What is the best medication for treating systolic hypertension?

Best Medication for Systolic Hypertension

Thiazide diuretics, specifically chlorthalidone, are the preferred first-line medication for systolic hypertension, with calcium channel blockers (dihydropyridines) as equally effective alternatives. 1

First-Line Treatment Options

Thiazide Diuretics (Preferred)

• Chlorthalidone 12.5-25 mg daily is the optimal thiazide diuretic due to its superior 24-hour blood pressure control and proven cardiovascular event reduction in landmark trials including SHEP and ALLHAT 1, 2
• Chlorthalidone reduces systolic blood pressure more effectively than hydrochlorothiazide (HCTZ), with 24-hour ambulatory monitoring showing 12.4 mmHg reduction versus 7.4 mmHg with HCTZ at equivalent doses 2
• The SHEP trial demonstrated that chlorthalidone-based treatment reduced stroke incidence by 36% (5-year absolute benefit of 30 events per 1000 participants) in isolated systolic hypertension 3
• In ALLHAT, chlorthalidone reduced heart failure risk more effectively than amlodipine, doxazosin, and similarly to lisinopril 4

Calcium Channel Blockers (Equally Effective Alternative)

• Dihydropyridine calcium channel blockers (amlodipine, felodipine) are equally effective first-line agents for isolated systolic hypertension 1, 5
• Amlodipine 5-10 mg daily produces comparable systolic blood pressure reduction to chlorthalidone (-14.6 mmHg vs -14.0 mmHg) with similar goal attainment rates (67% vs 69%) 5
• Multiple trials demonstrate effectiveness specifically in isolated systolic hypertension 1

ACE Inhibitors/ARBs (Third-Line or Comorbidity-Driven)

• ACE inhibitors (lisinopril) and ARBs are effective alternatives, particularly when comorbidities like left ventricular hypertrophy, diabetes, or chronic kidney disease are present 1, 6
• Consider as second choice if patient has specific compelling indications 1

Treatment Algorithm

Step 1: Start with chlorthalidone 12.5 mg daily, titrate to 25 mg if needed after 2-4 weeks 1

Step 2: If blood pressure goal not achieved with monotherapy, add a dihydropyridine calcium channel blocker OR an ACE inhibitor/ARB 1

Step 3: Consider single-pill combination therapy to improve adherence 1

Alternative Step 1: If chlorthalidone unavailable or not tolerated, use dihydropyridine calcium channel blocker as initial monotherapy 1

Blood Pressure Targets

• Initial goal: <140/90 mmHg for all patients 1
• If well tolerated, target systolic blood pressure 120-129 mmHg for most adults to maximize cardiovascular risk reduction 1
• For patients ≥65 years, target systolic blood pressure 130-139 mmHg 1
• For high cardiovascular risk, diabetes, or chronic kidney disease, consider target <130 mmHg 1

Medications to AVOID

Beta-blockers should NOT be used as first-line therapy for isolated systolic hypertension or arterial stiffness, as they are less effective in reducing stroke compared to other agents 1

Alpha-blockers (doxazosin) should be avoided due to 2.04-fold increased risk of heart failure compared to chlorthalidone in ALLHAT 4

Special Considerations for Elderly Patients

• Start with lower doses and titrate more gradually due to increased risk of adverse effects 1
• Monitor standing blood pressure to detect postural hypotension, which is common in elderly patients 1
• Most elderly patients require two or more drugs to achieve target blood pressure 1
• Effective combinations include ARB or ACE inhibitor with dihydropyridine calcium channel blocker or thiazide diuretic 1
• Do not discontinue effective, well-tolerated therapy when patient reaches 80 years of age 1

Critical Pitfalls to Avoid

• Do not assume HCTZ and chlorthalidone are interchangeable - chlorthalidone provides superior 24-hour blood pressure control and greater nighttime systolic blood pressure reduction 2
• However, recent real-world evidence shows chlorthalidone carries higher risk of hypokalemia (HR 2.72), hyponatremia (HR 1.31), acute renal failure (HR 1.37), and type 2 diabetes (HR 1.21) compared to HCTZ, without significant cardiovascular benefit differences 7
• Monitor electrolytes and renal function closely when using chlorthalidone, particularly in elderly patients 7
• Avoid rapid dose escalation in elderly patients 1
• Do not ignore standing blood pressure measurements 1

Nuanced Evidence Discussion

While chlorthalidone remains the guideline-recommended thiazide based on landmark trial data 1, 3, the 2020 LEGEND study challenges this preference by showing no cardiovascular superiority over HCTZ in real-world practice, with significantly more adverse effects 7. This creates a clinical dilemma: prioritize the proven trial efficacy of chlorthalidone or the better safety profile of HCTZ in routine practice. Given the priority on morbidity and mortality outcomes, chlorthalidone remains first-line based on SHEP trial stroke reduction data 3, but HCTZ is a reasonable alternative when electrolyte disturbances or renal impairment are concerns 7.