What are the first-line and second-line pharmacologic treatment recommendations for hypertension in adults?

Pharmacologic Treatment of Hypertension in Adults: First-Line and Second-Line Recommendations

For adults with hypertension requiring pharmacologic treatment, initiate therapy with one of four first-line drug classes: thiazide or thiazide-like diuretics, ACE inhibitors, ARBs, or long-acting dihydropyridine calcium channel blockers. 1

First-Line Pharmacologic Agents

The WHO provides a strong recommendation (high-quality evidence) for using any of these four drug classes as initial treatment 1:

• Thiazide and thiazide-like diuretics (e.g., chlorthalidone, hydrochlorothiazide)
• ACE inhibitors (e.g., lisinopril, enalapril) 2
• Angiotensin receptor blockers (ARBs) (e.g., losartan, candesartan) 3
• Long-acting dihydropyridine calcium channel blockers (e.g., amlodipine)

Evidence Supporting First-Line Choices

Low-dose thiazides demonstrate the strongest evidence base, reducing mortality, stroke, coronary heart disease, and cardiovascular events 4. The 2017 ACC/AHA guidelines note that diuretics, particularly chlorthalidone, may provide optimal first-step therapy based on meta-analyses and large RCTs 1. ACE inhibitors show similar robust benefits, reducing mortality, stroke, CHD, and cardiovascular events 4.

Beta-blockers are NOT recommended as first-line agents because they are significantly less effective than diuretics for stroke prevention and cardiovascular events 1.

Treatment Initiation Strategy

Stage 1 Hypertension (BP 130-139/80-89 mmHg)

• Start with single-agent monotherapy in patients with BP goal <130/80 mmHg 1
• Titrate dosage and sequentially add agents as needed to reach target 1

Stage 2 Hypertension (BP ≥140/90 mmHg or >20/10 mmHg above goal)

• Initiate with two-drug combination therapy from different first-line classes 1
• Preferably use single-pill combination products to improve adherence and persistence 1
• Combination should include drugs from: diuretics (thiazide/thiazide-like), ACE inhibitors or ARBs, and long-acting dihydropyridine calcium channel blockers 1

Second-Line Approach: Adding Additional Agents

When blood pressure remains uncontrolled on initial therapy, the second-line approach involves:

Sequential Addition Strategy

• Add a second agent from a different first-line class if monotherapy is insufficient 1, 5
• Ensure complementary mechanisms of action 6
• Optimize doses of existing medications before adding additional agents 6

Three-Drug Combination

• Most patients require multiple agents for adequate BP control 1, 3, 2, 5
• Typical effective combination: diuretic + ACE inhibitor or ARB + calcium channel blocker 1

Resistant Hypertension (Uncontrolled on 3+ Agents)

• Add mineralocorticoid receptor antagonist (spironolactone) as fourth-line agent 6
• Effective even without biochemical evidence of aldosterone excess 6
• Ensure appropriate diuretic is included in the regimen 6

Special Population Considerations

Black Adults Without Heart Failure or CKD

• Initial treatment should include thiazide diuretic or calcium channel blocker 1
• ARBs show less benefit for stroke reduction in Black patients with left ventricular hypertrophy 3

Patients with Diabetes, CKD, or Proteinuria

• Prefer ACE inhibitor or ARB as initial agent 7
• ACE inhibitors have specific benefits in diabetes, atherosclerosis, left ventricular dysfunction, and renal insufficiency 8
• ARBs reduce progression of diabetic nephropathy in type 2 diabetes with proteinuria 3

Older Adults (≥65 Years)

• Exercise caution when initiating two-drug therapy due to hypotension risk 1
• Monitor BP carefully for orthostatic hypotension 1

Blood Pressure Targets

• <140/90 mmHg for all patients without comorbidities 1
• <130/80 mmHg for adults <65 years 9
• Systolic <130 mmHg for patients with known CVD (strong recommendation) 1, 9
• Systolic <130 mmHg for high-risk patients with diabetes, CKD, or high CVD risk (conditional recommendation) 1, 9

Critical Pitfalls to Avoid

Do not lower diastolic BP below 60 mmHg in high-risk patients with treated systolic BP <130 mmHg, as this may increase cardiovascular events 9. Optimal diastolic BP is 70-80 mmHg in this population 9.

Avoid high-dose thiazides as they do not reduce CHD events compared to low-dose thiazides 4.

ACE inhibitors and ARBs are absolutely contraindicated in pregnancy due to fetal injury and death risk 7.

Monitoring Schedule

• Monthly follow-up after initiating or changing medications until target BP achieved 1, 9
• Every 3-5 months for patients at goal 1, 9
• Monitor renal function and potassium within first 3 months for patients on ACE inhibitors, ARBs, or diuretics 9