First-Line Antihypertensive Therapy for Essential Hypertension
Chlorthalidone 12.5–25 mg once daily is the optimal first-line antihypertensive agent for otherwise healthy adults with essential hypertension, based on the strongest cardiovascular outcome evidence from the ALLHAT trial of over 50,000 participants demonstrating superior stroke prevention compared with ACE inhibitors and superior heart failure prevention compared with calcium channel blockers. 1, 2
Treatment Initiation Thresholds
Stage 1 hypertension (130–139/80–89 mmHg): Initiate pharmacotherapy when the patient has established cardiovascular disease or a 10-year ASCVD risk ≥10% calculated using the ACC/AHA Pooled Cohort Equations; otherwise, begin with lifestyle modification for up to 3 months before adding medication. 1, 2, 3
Stage 2 hypertension (≥140/90 mmHg): Start pharmacologic therapy immediately alongside lifestyle measures; do not delay treatment beyond 3 months to prevent therapeutic inertia. 1, 2, 3
Optimal First-Line Agent: Chlorthalidone
Chlorthalidone 12.5–25 mg once daily provides 24-hour blood pressure control due to its 40–60 hour half-life and large volume of distribution, making it pharmacokinetically superior to hydrochlorothiazide. 1, 4
In the ALLHAT trial, chlorthalidone reduced heart failure incidence by 38% compared with amlodipine and reduced stroke incidence by 15% compared with lisinopril, establishing it as the thiazide with the strongest cardiovascular outcome data. 1, 4, 5
Network meta-analysis from the 2017 ACC/AHA systematic review demonstrated that thiazide diuretics were associated with significantly lower risk of stroke and cardiovascular events compared with beta-blockers and lower risk of heart failure compared with calcium channel blockers. 6
Chlorthalidone at 25 mg is more potent than hydrochlorothiazide 50 mg, particularly for overnight blood pressure reduction, which is critical for cardiovascular protection. 4
Alternative First-Line Agents When Thiazides Are Not Tolerated
Long-acting dihydropyridine calcium channel blockers (amlodipine 5–10 mg once daily or extended-release nifedipine) achieve cardiovascular event reduction comparable to chlorthalidone for all outcomes except heart failure, where thiazides remain superior. 1, 2, 7
ACE inhibitors (lisinopril 10–40 mg daily or ramipril) are reasonable alternatives, particularly when albuminuria or established coronary artery disease is present, but were 15% less effective for stroke prevention and 19% less effective for heart failure prevention than chlorthalidone in ALLHAT. 1, 2, 5
Angiotensin receptor blockers (losartan 50–100 mg daily or candesartan) provide blood pressure control and cardiovascular outcomes similar to ACE inhibitors with less cough and angioedema, but do not confer additional benefit over thiazides in uncomplicated hypertension. 1, 2, 7
Monotherapy vs. Combination Strategy
Stage 1 Hypertension Approach
- Start with single-agent monotherapy (chlorthalidone 12.5 mg or amlodipine 5 mg) and titrate upward before adding a second agent from a different class; reassess monthly until BP <130/80 mmHg is achieved. 1, 2, 3
Stage 2 Hypertension Approach
Begin with a two-drug combination from different first-line classes (e.g., chlorthalidone + ACE inhibitor/ARB or amlodipine + ACE inhibitor/ARB), preferably as a single-pill formulation to improve adherence. 1, 2, 3
Single-pill combinations markedly improve medication adherence and persistence compared with taking separate pills, which is critical for long-term blood pressure control. 2
Preferred two-drug regimens include: thiazide diuretic + (ACE inhibitor or ARB) or calcium channel blocker + (ACE inhibitor or ARB). 1, 2
Population-Specific Modifications
Black Patients Without Heart Failure or CKD
Initiate therapy with a thiazide diuretic (chlorthalidone) or calcium channel blocker rather than an ACE inhibitor or ARB as monotherapy, because renin-angiotensin system inhibitors are approximately 30–36% less effective for stroke prevention in this population due to lower renin activity. 1, 2, 3
ARBs may be better tolerated than ACE inhibitors (less cough and angioedema) but confer no additional cardiovascular benefit. 2
Patients with Diabetes Mellitus
Prefer an ACE inhibitor or ARB as initial therapy to protect renal function, especially when albuminuria ≥300 mg/day is present. 1, 2
All four first-line classes are acceptable when no renal indication exists, but ACE inhibitors/ARBs should be used if albuminuria is present to slow kidney disease progression. 1
Patients with Chronic Kidney Disease (Stage 3+ or Albuminuria)
ACE inhibitor or ARB is mandatory first-line therapy to decelerate eGFR decline and reduce proteinuria. 1, 2
Thiazide diuretics remain effective even when eGFR <30 mL/min/1.73 m² and should not be avoided solely because of reduced kidney function. 2
Blood Pressure Treatment Targets
General adult population: Aim for BP <130/80 mmHg. 1, 2, 3, 7
Patients with chronic kidney disease: Target <130/80 mmHg. 1, 2
Patients with stable ischemic heart disease: Target <130/80 mmHg. 1, 2
Community-dwelling adults ≥65 years: Aim for systolic <130 mmHg if tolerated, but exercise caution when initiating combination therapy in those at risk for orthostatic hypotension. 1, 2
In high-risk patients, diastolic pressure should not be lowered below 60–70 mmHg because excessive reduction may increase adverse cardiovascular events; the optimal diastolic range is 70–79 mmHg. 1, 2
Agents to Avoid as First-Line
Beta-blockers should NOT be used as first-line therapy in uncomplicated hypertension, especially in patients >60 years, because they are approximately 36% less effective than calcium channel blockers and 30% less effective than thiazides for stroke prevention. 1, 2, 3
Alpha-blockers (doxazosin) are not first-line options; in ALLHAT they were associated with an 80% higher rate of heart failure compared with chlorthalidone. 2, 4
Never combine an ACE inhibitor with an ARB (or add a direct renin inhibitor) because dual renin-angiotensin system blockade increases the risk of hyperkalemia and acute kidney injury without providing additional cardiovascular benefit. 1, 2
Hydrochlorothiazide doses <25 mg daily as monotherapy are discouraged because such low doses are unproven or less effective in outcome trials. 2
Monitoring and Follow-Up
Schedule monthly follow-up visits after medication initiation or dose changes until the blood pressure target is reached; thereafter, see the patient every 3–5 months for maintenance. 1, 2, 3
Check serum creatinine, estimated glomerular filtration rate, and potassium within 1–2 weeks of starting ACE inhibitors, ARBs, or diuretics, after each dose increase, and then annually thereafter. 1, 2, 3
An increase in serum creatinine of up to 50% above baseline or to 3 mg/dL (whichever is greater) is considered acceptable when initiating renin-angiotensin system inhibitors. 2
Out-of-office blood pressure monitoring (home or ambulatory) is essential to assess treatment response, detect white-coat effect, and identify masked uncontrolled hypertension. 2
Common Pitfalls to Avoid
Delaying combination therapy in stage 2 hypertension (≥140/90 mmHg) increases cardiovascular risk; two-drug therapy should be initiated immediately. 1, 2
Using beta-blockers as first-line agents in patients >60 years without a compelling indication (post-MI, heart failure with reduced ejection fraction, angina) leads to inferior stroke prevention. 1, 2
Excessive diastolic lowering below 60 mmHg in high-risk patients may increase adverse cardiovascular events, particularly in those with coronary artery disease. 1, 2
Failing to employ out-of-office blood pressure monitoring can miss white-coat or masked hypertension, compromising management decisions. 2
Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent diabetes. 4