Add Amlodipine as Third-Line Agent
For a patient on perindopril 8 mg/indapamide 2.5 mg with uncontrolled hypertension, add amlodipine 5 mg once daily as the third agent to create the guideline-recommended triple therapy combination. 1, 2
Rationale for Adding Amlodipine
The 2024 ESC Guidelines explicitly recommend escalating to three-drug combination therapy when BP remains uncontrolled on dual therapy, specifically using a RAS blocker (perindopril) + thiazide-like diuretic (indapamide) + dihydropyridine calcium channel blocker (amlodipine), preferably as a single-pill combination. 1
This triple combination targets three complementary mechanisms: renin-angiotensin system blockade, vasodilation, and volume reduction, providing superior BP control compared to maximizing doses of existing dual therapy. 2
The American College of Cardiology and European Society of Cardiology both prioritize adding a third drug class over increasing doses of current medications when BP targets are not met. 1, 2
Specific Dosing Protocol
Start with amlodipine 5 mg once daily. 2
Titrate to amlodipine 10 mg after 2-4 weeks if BP remains above target. 2
Reassess BP within 2-4 weeks after initiating amlodipine. 2
Consider switching to a fixed-dose single-pill combination of perindopril/indapamide/amlodipine (available as Triplixam®) to improve adherence, as fixed-dose combinations are explicitly recommended by ESC guidelines. 1, 3
Blood Pressure Targets
Target systolic BP of 120-129 mmHg for most adults, provided treatment is well tolerated. 1
For patients with diabetes, target <130/80 mmHg, but avoid going below 120/80 mmHg due to increased adverse events. 1, 4
If the 120-129 mmHg target is poorly tolerated, apply the ALARA principle (as low as reasonably achievable). 1
Monitoring Requirements
Check serum creatinine and potassium within 2-4 weeks after adding amlodipine, particularly important given the ACE inhibitor + diuretic combination already in use. 2
Monitor for peripheral edema, which occurs in approximately 10% of patients on amlodipine 10 mg, though this is attenuated by the concurrent ACE inhibitor. 2
Achieve target BP within 3 months of treatment modification. 2
Critical Pitfalls to Avoid
Do not delay intensification if BP is ≥160/100 mmHg (stage 2 hypertension), as this significantly increases cardiovascular risk. 2
Do not add an ARB to the existing perindopril—combining two RAS blockers increases adverse effects (hyperkalemia, acute kidney injury) without cardiovascular benefit. 1, 2
Do not use beta-blockers as third-line unless specific indications exist (angina, post-MI, heart failure with reduced ejection fraction, or heart rate control). 1, 2
Do not neglect lifestyle modifications: sodium restriction to <2 g/day, weight loss if overweight, regular exercise, and alcohol limitation to <100 g/week. 2
Evidence Supporting This Approach
The ADVANCE trial demonstrated significant cardiovascular benefits with perindopril/indapamide combination, achieving systolic BP of 135 mmHg versus 140 mmHg with placebo. 1, 4
The PIANIST study confirmed significant antihypertensive effects of the perindopril/indapamide/amlodipine triple combination across various stages of hypertension. 5
Clinical trials show that switching from two-pill perindopril/indapamide + amlodipine to single-pill triple combination reduces pill burden and improves adherence without compromising efficacy or tolerability. 3