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The current status of amiodarone adverse event monitoring
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Amiodarone was discovered in 1961, but was not approved by the FDA until 1985. Although classified as a class III antiarrhythmic, amiodarone exhibits properties of class I, II and IV antiarrhythmics as well.
Amiodarone use has increased in recent decades after the CAST trial found increased mortality with class I antiarrhythmics in post-MI patients. Today, amiodarone is a widely used antiarrhythmic with FDA-approved labeling for the treatment of life-threatening ventricular arrhythmias. Amiodarone is also used off-label to convert and maintain normal sinus rhythm in patients with atrial fibrillation. In fact, current practice guidelines recommend amiodarone as first-line therapy in AF patients with hypertension and left ventricular hypertrophy, or HF, despite lack of FDA-approved indications for these uses.
Adverse effects and toxicities
Dave L. Dixon
Janice Kim
Although amiodarone is highly efficacious in maintaining normal sinus rhythm, its use is limited by a multitude of adverse effects and noncardiac toxicities (see Table 1 below). Approximately 15% of patients taking amiodarone will experience adverse effects within the first year of use and, with time, up to 50% will experience adverse effects with long-term use.
Several characteristics of amiodarone increase its capability to adversely affect the body, including high lipophilicity, a very long half-life of 58 days, extensive hepatic metabolism and a similar structure to thyroxine. Consequently, amiodarone affects multiple organ systems and can lead to toxicities of the liver, thyroid, lungs and eyes. Amiodarone also affects the central nervous and gastrointestinal system.
Although most adverse effects associated with amiodarone are manageable without stopping the drug, it may take months after discontinuation before an adverse effect is reversed due to the drug’s long half-life. Therefore, monitoring of patients receiving amiodarone therapy is essential to the early detection of adverse effects and toxicities.
Follow-up and monitoring
Patients on long-term amiodarone therapy should receive careful follow-up (eg, every 6 months) to identify the presence of potential adverse effects or toxicities. A thorough history of the patient’s complaints is essential, as patients on amiodarone can experience a variety of symptoms that can be incorrectly attributed to aging, AF or other medications. A physical exam can also help identify thyroid nodules, changes in vital signs, skin color or respiratory sounds.
The North American Society of Pacing and Electrophysiology (NASPE) provides minimum monitoring recommendations for clinicians who treat patients receiving amiodarone therapy (see Table 2). Of note, several tests are recommended before the initiation of amiodarone to ensure adequate comparisons are available for follow-up tests. Other tests (eg, ophthalmologic evaluation and ECG) are only necessary when clinically indicated. Serum amiodarone levels also may be obtained to help troubleshoot patients who are not responding to therapy and to assess adherence when compliance issues are suspected. However, it is important to note that serum amiodarone levels may not always correspond with pharmacological activity or toxicity.
Besides the NASPE monitoring recommendations, medication profiles of patients on amiodarone should be reviewed for potential drug-drug interactions. Amiodarone affects multiple CYP450 isoenzymes, but is a major substrate of CYP3A4 and inhibits CYP3A4 and CYP2C9, which can lead to increased concentrations of other drugs commonly used in cardiology patients (eg, warfarin, digoxin, simvastatin). In fact, patients already receiving warfarin at the time of amiodarone initiation may require as much as a 30% reduction in their warfarin dose to prevent over-anticoagulation.
Challenges, team approach
Amiodarone adverse event monitoring can be challenging because it is often unclear which clinician is responsible — the initial prescriber (often a cardiologist) or the primary care provider, who may see the patient more frequently. Coordination of care is important to ensure adequate monitoring and prevent monitoring duplication.
One retrospective analysis of 1,055 patients across 10 HMOs found only 50% of ambulatory patients had received appropriate thyroid and liver monitoring at follow-up. Amiodarone adverse event monitoring also is problematic outside of the United States, as a study of 58 new amiodarone users in New Zealand found baseline testing of thyroid and liver function was performed in only 61% and 44%, respectively. This trend continued at 6 months (thyroid, 32%; liver 41%) and 1 year (thyroid and liver, 35%).
Although the available evidence on amiodarone monitoring frequency is limited and primarily includes self-reported data from individual sites, there is much room for improvement to ensure baseline and follow-up monitoring are performed.
One potential solution under investigation is to utilize pharmacists to monitor patients taking amiodarone. Spence and colleagues evaluated a pharmacist-managed amiodarone program in a managed care setting and compared it with usual care. The intervention included 181 patients and the usual care group included 2,111 patients who were identified using prescription refill history. Patients monitored in the pharmacist-managed program were significantly more likely to receive appropriate laboratory monitoring and pulmonary function tests. Furthermore, a greater proportion of patients in the pharmacist-managed group was switched to a non-interacting statin or received a statin dose reduction when necessary. Researchers also found that every dollar invested in the monitoring service returned a $2 return on investment, based on the assumption that the ED visits and hospitalizations were avoidable. Although these results suggest there may be value in pharmacist-managed amiodarone monitoring clinics, the available literature is limited to small sample size and lack of a comparator group.
Early detection of amiodarone-associated adverse events is essential to limit a patient’s risk for developing significant adverse effects and long-term sequelae. Although it was hoped that other agents (eg, dronedarone) might provide a safer and equally effective option, amiodarone remains the rhythm control agent of choice for AF patients with HF and/or LV hypertrophy. Considering the poor adherence with monitoring recommendations, it may take a “team approach” to ensure patients on amiodarone are adequately monitored.
Disclosure: Dixon and Kim report no relevant financial disclosures.