Based on the ALLHAT trial, which antihypertensive medication should be used as first‑line therapy in adults with hypertension and high cardiovascular risk?

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Last updated: February 17, 2026 • View editorial policy

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Thiazide-Type Diuretics as First-Line Therapy Based on ALLHAT

Based on the ALLHAT trial, thiazide-type diuretics (specifically chlorthalidone 12.5-25 mg daily) should be the preferred first-line antihypertensive medication for adults with hypertension and high cardiovascular risk. 1

Primary Outcome Findings

The ALLHAT trial randomized 42,418 high-risk hypertensive patients aged ≥55 years to chlorthalidone, amlodipine, lisinopril, or doxazosin (stopped early). 1, 2

For the primary outcome of fatal coronary heart disease or nonfatal myocardial infarction, all drug classes performed equivalently:

  • Amlodipine vs chlorthalidone: RR 0.98 (95% CI 0.90-1.07) 1, 2
  • Lisinopril vs chlorthalidone: RR 0.99 (95% CI 0.91-1.08) 1, 2
  • Doxazosin vs chlorthalidone: RR 1.03 (95% CI 0.90-1.17) 1

Critical Secondary Outcomes Favoring Thiazides

The superiority of chlorthalidone emerged in preventing major cardiovascular complications, which directly impact morbidity and mortality: 1

Heart Failure Prevention

Chlorthalidone demonstrated marked superiority in preventing heart failure, the most striking difference in ALLHAT:

  • Doxazosin: RR 2.04 (95% CI 1.79-2.32) - doubling of heart failure risk 1, 3, 4
  • Amlodipine: RR 1.38 (95% CI 1.25-1.52) 1, 2
  • Lisinopril: RR 1.19 (95% CI 1.07-1.31) 1, 2

Independent validation confirmed these heart failure diagnoses with 71-84% agreement, and ejection fraction measurements showed 63-70% of patients had EF ≤40%. 3, 4

Stroke Prevention

Chlorthalidone reduced stroke risk compared to ACE inhibitors and alpha-blockers:

  • Lisinopril: RR 1.15 (95% CI 1.02-1.30) - 15% increased stroke risk 1, 2
  • Doxazosin: RR 1.15 (95% CI 1.01-1.40) 1
  • Amlodipine: no significant difference 1

Combined Cardiovascular Disease

Chlorthalidone prevented more composite cardiovascular events:

  • Doxazosin: RR 1.25 (95% CI 1.17-1.33) 1
  • Lisinopril: RR 1.10 (95% CI 1.05-1.16) 1, 2

Blood Pressure Control Differences

Chlorthalidone achieved superior blood pressure control, which partially explains outcome differences: 2

  • Lisinopril: 2 mmHg higher systolic BP at 5 years (P<.001) 2
  • Amlodipine: 0.8 mmHg higher systolic BP at 5 years (P=.03) 2

In Black patients, the blood pressure control differences were even more pronounced, contributing to worse outcomes with lisinopril. 1, 5

Treatment-Resistant Hypertension

Chlorthalidone-based therapy resulted in the lowest rates of treatment-resistant hypertension: 6

  • Chlorthalidone: 9.6% developed treatment-resistant hypertension 6
  • Amlodipine: 11.4% 6
  • Lisinopril: 19.7% - double the rate of chlorthalidone 6

Contemporary Guideline Integration

The 2017 ACC/AHA systematic review incorporating ALLHAT and 40 other trials confirmed no mortality difference between drug classes but validated thiazide superiority for heart failure prevention. 1

Network meta-analysis comparing all classes to thiazides showed: 1

  • All-cause mortality: no significant differences across classes 1
  • Heart failure: ACEIs RR 1.2 (95% CrI 0.91-1.5), CCBs RR 0.97 (95% CrI 0.90-1.1) 1
  • Beta-blockers showed 20% increased cardiovascular mortality vs thiazides (borderline significant) 1

Important Caveats and Exceptions

While thiazides should be first-line for most high-risk hypertensive patients, specific clinical scenarios warrant alternative initial therapy: 7, 5

When to Choose ACE Inhibitors/ARBs Instead:

  • Patients with albuminuria or proteinuria (renoprotective effects) 7, 5
  • Heart failure with reduced ejection fraction 7
  • Post-myocardial infarction 7

When to Choose Calcium Channel Blockers Instead:

  • Black patients (equivalent or superior outcomes to thiazides) 7, 5
  • Patients on lithium therapy (avoid thiazide-lithium interaction) 8
  • Isolated systolic hypertension in elderly 7

Absolute Contraindications:

  • Alpha-blockers (doxazosin) should not be first-line due to doubled heart failure risk 1, 7
  • ACE inhibitors/ARBs are contraindicated in pregnancy 7

Cost Considerations

Thiazide-type diuretics are substantially less expensive than newer agents, providing equivalent or superior outcomes at lower cost. 1, 2 This cost-effectiveness strengthened JNC VII recommendations favoring diuretics as first-line therapy. 1

Study Limitations to Consider

ALLHAT enrolled predominantly treated patients (90%) with baseline BP 146/84 mmHg, essentially studying treatment switching rather than true first-line therapy in untreated patients. 1 However, this reflects real-world clinical practice where most hypertensive patients are already on some therapy. 1

Event validation was performed on only 10% of CHD and stroke events, with 66% confirmation rate for heart failure in the validated subset. 1 Despite this limitation, independent validation studies confirmed the heart failure findings. 3, 4

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

5
Guideline

Comparative Efficacy and Patient-Specific Considerations for Lisinopril and Amlodipine

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

7
Guideline

Antihypertensive Drug Classes and Their Effects

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

8
Guideline

Optimal Antihypertensive Treatment for Patients on Lithium Therapy

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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