What is the therapeutic approach for hypertension using Perindopril (angiotensin-converting enzyme inhibitor) and Indapamide (thiazide-like diuretic)?

Perindopril/Indapamide for Hypertension Management

Initial Dosing Strategy

Start with perindopril 2 mg/indapamide 0.625 mg once daily as first-line therapy for most patients with hypertension. 1, 2

• This low-dose fixed combination provides effective blood pressure control while minimizing adverse effects compared to higher-dose monotherapy 2, 3
• The combination can be taken with or without food, though food reduces perindoprilat formation by approximately 43%, which is likely clinically insignificant 4
• Single-pill combinations are strongly preferred over separate pills to improve adherence and persistence 5

Dose Titration Protocol

If blood pressure remains uncontrolled after 3 months, increase to perindopril 4 mg/indapamide 1.25 mg once daily, with a maximum dose of perindopril 8 mg/indapamide 2.5 mg once daily. 1

• For patients with blood pressure ≥160/100 mmHg, consider starting directly with the maximum dose of 8 mg/2.5 mg for more aggressive control 1
• Reassess blood pressure 2-4 weeks after any dose adjustment 1
• The ADVANCE trial demonstrated significant cardiovascular benefit using this titration strategy (starting at 2 mg/0.625 mg, advancing to 4 mg/2.5 mg after 3 months) 1

Blood Pressure Targets

Target systolic blood pressure of 120-129 mmHg for most adults, provided treatment is well tolerated. 6

• For patients with diabetes, aim for <130/80 mmHg 1
• Do not target <120/80 mmHg as this increases adverse events 1
• Achieved blood pressure in the ADVANCE trial was 135 mmHg systolic in the treatment group versus 140 mmHg in placebo 1

When Initial Combination Fails

If blood pressure remains elevated on maximum-dose perindopril/indapamide (8 mg/2.5 mg), add a dihydropyridine calcium channel blocker, preferably amlodipine 5-10 mg daily. 6

• This creates the preferred three-drug combination of ACE inhibitor + thiazide-like diuretic + calcium channel blocker 5, 6
• Triple therapy with perindopril/indapamide/amlodipine achieves blood pressure control rates exceeding 80% 6, 7
• Do NOT add another ACE inhibitor, ARB, or direct renin inhibitor—this increases hyperkalemia, syncope, and acute kidney injury without cardiovascular benefit 1, 5

Resistant Hypertension Management

After maximally tolerated triple therapy (perindopril/indapamide/amlodipine), assess adherence first, then add spironolactone as fourth-line agent. 5

• If spironolactone is not tolerated, consider eplerenone (50-200 mg, possibly twice daily) or a vasodilating beta-blocker (labetalol, carvedilol, or nebivolol) 5
• Refer to an expert center for appropriate work-up of resistant hypertension 5
• Only after these agents fail should hydralazine, amiloride, centrally acting agents, or alpha-blockers be considered 5

Monitoring Requirements

Check blood pressure at every routine visit or at least every 6 months. 1

• Monitor serum creatinine, eGFR, and potassium at least annually, more frequently in patients with renal impairment risk 1
• Check renal function and electrolytes 1-2 weeks after initiating triple therapy 6
• Monitor for hyperkalemia, particularly in patients with renal insufficiency, diabetes, or those on potassium supplements/potassium-sparing diuretics 4

Special Populations and Considerations

This combination is effective in elderly patients (65-85 years) and those with reduced renal function. 2, 8

• For patients with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), perindopril/indapamide is particularly beneficial due to ACE inhibitor renoprotective effects 1
• Black patients may have less blood pressure response to ACE inhibitor monotherapy and higher angioedema risk, though combination therapy with a diuretic improves efficacy 4
• The combination reduces target organ damage including left ventricular hypertrophy and diabetic microvascular complications 5, 1, 3

Evidence Base for Cardiovascular Outcomes

The PROGRESS trial demonstrated approximately 30% reduction in recurrent stroke with perindopril (frequently combined with indapamide) in patients with cerebrovascular disease, regardless of baseline blood pressure. 5

• Benefits were seen in both hypertensive and normotensive patients at baseline 5
• The ADVANCE trial showed significant reductions in cardiovascular death, nonfatal stroke/MI, and microvascular complications in type 2 diabetes 1
• This combination reduces pulse pressure and arterial stiffness, independent cardiovascular risk factors 3

Critical Safety Warnings

Discontinue immediately if angioedema occurs (swelling of face, extremities, eyes, lips, tongue, hoarseness, or difficulty swallowing/breathing). 4

• Avoid potassium supplements, salt substitutes containing potassium, and potassium-sparing diuretics unless specifically indicated and closely monitored 4
• Hypotension may occur, especially with the first dose or in volume-depleted patients—ensure adequate hydration 4
• Persistent nonproductive cough occurs in 12% of patients on perindopril (versus 4.5% on placebo) and resolves after discontinuation 4
• Women of childbearing age must be counseled about pregnancy risks; discontinue ACE inhibitors immediately if pregnancy occurs 4