Is the combination of perindopril (angiotensin-converting enzyme inhibitor) and diltiazem (calcium channel blocker) a safe combination?

Safety of Perindopril and Diltiazem Combination

The combination of perindopril (ACE inhibitor) and diltiazem (non-dihydropyridine calcium channel blocker) should be used with caution due to potential risks of bradycardia, heart block, and worsening heart failure, particularly in patients with left ventricular dysfunction. 1

Pharmacological Considerations

Mechanism of Concern

• Diltiazem is a non-dihydropyridine calcium channel blocker that slows atrioventricular nodal conduction and has negative inotropic effects 2
• Perindopril is an ACE inhibitor that reduces peripheral arterial resistance and improves arterial wall compliance 3
• When combined, these medications may have additive effects on blood pressure reduction and potentially on cardiac conduction

Risk Factors for Adverse Events

• Left ventricular dysfunction or heart failure
• Pre-existing conduction abnormalities
• Bradycardia
• Hypotension
• Advanced age
• Renal impairment

Evidence-Based Recommendations

General Safety Guidelines

1. Preferred Alternatives:

   • ACE inhibitors like perindopril combine more safely with dihydropyridine CCBs (e.g., amlodipine) rather than non-dihydropyridine CCBs like diltiazem 1
   • Perindopril + thiazide diuretic is a well-established and safer combination 3, 4

2. Monitoring Requirements if Combination Used:

   • Regular monitoring of blood pressure
   • ECG monitoring for conduction abnormalities
   • Heart rate monitoring
   • Assessment for signs of heart failure
   • Renal function monitoring

Special Clinical Scenarios

Hypertension Management

• For patients with hypertension requiring combination therapy, perindopril has shown synergistic effects with thiazide diuretics 5
• The ADVANCE trial demonstrated that treatment with perindopril and indapamide to an achieved systolic blood pressure of 135 mmHg significantly decreased cardiovascular event rates 2

Coronary Artery Disease

• While both medications are used in coronary artery disease, the American Heart Association recommends long-acting dihydropyridine CCBs rather than non-dihydropyridine CCBs when combining with ACE inhibitors 2
• In patients with angina, diltiazem or verapamil should not be used in patients with heart failure or LV systolic dysfunction 2

Atrial Fibrillation

• In rare cases of uncontrolled rapid atrial fibrillation where single-agent treatment is inadequate, a cautious combination might be considered 2
• The NORDIL study had approximately 700 patients who took beta-blockers with diltiazem without reported syncope or pacemaker implantation, but this does not establish safety with ACE inhibitors 2

Clinical Decision Algorithm

1. Assess patient risk factors:

   • Presence of heart failure or LV dysfunction (contraindication)
   • Pre-existing bradycardia or conduction abnormalities (contraindication)
   • Hypotension (contraindication)
   • Renal function (may require dose adjustment)

2. Consider alternative combinations first:

   • Perindopril + dihydropyridine CCB (e.g., amlodipine)
   • Perindopril + thiazide diuretic
   • ARB + dihydropyridine CCB

3. If perindopril + diltiazem combination is deemed necessary:

   • Start with lower doses of both medications
   • Monitor blood pressure, heart rate, and ECG closely
   • Assess for symptoms of heart failure
   • Regular follow-up within 1-2 weeks of initiation
   • Consider discontinuation if adverse effects occur

Conclusion

While the combination of perindopril and diltiazem is not absolutely contraindicated, it should be used with caution and close monitoring. Alternative combinations with better safety profiles should be considered first, particularly in patients with cardiac conduction abnormalities or left ventricular dysfunction.