Amiodarone toxicity – nastier than you think

13th January 2024, Conjoint A/Prof Chee L Khoo

Amiodarone toxicity

Amiodarone started life as an anti-angina drug but it’s used primarily for its anti-arrhythmic properties these days. That’s not because it is such a good anti-arrhythmic agent (AAD) but because there just aren’t that many good and safe anti-arrhythmic agents around. We are all aware of amiodarone’s thyroid effects (hypo or hyper) and we monitor them closely as long as they are on amiodarone. It is lipophilic and can accumulate in many tissues at high concentration and potentially causes irreversible toxicity. A recent Israeli study highlighted the pulmonary complications associated with amiodarone use. It is worthwhile getting familiar with what the complications are. I can’t recall a cardiologist looking out for them.

How useful is amiodarone in Atrial Fibrillation (AF)?

The AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial was conducted to examine two treatment strategies for AF, namely rate control or rhythm control (1,2). All-cause mortality, the primary outcome measure, showed a trend toward excess mortality in the rhythm control arm. The AADs, amiodarone, sotalol, flecainide and propafenone used in the rhythm arm have been cited previously as a potential cause of the excess mortality (3). In the AFFIRM trial, overall, cardiovascular hospitalisation event rates during follow-up were higher for all groups on AADs. In particular, death, intensive care unit hospital stay, and non-CV death were more frequent with amiodarone.

A secondary analysis of the AFFIRM trial suggested that, not only does amiodarone not have cardiovascular mortality benefit, it could significantly increase the hazard of non-cardiovascular death when compared with rate control agent (4). Concerns raised by these alarming findings were later quelled with a systematic review and meta-analyses of trials investigating the use of AAD for the treatment of patients with persistent AF (5). Once again, the results were disappointing. There were no survival benefit nor reduction of hospitalisations in amiodarone-treated patients.

Amiodarone and its metabolites are lipophilic. They accumulate in adipose tissue, liver, lung, skin, thyroid, eyes, and nervous system at high concentrations, interacting with metabolism and eventually causing toxicity. Although the lungs account for <5% of all complications, its involvement has the most clinically significant impact and may contribute to patient mortality (6). The incidence is somewhat dose-related. Pneumonitis can occur in 0.1 – 0.6% of patients on the small dose of 200mg per day. Unfortunately, drug withdrawal may not be sufficient to reverse the lung damage with subsequent pulmonary fibrosis which has a mortality rate ranging from 10% to 33%, depending on disease progression at the time of diagnosis (7).

A meta-analysis of randomised controlled trials looking at prophylactic amiodarone for the prevention of arrhythmic death in high-risk patients with recent myocardial infarction or congestive heart failure revealed a high incidence of ‘lung infiltrates’ (between 3.1 – 6.3%) in three trials, even with a short mean follow-up duration ranging from 1.62 to 2.15 years (8). Similar short duration trials also showed high rate of lung infiltrates (odds ratio 3.1) (9).

Tsaban and colleagues published recently in the European Heart Journal to clarify the association of low-dose amiodarone therapy with the occurrence of interstitial lung disease (ILD), lung cancer, and all-cause mortality (10). It was a retrospective nationwide cohort study using electronic medical records from Israel’s largest healthcare maintenance organisation. 6039 amiodarone-exposed patients were matched 1:1 with controls unexposed to amiodarone based on age, sex, ethnicity, and AF diagnosis duration After a mean follow-up of 4.2 years, ILD occurred in 242 (2.0%) patients. Statistically, amiodarone exposure was NOT significantly associated with ILD [hazard ratio (HR): 1.45, 95% confidence interval (CI): 0.97, 2.44, P = 0.09] but there was a trend towards ILD. Furthermore, the provided risk ratios per year during the 10-year follow-up showed a significantly increased risk for ILD between the second and the eighth year. Numbers of participants at risk steeply drop after year 8, and the crossing of curves suggests that the proportional hazards assumption no longer applies after that period.

Amiodarone was also not associated with primary lung cancer (HR: 1.18, 95% CI: 0.76, 2.08, P = 0.53) but once again, there was an increased trend. Data on the potential association of amiodarone with all-cause cancer is conflicting. This had been raised by the results of a previous Taiwan National Health Insurance Research database analysis. The study suggested a dose dependent risk of incident cancer, especially in male patients (11) but the association was not confirmed by a subsequent Danish nationwide cohort analysis (12).

