binding, it takes a very long time to be eliminated from the body with a half-life of 52 to 100 days. Upon discontinuation of amiodarone therapy, pharmacologic effects could continue for 1 to 3 months (Florek & Girzadas, 2021). The importance to prescribers is to monitor for potential adverse effects which could dictate discontinuation of the medication. Despite being off amiodarone, continued monitoring needs to be done because of the long half-life. Amiodarone is also a potent inhibitor of the cytochrome P450 system, specifically the 3A4 and 2C8 pathways. When a medication is given along with amiodarone, the metabolism is inhibited (slowed) and thus the effect of the second medication is prolonged in the system. Some specific examples of this are related to the use of amiodarone with warfarin, when much smaller doses of warfarin are needed. For example, a dose of warfarin when combined with amiodarone may need to be as low as 2.5 mg daily versus a typical dose of 5mg daily. Monitoring the INR daily when the patient is inpatient and then following the patient closely outpatient is best practice. The range goal of INR for AF is 2.0 to 3.0, with a target of 2.5. Caveats to this include if the patient is at a higher risk of falls, then keeping the INR closer to 2.0 would be warranted. Another example of potential drug-drug interactions with amiodarone is with digoxin. Recall, digoxin has a narrow therapeutic index, thus toxicity can be seen quickly. Clinicians typically reduce the dose of digoxin by 50% and follow digoxin levels (Florek & Girzadas, 2021; Kumar, 2017). Amiodarone-induced pulmonary toxicity (APT) is noted in the literature. The pathophysiology related to APT is hypothesized to be related to the cytotoxic effects to type II pneumocytes/lung parenchyma and immune meditated mechanism in genetically predisposed patients, those with advanced age, in patients receiving doses greater than 400 mg per day for longer than 2 months or 200 mg per day for 2 years. Here, the patient can develop a chronic cough, dyspnea, bilateral inspiratory crackles, and interstitial infiltrates on CXR. Pulmonary fibrosis and acute respiratory distress syndrome can develop, although chronic interstitial pneumonitis is most common. The treatment of APT is stopping amiodarone with the initiation of corticosteroid therapy. Mortality from amiodarone-induced pulmonary toxicity has been reported to be close to 10%. Clinical practice implications include obtaining baseline CXR and pulmonary functions tests (PFTs) and repeating every 12 months or with advent of respiratory symptoms (Florek & Girzadas, 2021; Giardina & Zimetbaum, 2018). The chemical structure of amiodarone is similar to thyroxine with high iodine content. Patients can develop either hypothyroidism or hyperthyroidism from direct toxic effects on thyroid cells and inhibition of thyroid hormone production and binding. Hypothyroidism is normally treated with levothyroxine. Amiodarone can be continued based on the clinician’s recommendation. Hyperthyroidism is more difficult to treat and usually requires stopping amiodarone, and antithyroid medications may be needed. Patients on amiodarone should have baseline thyroid tests (TSH, free T4) with follow-up every 6 months (Florek & Girzadas, 2021). Anticoagulation Timing of initiating anticoagulation should be based on the time in AF and the patient’s risk stratification of thromboembolism with AF. The most widely utilized risk stratification the CHA 2 DS 2 ‑VASc scoring is utilized in patients with nonvalvular AF. For each clinical condition, age, or sex category, 1 point is given, with 2 points given for age > 75 and prior thromboembolism. The maximum score is 9:
As previously stated, amiodarone is taken up and stored in many tissues, one of which is in the skin, potentially leading to amiodarone-induced pigmentation (ceruloderma) as related to sun exposure. The typical appearance of the skin is caused by deposition of melanin and lipofuscin in the dermis causing a characteristic color of blue, referred to as “blue man syndrome” (Giardina & Zimetbaum, 2018). The occurrence of ceruloderma is seen in 1% to 3% of patients on chronic amiodarone therapy, preferentially affecting men. Patients are advised to avoid sun exposure. Complete resolution of the hyperpigmentation may take up to a year or more (Giardina & Zimetbaum, 2018; Rosenthal & Burchum, 2018). As previously noted, amiodarone is taken up into the liver tissue. Thus, patients should be closely monitored for hepatotoxicity with LFT elevation, including AST and ALT. These enzymes should be monitored at baseline and every 6 months. Approximately 25% of patients will experience a transient rise in serum aminotransferase concentrations. The incidence of elevated LFTs is associated more with the use of IV amiodarone and can be seen within 24 hours of administration or up to 3 days. The drug should be discontinued and, if possible, should not be reintroduced. Rarely, if there are no other alternatives to amiodarone, clinicians are advised to use the lowest possible dose of < 200 mg/day (Giardina & Zimetbaum, 2018). The nuances of amiodarone are important to review. Implications for amiodarone prescribing are numerous related to its chemical makeup, its lipid solubility, long half-life, and related side/ adverse effects. It is important to note that the side effects are dose and time related; hence the higher the dose and the longer length of use, the more closely the clinician will need to monitor for these side effects. As a result, a prescriber may decide to stop amiodarone after a period based on the risk- benefit on continued use. For example, if a patient develops AF postoperatively and converts to and maintains NSR, then amiodarone can be discontinued during outpatient follow up based on risk of recurrence of AF. As well, with permanent AF, amiodarone may be discontinued. Evidence-based practice! The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was a landmark trial that changed the management guidelines for AF by examining the management of AF. This trial enrolled 4,060 patients who were randomized to rate control versus rhythm control. The endpoint of the trial was “all-cause mortality.” The result of the trial was there was no survival advantage to DC cardioversion and antiarrhythmic drugs. Hence, rate control and anticoagulation were the priority with beta blockers and CCB. Digoxin was associated with higher all-cause, cardiovascular, and arrhythmia-related mortality, regardless of gender and presence or absence of HF. Follow-up post hoc analysis of the AFFIRM trial revealed more symptomatic heart failure in the rate control group, and patients were less symptomatic in sinus rhythm. Therefore, conversations between the provider and patient/family need to occur on survival benefit, presence of symptoms, heart failure, and cost of medications (Chung et al., 2020; Schub & Avital, 2021). ● Vascular disease (Angiographically significant CAD, previous myocardial infarction, PAD, or aortic plaque): 1 ● Age 65 to 74: 1 ● Sex (female sex): 1 The following recommendations are given for CHA 2 DS 2 ‑VASc scoring: 0 : No antithrombotic therapy, or therapy with low-dose aspirin (81–325 mg/day). 1 : Therapy with low-dose aspirin or oral anticoagulant (warfarin [INR 2.0–3.0], or direct oral anticoagulant). ≥2 : Oral anticoagulant recommended. (Chen et al., 2020; Chung et al., 2020; Heidenreich et al., 2021; Schub & Avital, 2021)
● Congestive heart failure: 1 ● Hypertension (> 140/90): 1 ● Age ≥75 years: 2 ● Diabetes mellitus: 1 ● Prior Stroke or TIA or thromboembolism: 2
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