What are the risks of using hydroxychloroquine (Plaquenil) in patients with atrial fibrillation?

Hydroxychloroquine and Atrial Fibrillation: Cardiac Risk Assessment

Hydroxychloroquine carries a significant risk of QT interval prolongation and ventricular arrhythmias in patients with atrial fibrillation, particularly when combined with other risk factors, and requires careful cardiac monitoring and risk stratification before use. 1

Primary Cardiac Risks

QT Prolongation and Ventricular Arrhythmias

• Fatal and life-threatening cardiotoxicity, including cardiomyopathy and ventricular arrhythmias (including torsades de pointes), have been documented with hydroxychloroquine treatment. 1

• Hydroxychloroquine has a direct potential to prolong the QT interval, with the magnitude of prolongation increasing with higher drug concentrations. 1

• In a large retrospective study of 819 patients on chronic hydroxychloroquine therapy, 7% developed QTc intervals of 470-500 ms, and 1.5% exceeded 500 ms. 2

• Among patients with baseline electrocardiograms, mean QTc increased from 424.4 ms to 432.0 ms during hydroxychloroquine treatment (p <0.0001), with 3.9% experiencing either >15% QTc prolongation or on-treatment QTc >500 ms. 2

Specific Risk Factors in AF Patients

Patients with atrial fibrillation face compounded risk when using hydroxychloroquine due to multiple overlapping cardiac vulnerabilities:

• History of atrial fibrillation is an independent risk factor for prolonged QTc during hydroxychloroquine therapy. 2

• Chronic kidney disease and heart failure are additional independent risk factors for QT prolongation with hydroxychloroquine. 2

• Hypokalemia is a modifiable risk factor that significantly increases the risk of drug-induced QT prolongation and torsades de pointes when using hydroxychloroquine. 3

Absolute Contraindications and High-Risk Scenarios

Avoid hydroxychloroquine administration in patients with:

• Congenital or documented acquired QT prolongation 1

• Cardiac disease including heart failure or myocardial infarction 1

• Proarrhythmic conditions such as bradycardia (<50 bpm) 1

• History of ventricular dysrhythmias 1

• Uncorrected hypokalemia and/or hypomagnesemia 1

• Concomitant administration with other QT interval-prolonging agents, as this increases risk for ventricular arrhythmias 1

Drug Interactions of Critical Importance

Medications That Amplify Cardiac Risk

• Hydroxychloroquine is not recommended in patients taking other drugs with QT prolongation potential. 1

• The American Heart Association identifies both hydroxychloroquine and tricyclic antidepressants as sodium channel blockers causing QRS prolongation and life-threatening cardiotoxicity. 4

• Additive QT prolongation risk exists with multiple cancer drugs including cabozantinib, ceritinib, crizotinib, nilotinib, osimertinib, vandetanib, vemurafenib, oxaliplatin, and arsenic trioxide. 5

• Hydroxychloroquine is contraindicated with ondansetron >8mg, domperidone, and citalopram due to torsades de pointes risk. 5

• Combination with corticosteroids, cisplatin, and other chemotherapeutic agents increases hypokalemia risk, further elevating arrhythmia potential. 3

Mandatory Monitoring Protocol

Pre-Treatment Assessment

Before initiating hydroxychloroquine in any patient with atrial fibrillation:

• Obtain baseline ECG to assess QTc interval 1

• Correct all electrolyte imbalances, particularly potassium and magnesium 1

• Review all concomitant medications for QT-prolonging potential 1

• Assess for cardiac disease, heart failure, and renal function 2

Ongoing Cardiac Surveillance

• Monitor cardiac function as clinically indicated during hydroxychloroquine therapy 1

• Maintain strict electrolyte monitoring, particularly potassium levels, especially when adding other medications that may affect potassium 3

• Patients with risk factors for QT prolongation should be closely monitored, as the combination of hypokalemia and QT prolongation significantly increases risk of torsades de pointes and sudden cardiac death 3

• Regular follow-up ECGs are required when combining hydroxychloroquine with other cardiotoxic medications 4

Dosing Considerations to Minimize Risk

• The recommended dose should not be exceeded, as QT prolongation magnitude increases with drug concentration. 1

• Daily doses exceeding 5 mg/kg actual body weight increase the incidence of retinopathy and should be avoided 1

• Standard dosing for rheumatologic conditions: 200-400 mg daily 1

When to Discontinue Therapy

Discontinue hydroxychloroquine immediately if:

• Cardiotoxicity is suspected or demonstrated by tissue biopsy 1

• QTc exceeds 500 ms or increases >15% from baseline 2

• Signs of ventricular arrhythmias develop 1

• Severe electrolyte disturbances cannot be corrected 3

Nuanced Evidence Considerations

While two population-based studies from Taiwan showed no increased risk of cardiac arrhythmia with hydroxychloroquine in patients with rheumatic diseases 6, 7, these findings must be interpreted cautiously:

• The FDA drug label explicitly warns of fatal cardiotoxicity and QT prolongation 1

• Real-world data from 819 patients demonstrated measurable QT prolongation in a significant fraction of patients 2

• Patients with atrial fibrillation represent a higher-risk population than general rheumatologic patients 2

• The absence of statistical significance in population studies does not eliminate individual patient risk, particularly in those with multiple risk factors 1

In clinical practice, the FDA warnings and documented cases of fatal cardiotoxicity should take precedence over population-level reassurance, especially in patients with pre-existing atrial fibrillation. 1