On the plus side, amiodarone was associated with reduced mortality risk (HR: 0.65, 95% CI: 0.60, 0.72, P < 0.001). In other words, in a contemporary AF population, low-dose amiodarone was associated with a trend towards increased risk of ILD (15%-45%) but a clinically negligible change in absolute risk (maximum of 1.8%), no increased risk of PLC, and a lower risk of all-cause mortality. As noted above, previous studies have shown no mortality benefit with amiodarone.

In summary, the data on the potential lung toxicity of amiodarone in the management of AF remains uncertain. The headline conclusion from the recent paper by Tsaban suggested that low dose amiodarone is not associated with significant interstitial lung disease or primary lung cancer although did show a small clinically marginal statistical association with increased risk of ILD between 2 and 8 years of follow-up. The overall absolute incidence was small (2% for ILD and 0.8% for PLD). This was at odds with previous data. It was suggested that perhaps, the previous studies used higher doses of amiodarone (>400mg/day) but two meta-analyses of randomised trials, including amiodarone exposure irrespective of dosage, showed an increased risk of ILD with amiodarone treatment (13,14).

Amiodarone can be an effective anti-arrhythmic agent for maintaining sinus rhythm among patients with AF. The recent EAST-AFNET 4 study showed that an early rhythm control strategy is associated with reduced cardiovascular risk (15). However, due to considerable possible side effects and contradictory data on long-term clinical benefits, most recent guidelines recommend amiodarone as a last resort for rhythm control for AF patients (16).

References:

  1. The Planning and Steering Committees of the AFFIRM Study for the NHLBI AFFIRM Investigators Atrial fibrillation follow-up investigation of rhythm management—the AFFIRM study design Am J Cardiol, 79 (1997), pp. 1198-1202
  2. The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation N Engl J Med, 347 (2002), pp. 1825-1833
  3. S.D. Corley, A.E. Epstein, J.P. DiMarco, et al., AFFIRM Investigators Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study Circulation, 109 (2004), pp. 1509-1513
  4. Saksena S, Slee A, Waldo AL, Freemantle N, Reynolds M, Rosenberg Y, et al. Cardiovascular outcomes in the AFFIRM trial (atrial fibrillation follow-up investigation of rhythm management). An assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched analyses. J Am Coll Cardiol 2011;58:1975–85. https://doi.org/10.1016/j.jacc.2011.07.036
  5. Doyle JF, Ho KM. Benefits and risks of long-term amiodarone therapy for persistent atrial fibrillation: a meta-analysis. Mayo Clin Proc 2009;84:234–42. https://doi.org/10.1016/S0025-6196(11)61140-3
  6. van Erven L, Schalij MJ. Amiodarone: an effective antiarrhythmic drug with unusual side effects. Heart 2010;96:1593–600. https://doi.org/10.1136/hrt.2008.152652
  7. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet 2017;389: 1941–52. https://doi.org/10.1016/S0140-6736(17)30866-8
  8. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet 1997;350:1417–24. https://doi.org/10.1016/S0140-6736(97)05281-1
  9. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997;30:791–8. https://doi.org/10.1016/s0735-1097(97)00220-9
  10. Tsaban G, Ostrovski D, Alnsasra H, et al. Amiodarone and pulmonary toxicity in a contemporary population of atrial fibrillation patients, a nationwide Israeli study. Eur Heart J 2024;45:ehad726. https://doi.org/10. 1093/eurheartj/ehad726
  11. Su VY, Hu YW, Chou KT, Ou SM, Lee YC, Lin EY, et al. Amiodarone and the risk of cancer: a nationwide population-based study. Cancer 2013;119:1699–705. https://doi.org/10.1002/cncr.27881
  12. Rasmussen PV, Dalgaard F, Hilmar Gislason G, et al. Amiodarone treatment in atrial fibrillation and the risk of incident cancers: a nationwide observational study. Heart Rhythm 2020;17:560–6. https://doi.org/10.1016/j. hrthm.2019.11.025
  13. Ruzieh M, Moroi MK, Aboujamous NM, et al. Meta-analysis comparing the relative risk of adverse events for amiodarone versus placebo. Am J Cardiol 2019;124:1889–93. https://doi.org/10.1016/j.amjcard.2019.09.008
  14. Piccini JP, Berger JS, O’Connor CM. Amiodarone for the prevention of sudden cardiac death: a meta-analysis of randomized controlled trials. Eur Heart J 2009;30:1245–53. https://doi.org/10.1093/eurheartj/ehp100
  15. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial. Eur Heart J. 2022 Mar 21;43(12):1219-1230. doi: 10.1093/eurheartj/ehab593. PMID: 34447995; PMCID: PMC8934687.
  16. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021;42:373–498. https://doi.org/10.1093/eurheartj/ehaa612