What is the best first‑line antihypertensive for isolated systolic hypertension in adults over 60 years old?

Best Antihypertensive for Isolated Systolic Hypertension in Older Adults

Thiazide-type diuretics (chlorthalidone or hydrochlorothiazide) and dihydropyridine calcium channel blockers are the only drug classes with robust randomized controlled trial evidence demonstrating reduction in cardiovascular mortality, stroke, and cardiac events in isolated systolic hypertension, making them the preferred first-line agents. 1, 2, 3

Primary First-Line Recommendation

Start with a thiazide-type diuretic as the initial agent, specifically:

• Chlorthalidone 12.5 mg daily, titrated to 25 mg if needed after 4-8 weeks 1, 4
• Alternatively, hydrochlorothiazide 12.5-25 mg daily if chlorthalidone is unavailable (though chlorthalidone has superior 24-hour blood pressure control) 1, 4

The European Society of Cardiology and multiple randomized trials establish thiazide diuretics as having the strongest outcome evidence specifically in isolated systolic hypertension, with proven reductions in stroke (ARR 1.13), cardiac events (ARR 1.25), and mortality (ARR 1.64) in adults over 60 years 5, 1, 2. The SHEP trial demonstrated these benefits using low-dose chlorthalidone, making it the gold standard 2, 6.

Alternative First-Line Option

Dihydropyridine calcium channel blockers are equally appropriate as initial therapy, particularly:

• Amlodipine 5 mg daily, titrated to 10 mg if needed 1, 4
• Other dihydropyridines (e.g., nifedipine extended-release) 3, 6

Multiple trials of isolated systolic hypertension have shown dihydropyridine CCBs reduce cardiovascular events comparably to thiazides 1, 3. Choose a CCB when thiazides are contraindicated (e.g., gout, severe hyponatremia) or poorly tolerated 1, 4.

Treatment Algorithm

Step 1: Initiate monotherapy

• Begin with chlorthalidone 12.5 mg daily OR amlodipine 5 mg daily 1, 4
• Use gradual dose titration in elderly patients to minimize adverse effects 1, 7
• Measure blood pressure in both sitting and standing positions to detect orthostatic hypotension 1, 8

Step 2: Assess response at 4-8 weeks

• Target systolic blood pressure <150 mm Hg (strong recommendation, high-quality evidence) 5
• For patients with prior stroke/TIA, target <140 mm Hg (moderate-quality evidence) 5
• For high cardiovascular risk patients, consider <140 mm Hg based on individualized assessment 5

Step 3: Add second agent if target not achieved

• If started on thiazide: add dihydropyridine CCB (amlodipine 5-10 mg) 1, 8
• If started on CCB: add thiazide diuretic (chlorthalidone 12.5-25 mg) 1, 8
• Alternative: add ACE inhibitor or ARB if comorbidities present (diabetes, chronic kidney disease, left ventricular hypertrophy) 1, 3

Step 4: Triple therapy if needed

• Combine thiazide + dihydropyridine CCB + ACE inhibitor/ARB 1, 8
• Consider single-pill combination formulations to improve adherence 1, 8

Agents to Avoid as First-Line

Do not use beta-blockers as initial therapy for isolated systolic hypertension unless compelling indications exist (coronary artery disease, heart failure, post-myocardial infarction) 1, 4. The LIFE trial demonstrated that losartan reduced stroke more effectively than atenolol in elderly patients with isolated systolic hypertension, and meta-analyses show beta-blockers provide less cardiovascular event prevention than diuretics or CCBs 1, 4.

ACE inhibitors and ARBs are acceptable but not preferred as monotherapy for isolated systolic hypertension, as they lack the robust outcome trial evidence that thiazides and CCBs possess in this specific population 1, 3. Reserve them for patients with compelling indications or as add-on therapy 1, 3.

Critical Monitoring Points

• Check electrolytes (potassium, sodium) and creatinine 2-4 weeks after starting thiazide diuretics to detect hypokalemia, hyponatremia, or renal dysfunction 5, 7
• Measure standing blood pressure at every visit because elderly patients have increased risk of orthostatic hypotension, particularly with diuretics 1, 8
• Reassess blood pressure within 4 weeks of any medication adjustment 8, 4
• Monitor for adverse effects: electrolyte disturbances and orthostatic hypotension with thiazides; peripheral edema, headache, and dizziness with CCBs 5

Common Pitfalls to Avoid

• Do not use rapid dose escalation in elderly patients—start low and titrate gradually over 4-8 week intervals 1, 7
• Do not ignore standing blood pressure measurements, as failure to detect orthostatic hypotension increases fall risk 1, 8
• Do not discontinue effective therapy solely because a patient reaches 80 years of age—continuation is recommended when well tolerated 1, 8
• Do not prescribe agents lacking outcome evidence (e.g., cilnidipine, newer CCBs without mortality data) when guideline-recommended drugs with proven cardiovascular benefit are available 1
• Do not target systolic blood pressure below 120 mm Hg in frail elderly patients, as aggressive lowering increases risk of hypotension, syncope, and falls without additional mortality benefit 5

Concurrent Lifestyle Modifications

Initiate or intensify nonpharmacologic interventions alongside drug therapy 5:

• Sodium restriction to <2.3 g (100 mEq) daily 8, 9
• Weight loss if overweight (target BMI <25 kg/m²) 8, 9
• DASH dietary pattern (high in fruits, vegetables, whole grains, low-fat dairy) 8, 9
• Aerobic exercise ≥150 minutes/week of moderate intensity 8, 9
• Alcohol limitation to <14 units/week for men, <8 units/week for women 8