1C adverse effects and interactions

CardioNerds (Dr. Colin Blumenthal, Dr. Kelly Arps, and Dr. Natalie Marrero) discuss anti-arrhythmic drugs in the management of atrial fibrillation and atrial flutter with electrophysiologist Dr. Andrew Epstein. We discuss two major classes of anti-arrhythmic drugs, class IC and class III, as well as digoxin. Dr. Epstein explains their mechanisms of action, indications and specific patient populations in which they would be particularly helpful, efficacy, adverse side effects, contraindications, and key drug-drug interactions. We also elaborate on defining clinical trials and their clinical implications. Given the large burden of atrial fibrillation and atrial flutter in our patient population and the high prevalence of anti-arrhythmic drug use, this episode is sure to be applicable to many practicing physicians and trainees. Audio editing by CardioNerds academy intern, Grace Qiu. 

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Pearls

1. Anti-arrhythmic drugs should not be thought of as an alternative to ablation but, instead, should be considered an adjunct to catheter ablation.  

2. Class IC anti-arrhythmic drugs, flecainide and propafenone, are highly efficacious for acute cardioversion and a great option for patients with infrequent episodes of AF who do not have a history of ischemic heart disease.   

3. Class III anti-arrhythmic drugs like ibutilide, sotalol, and dofetilide, are highly effective for acute conversion; however, they require hospitalization for close monitoring during initiation and dose titration given the risk of prolonged QT.  

4. Amiodarone should not be used as a first line agent given its toxicities, prolonged half-life, large volume of distribution, and drug-drug interactions.  

5. Dr. Epstein notes that, “All drugs are poisons with a few beneficial side effects,” when highlighting the many adverse side effects of anti-arrhythmic drugs, particularly amiodarone, and the importance of balancing their benefit in rhythm control with their side effect profile.  

Notes

Notes: Notes drafted by Dr. Natalie Marrero. 

1. What are the Class IC anti-arrhythmic drugs and what indications exist for their use?  

• Class IC anti-arrhythmic drugs are anti-arrhythmic drugs that work by blocking sodium channels and, thereby, prolonging depolarizing.  

• Class IC anti-arrhythmic drugs include flecainide and propafenone.  

• Class IC anti-arrhythmic drugs are good agents to use in patients that have infrequent episodes of AF and do not want daily dosing as these agents can be used by patients when they feel palpitations and desire acute conversion back to sinus rhythm (“pill in the pocket” approach).   

2. What are the adverse consequences and/or contraindications to using a class IC agent? 

• Class IC anti-arrhythmic agents are contraindicated in patients with a history of ischemic heart disease based on increased mortality associated with their use in these patients in the CAST trial.  

• Given the results of the CAST trial, providers should screen annually for ischemia via a functional stress test in patients on these drugs at risk for coronary disease.  

• These drugs can increase 1:1 conduction of atrial flutter and, therefore, require concomitant use of a beta blocker.  

• These agents are generally well-tolerated without any organ toxicities; however, they can precipitate heart failure in patients with cardiomyopathies, cause sinus node depression, and unmask genetic arrythmias such as a Brugada pattern.  

3. What are the class III agents and what are indications for their use?  

• Class III agents are drugs that block the potassium channel, prolonging the QT, and include Ibutilide, Sotalol, and Dofetilide.   

• Class III agents can be considered in patients with or without a history of ischemic heart disease that desire effective acute chemical cardioversion and are willing to go to the hospital for close monitoring during dose initiation and titration.  

• Other specific circumstances in which one can use these agents, specifically Ibutilide, are in patients with recurrent atrial fibrillation and Wolf Parkinson White (due to slowed conduction via the accessory pathway). 

4. What are the adverse consequences and/or contraindications to using a class III agent? 

• Ibutilide, Sotalol, and Dofetilide prolong the QT and increase the risk of torsade de pointes, which is why they require ECG monitoring in-patient during drug initiation and dose titration.   

• These agents are generally well-tolerated.  

• Sotalol should be avoided or used cautiously in patients with left ventricular dysfunction, while dofetilide can be used and has dose-response beneficial effects in patients with left ventricular dysfunction.  

• Both sotalol and dofetilide are renally cleared with specific creatinine clearance cutoffs (CrCl < 20 for dofetilide and CrCl <40 for sotalol) and their dose should be adjusted based on the patient’s creatinine clearance (not eGFR). 

5. What is the mechanism of action and indications for using amiodarone?  

• Amiodarone is a class III anti-arrhythmic agent, so it blocks the potassium channel prolonging the QT. Amiodarone is a “dirty drug” as it also has Class I (sodium channel blockade), Class II (antisympathetic action), and Class IV (calcium channel blockade) actions.   

• Amiodarone should be used as a second line agent.  

• Amiodarone can be considered in young, stable outpatients who are already in sinus rhythm especially greater than 60 beats per minute for outpatient loading.  

6. What are the drawbacks of amiodarone?  

• Amiodarone, given its large volume of distribution and need to reach ~10 g for efficacy in conversion, takes a longer time to load and, therefore, a longer time to cardiovert.  

