 mg, possibly twice daily) or vasodilating beta-blockers (labetalol, carvedilol, nebivolol) 1

Special Population Considerations

Black Patients

• Initial therapy should include a thiazide diuretic or calcium channel blocker rather than ACE inhibitors or ARBs alone, as these are less effective in Black populations (typically low-renin hypertension) 1, 7, 9

Pediatric Patients (Ages 6-16)

• Lisinopril and losartan have demonstrated efficacy in pediatric hypertension at weight-based dosing 7, 9
• Doses >1.25 mg lisinopril (or 0.02 mg/kg) show antihypertensive efficacy 7

Pregnancy

• ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, direct renin inhibitors, and neprilysin inhibitors are absolutely contraindicated in pregnancy and should be avoided in women of childbearing potential not using reliable contraception 2

Common Pitfalls to Avoid

• Using beta-blockers as first-line therapy in uncomplicated hypertension—they are inferior to thiazides for cardiovascular outcomes 1, 2, 4
• Combining ACE inhibitors with ARBs—this increases adverse events without benefit 1, 2
• Using high-dose thiazides—low-dose thiazides are more effective for CHD prevention 4
• Inadequate monitoring of electrolytes and renal function in patients on ACE inhibitors, ARBs, or diuretics 1, 2
• Delaying pharmacological therapy in patients with significantly elevated blood pressure (≥160/100 mmHg)—prompt dual therapy is indicated 1, 2
• Failing to assess medication adherence before escalating therapy or diagnosing resistant hypertension 1