What is the first line of medication for an adult patient with primary hypertension and no significant comorbidities?

First-Line Medication for Hypertension

For adults with primary hypertension and no significant comorbidities, initiate treatment with a thiazide or thiazide-like diuretic, ACE inhibitor, ARB, or long-acting dihydropyridine calcium channel blocker, with thiazide diuretics (particularly chlorthalidone) being the preferred choice based on superior evidence for preventing cardiovascular events, stroke, and heart failure. 1

Primary Drug Class Selection

The most recent WHO guidelines (2022) provide a strong recommendation with high-quality evidence that any of four drug classes can be used as first-line therapy: 1

• Thiazide and thiazide-like diuretics (chlorthalidone, hydrochlorothiazide, indapamide)
• ACE inhibitors (lisinopril, enalapril, ramipril)
• Angiotensin receptor blockers (ARBs) (losartan, valsartan, candesartan)
• Long-acting dihydropyridine calcium channel blockers (amlodipine, nifedipine)

The 2017 ACC/AHA guidelines similarly recommend these four classes as first-line agents, emphasizing that thiazide diuretics (especially chlorthalidone) and calcium channel blockers are preferred options due to their proven efficacy in reducing cardiovascular outcomes. 1

Why Thiazide Diuretics Are Preferred

Thiazide diuretics, particularly chlorthalidone, demonstrate superior outcomes in head-to-head trials: 2, 3

• More effective than ACE inhibitors in preventing stroke (ARR 0.6%) 3
• Superior to calcium channel blockers in preventing heart failure (ARR 1.2%) 3
• Reduce total cardiovascular events compared to beta-blockers (ARR 0.6%) and alpha-blockers (ARR 3.1%) 3
• Fewer withdrawals due to adverse effects compared to beta-blockers (ARR 2.2%) and ACE inhibitors (ARR 1.0%) 3

Chlorthalidone is specifically preferred over hydrochlorothiazide due to its prolonged half-life and proven reduction in cardiovascular disease in clinical trials. 1

Treatment Initiation Strategy

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

• Start with single-agent monotherapy at standard dosing 1, 4
• Titrate upward as needed to reach target blood pressure 1, 4
• Add a second agent from a different class if target not achieved after adequate trial 1, 4

For Stage 2 Hypertension (≥140/90 mmHg):

• Initiate with two-drug combination therapy from different first-line classes 1, 4
• Preferably use single-pill combination products to improve adherence 1
• Recommended combinations: thiazide + ACE inhibitor/ARB, thiazide + calcium channel blocker, or ACE inhibitor/ARB + calcium channel blocker 1
• Patients with BP ≥160/100 mmHg should be treated promptly with careful monitoring and rapid dose adjustment 1

Blood Pressure Targets

Target BP <140/90 mmHg for all patients without comorbidities (strong recommendation, moderate-quality evidence). 1

For patients with cardiovascular disease or high cardiovascular risk (≥10% 10-year ASCVD risk), target BP <130/80 mmHg. 1

What NOT to Use as First-Line

Beta-blockers are NOT recommended as first-line therapy unless the patient has specific cardiovascular comorbidities such as ischemic heart disease or heart failure, as they are significantly less effective for cardiovascular prevention and stroke protection compared to diuretics and calcium channel blockers. 1, 2

Never combine ACE inhibitors with ARBs (or with direct renin inhibitors), as this is potentially harmful and increases risks of hyperkalemia and acute kidney injury without additional benefit. 1

Monitoring Schedule

• Monthly follow-up after initiating or changing medications until target BP is achieved 1, 4
• Every 3-5 months once blood pressure is controlled 1, 4
• Monitor renal function and electrolytes 2-4 weeks after starting ACE inhibitors, ARBs, or diuretics 1, 4

Common Pitfalls to Avoid

Avoid using inadequate doses of thiazide diuretics. Many triple-combination products contain lower-than-optimal doses of thiazide diuretics, reducing their effectiveness. 1

Do not delay treatment for extensive testing. Laboratory screening for comorbidities should only be obtained when it does not delay or impede starting treatment. 1

Beware of diastolic BP <60 mmHg. Recent evidence suggests that lowering diastolic BP below 60 mmHg may be associated with increased cardiovascular risk in patients with treated SBP <130 mmHg, with optimal diastolic BP appearing to be 70-80 mmHg. 1