What is the recommended treatment approach for isolated systolic hypertension in adults, including target blood pressure, lifestyle modifications, and first‑line pharmacologic therapy?

Treatment of Isolated Systolic Hypertension in Adults

For isolated systolic hypertension, initiate a thiazide-like diuretic (chlorthalidone 12.5–25 mg daily) as first-line therapy, targeting a systolic blood pressure <130 mmHg in most adults, with combination therapy required when systolic pressure is ≥140 mmHg or >20 mmHg above goal. 1

Blood Pressure Targets

• General adult population (<65 years): Aim for systolic <130 mmHg and diastolic <80 mmHg. 12
• Community-dwelling adults ≥65 years: Target systolic <130 mmHg if tolerated; this applies specifically to non-institutionalized, ambulatory older adults. 13
• High-risk patients (CVD, diabetes, CKD): Target <130/80 mmHg. 13
• Diastolic floor: Avoid lowering diastolic pressure below 70 mmHg in high-risk patients, particularly those with coronary artery disease, as excessive reduction may increase adverse cardiovascular events. 14

First-Line Pharmacologic Therapy

Optimal Initial Agent: Chlorthalidone

• Chlorthalidone 12.5–25 mg once daily is the preferred first-line agent for isolated systolic hypertension because it provides superior 24-hour blood pressure control and the strongest cardiovascular outcome evidence from the ALLHAT trial (>50,000 participants). 15
• In ALLHAT, chlorthalidone reduced heart failure incidence by 38% compared with amlodipine and stroke incidence by 15% compared with lisinopril. 1
• Start at 12.5 mg daily to minimize metabolic side effects (hypokalemia, hyperglycemia); titrate to 25 mg after 4 weeks if systolic pressure remains ≥130 mmHg. 1

Alternative First-Line Agents

• Long-acting dihydropyridine calcium-channel blockers (amlodipine 5–10 mg daily or extended-release nifedipine) are equally effective for systolic blood pressure reduction and stroke prevention but less effective than thiazides for heart failure prevention. 156
• ACE inhibitors or ARBs may be used when compelling indications exist (diabetes with albuminuria, chronic kidney disease, post-myocardial infarction) but are less effective than thiazides for isolated systolic hypertension in the general population. 15

Treatment Initiation Strategy by Blood Pressure Level

Stage 1 Isolated Systolic Hypertension (130–139 mmHg)

• Begin with single-agent monotherapy (chlorthalidone 12.5 mg) and titrate upward before adding a second drug. 13
• Initiate pharmacologic therapy when 10-year ASCVD risk is ≥10% (calculated with ACC/AHA Pooled Cohort Equations) or when established cardiovascular disease, diabetes, or chronic kidney disease is present. 1
• If lifestyle modification alone is attempted, reassess after 3 months; add medication if systolic pressure remains ≥130 mmHg. 1

Stage 2 Isolated Systolic Hypertension (≥140 mmHg or >20 mmHg above goal)

• Initiate two-drug combination therapy immediately from different first-line classes, preferably as a single-pill formulation to improve adherence. 132
• Preferred combinations:
  • Chlorthalidone + ACE inhibitor or ARB 15
  • Calcium-channel blocker + ACE inhibitor or ARB 15
• Single-pill combinations markedly improve medication adherence and persistence compared with separate pills. 1

Population-Specific Recommendations

Black Patients Without Heart Failure or CKD

• Initiate therapy with chlorthalidone or a calcium-channel blocker rather than an ACE inhibitor or ARB, because renin-angiotensin system blockers are 30–36% less effective for stroke prevention in this population due to lower renin activity. 17

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. 13
• Target blood pressure <130/80 mmHg. 13

Patients with Chronic Kidney Disease (Stage 3+ or Albuminuria)

• ACE inhibitor or ARB is first-line to decelerate eGFR decline and reduce proteinuria. 1
• Thiazide diuretics remain effective even when eGFR <30 mL/min/1.73 m² and should not be avoided solely because of reduced kidney function. 1

Patients with Coronary Artery Disease or Post-MI

• Combine a β-blocker with an ACE inhibitor or ARB as foundational therapy; if systolic pressure remains uncontrolled, add a dihydropyridine calcium-channel blocker. 1
• β-blockers should be continued for ≥3 years post-MI. 1

Escalation to Triple Therapy

• If systolic pressure remains uncontrolled after 3 months on a two-drug regimen, escalate to triple therapy (ACE inhibitor or ARB + calcium-channel blocker + thiazide-like diuretic), preferably as a single-pill combination. 1
• If blood pressure remains ≥130/80 mmHg despite triple therapy, add a mineralocorticoid-receptor antagonist (spironolactone) and refer to a hypertension specialist. 1

Agents to Avoid as First-Line

• β-blockers should not be used as first-line therapy in uncomplicated isolated systolic hypertension, especially in patients >60 years, because they are ≈36% less effective than calcium-channel blockers and ≈30% less effective than thiazides for stroke prevention. 136
• α-blockers are not recommended as first-line agents because they are less effective for cardiovascular disease prevention than thiazide diuretics. 1

Monitoring and Follow-Up

• Baseline laboratory evaluation: Obtain serum creatinine, eGFR, potassium, sodium, fasting glucose, and lipid panel before initiating therapy. 1
• Repeat labs 1–2 weeks after starting a thiazide diuretic, ACE inhibitor, or ARB to detect hypokalemia, hyperkalemia, or changes in renal function; an increase in creatinine up to 50% above baseline or to 3 mg/dL (whichever is greater) is acceptable. 17
• Monthly follow-up visits after initiating or adjusting therapy until systolic pressure <130 mmHg is achieved, then every 3–5 months for maintenance. 13
• Out-of-office blood pressure monitoring (home or 24-hour ambulatory) is essential to confirm the diagnosis, assess treatment response, and detect white-coat or masked hypertension. 1

Lifestyle Modifications (Mandatory for All Patients with BP ≥120/70 mmHg)

• Sodium restriction to <1,500 mg/day. 1
• DASH dietary pattern (high in fruits, vegetables, whole grains, low-fat dairy). 12
• Weight reduction to achieve BMI <25 kg/m². 1
• Aerobic exercise 90–150 minutes per week. 12
• Alcohol moderation (≤2 drinks/day for men, ≤1 drink/day for women). 12
• Potassium supplementation 3,500–5,000 mg/day when not contraindicated. 1
• Smoking cessation. 1

Common Pitfalls to Avoid

• Delaying combination therapy in stage 2 hypertension (≥140 mmHg systolic) increases cardiovascular risk; initiate two-drug therapy immediately. 1
• Using β-blockers as first-line agents in patients >60 years without a compelling indication leads to inferior stroke prevention. 16
• Excessive diastolic lowering below 60 mmHg in high-risk patients may increase adverse cardiovascular events, particularly in those with coronary artery disease. 14
• Combining an ACE inhibitor with an ARB (or adding a direct renin inhibitor) should be avoided due to lack of benefit and higher adverse-event risk (hyperkalemia, acute kidney injury). 81
• Failing to employ out-of-office blood pressure monitoring can miss white-coat or masked hypertension, compromising management. 1