• Amiodarone is associated with multiple organ toxicities including pulmonary fibrosis, thyroid toxicity (both hypothyroidism and hyperthyroidism), peripheral neuropathy, sinus bradycardia, QT prolongation, corneal deposits, retinitis and vision loss.  

• Given the organ toxicities, patients on amiodarone should have their LFTs and TSH, a chest X-ray, and electrocardiogram checked at least every 6 months.  

• Amiodarone sensitizes patients to warfarin and increases digoxin levels, so if patients are on amiodarone with warfarin or digoxin, lower levels of warfarin or digoxin should be used.  

7. What is dronedarone? How does it differ from amiodarone?  

• Dronedarone is a class III antiarrhythmic, which means it works by blocking the potassium channel and prolonging the QT.  

• Dronedarone differs from amiodarone in that it lacks iodine moiety and, therefore, does not have the associated thyroid toxicities. It also has a shorter half-life and smaller volume of distribution.  

8. What are the contraindications to using dronedarone?  

• In the PALACE trial, dronedarone was associated with increased mortality in patients with heart failure, so it should be avoided in patients with clinical heart failure within the last six months.  

9. What is the mechanism of action and indication for using digoxin?  

• Digoxin has several mechanisms of action including increasing vagal tone, inhibiting the sodium potassium ATPase, and acting as a positive inotrope. 

• Digoxin is indicated as a second line drug when better rate control is needed.  

• Digoxin improves rate control by increasing vagal tone and so may have an impact on resting rates. However, exertional rates may remain unctonrolled since these are mediated by sympathetic tone.  

• Digoxin is a good option in patients that are not particularly active given that it decreases ventricular rate at rest, but not with exercise. 

• Digoxin may be particularly beneficial in patients with heart failure given its positive ionotropic effects.  

10. What are the adverse side effects of digoxin and special monitoring required for patients on digoxin?  

• Typically, digoxin levels are monitored, however they are usually not helpful as the levels are often drawn randomly. To be informative, the levels need to be a trough levels drawn right before the drug is given.  

• The literature contains conflicting results on the mortality associated with digoxin levels.  

• In general, the consensus in the field is that lower levels are better.  

• Digoxin is renally cleared, so levels should be closely monitored in patients with renal failure.  

References

1. Mar PL, Horbal P, Chung MK, et al. Drug interactions affecting antiarrhythmic drug use. Circulation: Arrhythmia and Electrophysiology. 2022;15(5):e007955. https://doi.org/10.1161/CIRCEP.121.007955. doi: 10.1161/CIRCEP.121.007955. 

2. Gianfranchi L, Luzi M, Solano A, et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med. 2004;351(23):2384–2391. https://doi.org/10.1056/NEJMoa041233. doi: 10.1056/NEJMoa041233. 

3. Barker AH, Echt DS, Arensberg D, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. N Engl J Med. 1991;324(12):781–788. https://doi.org/10.1056/NEJM199103213241201. doi: 10.1056/NEJM199103213241201. 

4. Markman Timothy M., Jarrah Andrew A., Ye T, et al. Safety of pill-in-the-pocket class 1C antiarrhythmic drugs for atrial fibrillation. JACC: Clinical Electrophysiology. 2022;8(12):1515–1520. https://doi.org/10.1016/j.jacep.2022.07.010. doi: 10.1016/j.jacep.2022.07.010. 

5. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: A report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2024;149(1):e1–e156. https://doi.org/10.1161/CIR.0000000000001193. doi: 10.1161/CIR.0000000000001193. 

6. Ferrari F, Santander IRMF, Stein R. Digoxin in Atrial Fibrillation: An Old Topic Revisited. Curr Cardiol Rev. 2020;16(2):141-146. doi:10.2174/1573403X15666190618110941 

7. Van Gelder I,C., Rienstra M, Bunting KV, et al. 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the european association for cardio-thoracic surgery (EACTS): Developed by the task force for the management of atrial fibrillation of the european society of cardiology (ESC), with the special contribution of the european heart rhythm association (EHRA) of the ESC. endorsed by the european stroke organisation (ESO). Eur Heart J. 2024;45(36):3314–3414. https://doi.org/10.1093/eurheartj/ehae176. doi: 10.1093/eurheartj/ehae176. 

8. Copaescu AM, Vogrin S, James F, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023;183(9):944-952. doi:10.1001/jamainternmed.2023.2986 

9. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383(14):1305-1316. doi:10.1056/NEJMoa2019422 

10. Anderson JL, Platia EV, Hallstrom A, et al. Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST). Circulation. 1994;90(6):2843-2852. doi:10.1161/01.cir.90.6.2843 

11.Akiyama T, Pawitan Y, Greenberg H, Kuo C, Reynolds-Haertle R, The CI. Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the cardiac arrhythmia suppression trial. Am J Cardiol. 1991;68(17):1551–1555. https://doi.org/10.1016/0002-9149(91)90308-8. doi: 10.1016/0002-9149(91)90308-8. 

12. Parkash R, Wells GA, Rouleau J, et al. Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial. Circulation. 2022;145(23):1693-1704. doi:10.1161/CIRCULATIONAHA.121.057095