What is the first-line treatment for a general adult population with primary hypertension and no compelling indications for specific antihypertensive agents?

First-Line Antihypertensive Treatment

For adults with primary hypertension and no compelling indications, initiate treatment with a thiazide or thiazide-like diuretic (preferably chlorthalidone 12.5-25 mg daily), calcium channel blocker (CCB), ACE inhibitor, or angiotensin receptor blocker (ARB), with thiazide diuretics having the strongest evidence for reducing cardiovascular mortality and morbidity. 1, 2, 3

Treatment Thresholds

• Initiate pharmacotherapy at BP ≥140/90 mmHg for all adults with primary hypertension 1
• Consider initiating treatment at BP 130-139/80-89 mmHg if the patient has established cardiovascular disease or 10-year ASCVD risk ≥10% 1, 2

Preferred First-Line Agents by Evidence Strength

Thiazide Diuretics (Strongest Evidence)

• Chlorthalidone 12.5-25 mg once daily is the optimal first choice based on the ALLHAT trial demonstrating superiority over ACE inhibitors for stroke prevention and over calcium channel blockers for heart failure prevention in over 50,000 patients 2, 3, 4
• Thiazide diuretics are the only class (along with ACE inhibitors) proven to reduce all-cause mortality compared to placebo, preventing approximately 2-3 deaths per 100 patients treated over 4-5 years 4, 5
• If chlorthalidone is unavailable, use hydrochlorothiazide 25 mg daily, which has demonstrated cardiovascular benefit in multiple placebo-controlled trials 2, 4
• Thiazides reduce total cardiovascular events by 0.6-3.1% compared to beta-blockers, calcium channel blockers, ACE inhibitors, and alpha-blockers 5

Calcium Channel Blockers (Equally Effective Alternative)

• Long-acting dihydropyridines such as amlodipine 5-10 mg once daily are equally effective as thiazides for all cardiovascular events except heart failure, where thiazides are superior 2, 3, 5
• CCBs probably reduce total cardiovascular events similarly to thiazides (ARR 1.0%) and are particularly effective for isolated systolic hypertension in older adults 3, 5
• Choose a CCB over a thiazide if the patient cannot tolerate diuretics or has specific indications such as angina pectoris 2, 6

ACE Inhibitors (Reasonable Alternative)

• ACE inhibitors such as lisinopril 10-40 mg daily or ramipril are effective first-line options, particularly for patients with albuminuria or established coronary artery disease 2, 4
• ACE inhibitors reduce all-cause mortality compared to placebo (similar to thiazides) but were less effective than chlorthalidone in preventing stroke in head-to-head trials 4, 5
• Thiazides reduce stroke by 0.6% more than ACE inhibitors (RR 0.89) and cause 1.0% fewer withdrawals due to adverse effects 5

Angiotensin Receptor Blockers (Equally Effective to ACE Inhibitors)

• ARBs such as losartan 50-100 mg daily are equally effective to ACE inhibitors for blood pressure control and cardiovascular outcomes 2, 7
• ARBs cause 1.8% fewer withdrawals due to adverse effects compared to ACE inhibitors (NNTB 55 over 4.1 years), primarily due to lower incidence of dry cough 7
• However, ARBs lack the placebo-controlled mortality data that ACE inhibitors possess, making ACE inhibitors theoretically preferable when renin-angiotensin system blockade is desired 7

Race-Specific Considerations

• For Black patients without heart failure or CKD, initiate with a thiazide diuretic or calcium channel blocker rather than an ACE inhibitor or ARB as monotherapy 1, 2, 3
• Combination therapy is specifically recommended for Black patients, comprising a diuretic and CCB, either with each other or with an ACE inhibitor/ARB 1
• Beta-blockers and renin-angiotensin system inhibitors are less effective at lowering blood pressure in Black patients 8

Monotherapy vs. Combination Therapy Strategy

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

• Start with single-agent therapy at standard dose, then titrate upward or add a second agent if BP remains uncontrolled after 2-4 weeks 2, 3
• Target BP <130/80 mmHg for patients with CVD or high cardiovascular risk; <140/90 mmHg for general population 1, 2

Stage 2 Hypertension (BP ≥160/100 mmHg or ≥20/10 mmHg Above Target)

• Initiate two first-line agents from different classes simultaneously, preferably as a single-pill combination 1, 2, 8
• Preferred two-drug combinations include: ACE inhibitor/ARB + CCB, ACE inhibitor/ARB + thiazide diuretic, or CCB + thiazide diuretic 1, 2, 8
• Single-pill combinations improve adherence but may contain suboptimal doses of the thiazide component 1

Agents to Avoid as First-Line

• Beta-blockers should NOT be used as first-line therapy unless specific comorbidities exist (coronary artery disease, heart failure with reduced ejection fraction, post-MI), as they are less effective than diuretics for stroke prevention and cardiovascular events 1, 2, 3
• Alpha-blockers are not recommended as first-line therapy because they are less effective for cardiovascular disease prevention than thiazide diuretics 3, 5
• Never combine an ACE inhibitor with an ARB (or with a renin inhibitor), as this increases adverse events including hyperkalemia and acute kidney injury without additional cardiovascular benefit 1, 8

Monitoring and Follow-Up

• Reassess monthly after medication initiation or changes until target BP is achieved, then every 3-5 months once controlled 2, 3
• Check electrolytes and renal function within 7-14 days when starting ACE inhibitors, ARBs, or diuretics, then at least annually 2, 8
• Measure standing BP in elderly patients to assess for orthostatic hypotension 2, 3

Common Pitfalls to Avoid

• Do not use beta-blockers as first-line unless compelling indications exist, as they have inferior stroke prevention compared to other classes 1, 2, 3
• Avoid rapid dose escalation in elderly patients, which increases risk of adverse effects; use more gradual titration 3
• Do not ignore the superior evidence for chlorthalidone over hydrochlorothiazide; chlorthalidone has the strongest head-to-head trial data 2, 3, 4
• Single-pill combinations may contain lower-than-optimal thiazide doses; verify adequate diuretic dosing when using combination products 1