What is the recommended dosage and treatment protocol for Perindopril (Angiotensin-Converting Enzyme Inhibitor) in managing hypertension and heart failure?

Perindopril Dosing and Treatment Protocol

Hypertension Management

Start perindopril at 4 mg once daily and titrate to 8 mg once daily for maintenance, with blood pressure control typically achieved in 60-70% of patients on monotherapy. 1, 2

Initial Dosing Strategy

• Standard patients: Begin with 4 mg once daily 1
• Elderly patients (>70 years): Start at 2 mg once daily for week 1, increase to 4 mg for week 2, then 8 mg for maintenance if tolerated 1
• Patients aged 65-70 years: Start at 4 mg once daily, given in one or two divided doses 1

Titration Protocol

• Titrate upward every 2 weeks until blood pressure measured just before the next dose is controlled 1, 3
• Maximum dose: 16 mg per day, though experience above 8 mg is limited in elderly patients 1
• Doses above 8 mg require close medical supervision 1
• Twice-daily dosing is slightly superior to once-daily (by 0.5-1.0 mmHg), though once-daily is acceptable 1

Expected Blood Pressure Reduction

• At 2 weeks: -15.8/-8.0 mmHg (systolic/diastolic) 3
• At 10 weeks: -21.1/-11.0 mmHg 3
• Blood pressure control rate at 10 weeks: 53.6% 3
• Antihypertensive effect maintained for 24 hours with trough/peak ratios >50% 2

Combination Therapy

• If blood pressure not controlled on perindopril alone, add a thiazide diuretic 1
• Patients already on diuretics: Discontinue diuretic 2-3 days before starting perindopril if possible to reduce risk of first-dose hypotension 1
• If diuretic cannot be stopped: Start perindopril at 2-4 mg daily with careful medical supervision for several hours until blood pressure stabilizes 1
• Patients with more cardiovascular risk factors require higher doses: 46% with one risk factor needed uptitration to 8 mg versus 64% with ≥4 risk factors 3

Renal Impairment Adjustments

• Creatinine clearance <30 mL/min: Safety and efficacy not established; perindoprilat elimination markedly decreased 1
• Dose adjustment required when creatinine clearance drops below 30 mL/min 1

Stable Coronary Artery Disease

In patients with stable CAD, start perindopril at 4 mg once daily for 2 weeks, then increase to 8 mg once daily for maintenance. 1

Evidence Base

• EUROPA trial demonstrated 20% relative risk reduction in cardiovascular death, MI, or cardiac arrest with perindopril 8 mg daily 4
• Mean blood pressure reduction: 5/2 mmHg 4
• Benefit similar in patients with and without hypertension 4

Dosing for CAD

• Standard patients: 4 mg once daily for 2 weeks, then 8 mg once daily 1
• Elderly patients (>70 years): 2 mg once daily for week 1,4 mg for week 2, then 8 mg for maintenance if tolerated 1

Heart Failure Management

For heart failure with reduced ejection fraction, perindopril should be initiated at 2 mg once daily and uptitrated to target dose of 4 mg once daily, always in combination with beta-blockers and diuretics. 4, 5

Initiation Protocol

• Start at 2 mg once daily in stable patients 4, 5
• Target maintenance dose: 4 mg once daily 5
• Always combine with beta-blockers and diuretics 4
• Initiate only in stable patients; defer in NYHA class IV or recent exacerbation (<4 weeks) until specialist consultation 4

Pre-Treatment Assessment

• Achieve euvolemia before starting ACE inhibitor 4
• Review and potentially reduce diuretic dose if no signs of congestion 4
• Avoid excessive diuresis before treatment 4
• Consider withholding diuretics for 24 hours before first dose 4

Monitoring Schedule

• Check blood pressure, renal function (creatinine), and potassium 5-7 days after initiation 4
• Recheck every 5-7 days until potassium values stable 4
• Monitor 1-2 weeks after each dose increment 4
• Once stable: Monitor at 3 months, then every 6 months 4

Expected Benefits

• Improved exercise tolerance and reduced heart failure symptoms within weeks to months 4, 5
• Improved hemodynamic parameters with minimal effect on blood pressure or heart rate 5
• Lower incidence of first-dose hypotension compared to captopril, enalapril, and lisinopril at equivalent starting doses 5

Critical Monitoring Parameters

Acceptable Changes After Initiation

• Creatinine increase up to 50% above baseline OR up to 266 μmol/L (3 mg/dL) OR eGFR ≥25 mL/min/1.73 m² (whichever is smaller) 4
• Potassium up to 5.5 mmol/L is acceptable 4

When to Reduce Dose

• If creatinine or potassium rise excessively: Stop nephrotoxic drugs (NSAIDs), stop potassium supplements, reduce diuretic dose if no congestion 4
• If rises persist: Halve ACE inhibitor dose and recheck in 1-2 weeks 4

When to Stop Treatment

• Potassium >5.5 mmol/L 4
• Creatinine increase >100% OR >310 μmol/L (3.5 mg/dL) OR eGFR <20 mL/min/1.73 m² 4
• Angioedema (absolute contraindication to rechallenge) 4
• Pregnancy 6
• Bilateral renal artery stenosis 6

Managing Adverse Effects

• Asymptomatic hypotension: No action required 4
• Symptomatic hypotension: Review vasodilators, reduce diuretic dose if no congestion, consider specialist advice 4
• Cough: Common but rarely requires discontinuation; if troublesome and proven due to ACE inhibitor, substitute ARB 4

Important Clinical Caveats

• Never combine perindopril with ARBs: Increases adverse events without added benefit 4, 6
• Avoid NSAIDs and COX-2 inhibitors: Block diuretic effects and increase renal dysfunction risk 4
• Avoid calcium channel blockers (verapamil, diltiazem) in heart failure due to negative inotropic effects 4
• It is very rarely necessary to stop an ACE inhibitor: Clinical deterioration likely if withdrawn; seek specialist advice before discontinuation 4
• Perindopril is superior to captopril in response rates (67-80% vs 44-57%) 2
• Tolerability rated as 'good' to 'excellent' by 95.9% of physicians 3