These drugs are first-line treatments for Afib patients with structurally normal hearts but are considered contraindicated in those with significant LVH, heart failure with low ejection fraction, or significant CAD.
A crucial aspect of using these agents safely is frequent application of ECG stress tests and resting tests using 12-lead ECG to monitor for and diagnose proarrhythmic adverse effects.
Type IC Electrophysiologic Properties and Effects on Cardiac Intervals
As outlined in a Cardiovascular Pharmacology Concepts article, type IC agents influence myocyte depolarization by binding to and blocking the fast sodium channels responsible for rapid depolarization of fast-response cardiac action potentials. They also influence repolarization by increasing effective refractory period, suppress abnormal automaticity, and have an indirect vagal effect. These effects are noted in all cardiac tissues.
A recent review in the American Journal of Cardiology (AJC) notes that 12-lead ECGs from patients taking flecainide show a concentration-dependent increase in the PR interval and the QRS complex:
- The PR interval is prolonged by 17 to 29%
- The QRS is prolonged by 11 to 27%
The effect on the JT interval is insignificant, as flecainide does not lengthen ventricular repolarization. The vast majority of the QT prolongation is due to QRS widening, and the rate-corrected QT interval (QTc) remains unchanged or increases by only 1 to 5%.
It is not clear exactly which factors determine flecainide's effectiveness in converting Afib to SR and suppressing Afib.
Ventricular Proarrhythmic Effects
The risk of ventricular proarrhythmia with type IC AADs was first identified in the 1980s. Type IC agents were used to suppress premature ventricular contractions and were considered potentially useful for reducing SCD post-MI in patients with frequent ventricular ectopy.
However, the landmark CAST study published in the New England Journal of Medicine in 1991 showed that the type IC agents encainide and flecainide increased the risk of SCD in post-infarct patients. Following CAST, the clinical use of type IC agents dropped precipitously, but there has been growing recognition of their safety and utility for patients with Afib and structurally normal hearts in the last 30 years.
The type IC AADs remain contraindicated in Afib patients with significant CAD or low left ventricular ejection fraction due to a high risk of proarrhythmic effect in this population. In addition, the AJC review notes that "flecainide, like many other sodium channel blocking drugs, may unmask the ECG pattern of underlying Brugada syndrome, leading to ventricular tachycardia and, thereby, a risk for sudden cardiac death."
That both ventricular and supraventricular proarrhythmias are associated with higher drug levels and significant QRS prolongation during 12-lead ECG monitoring is an important premonitory finding. Even in Afib patients with structurally normal hearts, therefore, ECG monitoring for QRS prolongation at rest has been recommended.
Supraventricular Proarrhythmias
In patients with Afib, type IC AADs may create worse supraventricular rhythms, according to research in EP Europace. The most common effect is a slowing atrial flutter rate, typically down to 200 bpm. Concomitant with this, given that flecainide does not slow AV conduction, 1:1 conduction can occur with a resulting dangerously high ventricular rate.
Slow atrial flutter induced by type IC drugs with 1:1 conduction is commonly associated with aberrant conduction due to IV conduction delay. To prevent the condition, current guidelines strongly recommend concurrent administration of AV blocking agents when type IC AADs are prescribed for patients with Afib.
Role of Resting ECG in Optimal Use of Type IC Drugs
A recent review in the World Journal of Cardiology suggested that all patients undergoing therapy with type IC agents should receive regular ECG monitoring upon initiation of the drugs or with upward titration. If QRS prolongation >25% occurs, then the drug dosage should be halved. If the QRS remains prolonged >25%, discontinuation is recommended.
In addition, this review and others have recommended that patients on type IC agents undergo a regular ECG stress test to assess for rate-dependent proarrhythmia or QRS prolongation.
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Role of Exercise ECG Testing
The 2011 ACC/AHA/ESC Afib Guidelines suggest a role for ECG monitoring at rest and with exercise ECG stress testing after initiation of type IC agents: "With class IC drugs, prolongation of the QRS interval should not exceed 50%. Exercise testing may help detect QRS widening that occurs only at rapid heart rates (use-dependent conduction slowing)."
These suggestions do not appear in the formal recommendations and are not accompanied by an assessment of the level of evidence, the strength of recommendation, or references.
Neither the 2014 focused update to the 2011 Afib guidelines nor the 2019 focused update mentions stress ECG testing for patients on type IC AADs. The 2014 update confirmed that type IC AADs can be initiated safely as an outpatient and continued the emphasis on ECG monitoring for QRS prolongation, but changed the QRS prolongation criteria to >25% and recommended that ECG be performed "near the time of peak drug concentration." Data supporting these various guideline recommendations is limited and mixed.
A study published in the AJC attempted to answer whether there is value in taking a routine ECG stress test for patients on flecainide for atrial tachydysrhythmias. This retrospective study looked at the results of symptom-limited exercise to detect significant QRS widening (defined as an increase in QRS of >25%). Only one of the 56 patients demonstrated QRS widening. This patient also experienced atrial tachycardia, and both the tachycardia and QRS widening resolved upon cessation of exercise.
The patient had a history of atrial tachycardia and secondary cardiomyopathy, which had normalized three years before initiation of flecainide. The researchers concluded that routine stress ECG testing on type IC AADs was "not warranted."
In contrast, another recent publication in the Indian Pacing and Electrophysiology Journal identified 300 patients from a retrospective chart review over a 65-month interval who were initiated on flecainide or propafenone for atrial arrhythmias. The patients had no evidence for CAD and had normal LV function by echocardiography. Drug therapy was initiated in the hospital. The single proarrhythmic event during drug loading was asymptomatic nonsustained ventricular tachycardia in a patient with slightly reduced LV function (EF 45%). No other resting ECG changes were noted.
During exercise testing, however, 15 of the patients had a proarrhythmic response (defined as QRS widening >25% or nonsustained ventricular tachycardia), and one patient exhibited ischemia.
The authors concluded that "soon after [drug] loading, all patients should undergo a maximal exertion exercise test to assess for proarrhythmic effects of use-dependent sodium channel blockade."
Current Expert Recommendations
In a 2020 American Journal of Cardiology review, Doctors Debra S. Echt and Jeremy N. Ruskin summarized their recommendations as follows:
- Upon initiation of type IC AADs, it is important to obtain 12-lead ECGs at baseline, at steady state, and before increasing the dosage.
- Flecainide is usually initiated at 100 mg bid, though a minority of patients will respond to doses as low as 50 mg bid. The dose may be escalated based on QRS duration prolongation of less than 50% over baseline after four days of administration.
Their article doesn't mention stress testing, but Dr. Ruskin shared with me via email that at his center at Massachusetts General Hospital, routine stress testing is performed prior to and periodically after starting type IC AADs to "exclude any obvious signs of ischemia and to assess the QRS response." The frequency of stress ECG testing varies depending on "patients' age, clinical status, risk factors, and pre-test probability of ischemic heart disease."
His approach is to lower the dose "if the QRS prolongs by more than 50% over baseline on the drug," and to "generally stop it if the QRS duration with stress exceeds 120 ms, or for new bundle branch blocks that do not resolve at a lower dose, or are unmasked at elevated rates on the treadmill or during regular exercise and detected on ECG monitoring."