What are the precautions and guidelines for using Cardizem (diltiazem) and digoxin together?

Using Cardizem (Diltiazem) and Digoxin Together

The combination of diltiazem and digoxin is effective and safe for rate control in atrial fibrillation, particularly when digoxin alone fails to control heart rate during exercise, but requires careful patient selection, dose monitoring, and avoidance in specific high-risk populations. 1

When to Use the Combination

Combination therapy is indicated when digoxin monotherapy provides inadequate rate control, especially during physical activity. 2

• Digoxin alone controls ventricular rate only at rest, failing to adequately control heart rate during exercise 2
• The combination of digoxin plus diltiazem is more effective than either agent alone both at rest and during exercise 2
• Target heart rate goals are 110-120 bpm at rest and adequate control during exertion 1

Patient Selection Criteria

This combination should only be used in patients with preserved left ventricular function (LVEF >40%). 1

Safe to Use:

• Patients with atrial fibrillation and preserved ejection fraction (LVEF >40%) 1
• Patients requiring rate control during both rest and exercise 2
• Patients with heart failure and preserved ejection fraction (HFpEF) 2

Contraindicated or Use with Extreme Caution:

• Severe left ventricular dysfunction (LVEF ≤40%) - diltiazem's negative inotropic effects can precipitate or worsen heart failure 2, 1
• Wolff-Parkinson-White syndrome - digoxin may facilitate conduction through accessory pathways 1
• Pre-existing bradycardia or AV block - risk of severe conduction disturbances 3
• Renal dysfunction - digoxin accumulation risk requires close monitoring 1, 4
• Hyperkalemia - significantly increases risk of fatal bradycardia and asystole 5

Dosing Strategy

Start with reduced doses and titrate cautiously while monitoring clinical response. 1, 6

Diltiazem Dosing:

• Start with 60 mg three times daily (180 mg/day total) 6, 7
• Optimal maintenance dose is 240 mg/day - this provides effective rate control with fewer side effects than higher doses 6
• Maximum dose up to 360 mg/day, but 75% of patients experience side effects at this dose 6
• Extended-release formulations can be dosed 240-720 mg/day 1

Digoxin Dosing:

• Maintenance dose 0.125-0.25 mg daily in patients with normal renal function 4
• Target serum digoxin level 0.5-0.9 ng/mL - higher levels offer no additional benefit but increase toxicity risk 4
• Reduce to 0.0625 mg daily in elderly patients (>70 years) 4

Critical Drug Interaction

Diltiazem increases digoxin plasma concentrations by approximately 20%, requiring digoxin dose adjustment and monitoring. 8

• The FDA label confirms diltiazem increases plasma digoxin levels by ~20% 8
• Monitor digoxin levels when initiating, adjusting, or discontinuing diltiazem to avoid over- or under-digitalization 8
• One study showed no change in digoxin levels (1.5 vs 1.3 ng/ml) with combination therapy, but individual variation exists 6
• Adjust digoxin dose downward if toxicity signs develop (nausea, visual changes, arrhythmias) 8

Monitoring Requirements

Close monitoring is essential, particularly during initiation and dose adjustments. 1, 8

Initial Monitoring:

• Digoxin serum levels when starting, adjusting, or stopping diltiazem 8
• Heart rate and blood pressure - check daily initially, then at clinic visits 9
• ECG monitoring for AV conduction abnormalities and bradycardia 3
• Renal function - digoxin is renally eliminated and requires dose adjustment in renal impairment 1

Ongoing Monitoring:

• Exercise testing or 24-hour Holter monitoring to assess rate control during activity 9
• Target resting heart rate <110 bpm 9
• Monitor for symptoms of excessive bradycardia (dizziness, syncope, fatigue) 9

Expected Clinical Effects

The combination significantly reduces heart rate at rest and during exercise compared to digoxin alone. 6, 10

• Mean heart rate reduction of 16-19% during exercise compared to digoxin monotherapy 6, 7
• Post-exercise heart rate reduced from 170 bpm on digoxin alone to 132 bpm with combination therapy 6
• Pressure-rate product (myocardial oxygen demand) decreased by 12.5-28% 6, 7
• Effects persist with continued therapy without tachyphylaxis 6

Critical Safety Warnings

Never combine diltiazem with beta-blockers - this carries a Class III (harm) recommendation due to excessive bradycardia risk. 1

• The European Society of Cardiology gives a Class III recommendation against combining calcium channel blockers with beta-blockers 1
• Risk of severe bradycardia, AV block, and asystole with triple therapy (diltiazem + digoxin + beta-blocker) 3
• Fatal asystole has been reported with diltiazem administration in patients with digoxin toxicity and hyperkalemia 5

Alternative Approaches

In patients with heart failure with reduced ejection fraction (HFrEF), beta-blockers combined with digoxin are preferred over diltiazem. 2, 1

• Beta-blockers reduce mortality in systolic heart failure, while diltiazem may worsen outcomes 2
• Beta-blockers provide better rate control during exercise than digoxin alone 2
• Combination of digoxin plus beta-blocker (atenolol or betaxolol) is effective and safer in HFrEF 2

Common Pitfalls to Avoid

• Do not use high-dose diltiazem (360 mg/day) - side effects occur in 75% of patients without additional benefit over 240 mg/day 6
• Do not assume digoxin levels remain stable - always recheck levels when adding diltiazem 8
• Do not use in decompensated heart failure - diltiazem's negative inotropic effects can be catastrophic 2, 1
• Do not overlook hyperkalemia - this combination with elevated potassium can cause fatal bradycardia 5
• Do not add beta-blockers to this combination - risk of severe conduction disturbances 1, 3