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Does cardioversion with amiodarone in the setting of a recent stroke increase stroke risk? 

Should patient be anticoagulated prior to cardioversion?

Background:

Cardioversion is the electrical or chemical process of restoring the heart’s normal rhythm and is often utilized in atrial fibrillation patients who have abnormal heart rhythms originating in the atria. Cardioversion can help to improve cardiac function and control the symptoms of atrial fibrillation which can include no symptoms to rapid heartbeat, shortness of breath, or fatigue.  Electrical cardioversion is the synchronized process of delivering electrical current to the heart which causes the heart cells to contract simultaneously and terminate the abnormal rhythm after which the heart is able to restore a normal heart beat¹.  Atrial fibrillation can be treated using rate-controlling drugs such as beta blockers, calcium channel blockers, digoxin that allow atrial fibrillation to persist or rhythm control which can help to maintain sinus rhythm and can be implemented with drugs such as amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, or sotalol.  The results of the AFFIRM trial indicate that managing atrial fibrillation with rhythm control strategy offers no survival advantage over the rate control strategy². 

Atrial fibrillation is one of the most common arrthmias and a major cause of ischemic stroke⁵.  The concern that arises is that during atrial fibrillation, is that there is a lack of complete heart contraction which can increase the possibility of blood clot formation in the heart, thus restoring a normal heart rhythm by cardioversion can dislodge the blood clot from the heart and lead to a heart attack or stroke.  This risk could be prevented by anticoagulation¹. 

Amiodarone Cardioversion Stroke Risk and Need for Anticoagulation

Amiodarone mechanism includes sodium, potassium, calcium channel, and noncompetitive b-blocking to maintain sinus rhythm, though serious adverse effects including increased stroke risk should be considered before initiating therapy⁵. 

In 1990, a case report of stroke after amiodarone cardioversion was reported in a 66 year old female patient with symptomatic paroxysmal atrial fibrillation for a duration of 5 weeks. The patient was not on any prophylactic antiarrhythmics, had hypertension, and not had previous ischemic heart disease or transient ischemic attacks. She was taking propranolol 160 mg daily for hypertension and eleven days after starting amiodarone the patient felt her heart rhythm change and had an improvement in symptoms.  Four hours later she developed sudden onset numbness and right-sided weakness with computed tomography confirming cerebral infarct³.

More recently, the 2013 FinCV study, focused on thromboembolic complications after cardioversion of acute atrial fibrillation lasting less than 48 hours. Embolic complications were evaluated during the 30 days after 5,116 successful cardioversions in 2,481 patients without oral anticoagulation or peri-procedural heparin therapy.  The results of the study indicate that there were 38 (0.7%; 95% confidence interval [CI]: 0.5% to 1.0%) definite thromboembolic events within 30 days (median 2 days, mean 4.6 days) after cardioversion which included 31 strokes. Additionally, 4 patients experienced a transient ischemic attack after cardioversion.  Independent predictors of definite embolic events included age (odds ratio [OR]: 1.05; 95% CI: 1.02 to 1.08), female sex (OR: 2.1; 95% CI: 1.1 to 4.0), heart failure (OR: 2.9; 95% CI: 1.1 to 7.2), and diabetes (OR: 2.3; 95% CI: 1.1 to 4.9).  The lowest risk was in no heart failure and age < 60 years patients (0.2%) and the highest risk of thromboembolism was found in heart failure and diabetes patients (9.8%).  The results show that even without anticoagulation embolic events are rare (<1%) within 30 days after cardioversion of acute atrial fibrillation with most embolic events occurring within 3 to 4 days after cardioversion, but the risk increases with increasing age, female sex, heart failure, and diabetes.  Results indicate that both the CHADS and CHADS2VASc were predictive for thromboembolism⁴. 

Published in 2015, a nationwide population-based cohort study in Taiwan of 7548 patients with atrial fibrillation were divided into two groups according to whether they received amiodarone.  Patient with a history of stroke who received amiodarone before the index date or the following 30 days, or those who experienced stroke within 30 days of receiving amiodarone were excluded.  The risk of ischemic stroke with amiodarone was 1.81 times (95% confidence interval [CI] 1.52–2.16), 1.79 times (95% CI 1.50–2.14), and 1.78 times(95% CI 1.49–2.13) higher without amiodarone in atrial fibrillation patients as shown by the statistical analysis of crude, Model 1, and Model 2 Cox proportional hazard regression models.  Additionally, the risk of ischemic stroke with amiodarone was higher in female patients and patients aged < 65 years, without comorbidities, who were also taking digoxin or had a low CHA2DS2VASc score.  The study concluded that treatment with amiodarone for atrial fibrillation is associated with an increased stroke risk and that digoxin and amiordarone increased the risks of stroke and the two drugs should be avoided together⁵. 

The Yapa 1990 case report highlighted that the risk of cerebral embolization after stroke is possible and anticoagulation should be started prior to treatment of atrial fibrillation with cardioversion³.  The AFFIRM trial also indicated that ischemic strokes occurred in 77 and 80 patients in the rate-control and rhythm-control groups, respectively (annual rate of approximately 1 percent per year in each group), with majority of strokes occurring in patients who had stopped warfarin or who had a subtherapeutic INR.  The rhythm control group included patients taking amiodarone and the trial suggested that the adverse effects of amiodarone might increase with longer use and continuous anticoagulation is recommended in atrial fibrillation patients with risk factors for stroke even when sinus rhythm is restored².  The Chen et al 2015 trial reported that antiplatelet agents and warfarin had a similar protective effect in decreasing the stroke risk of amiodarone and furthermore mentioned that to decrease stroke risk, atrial fibrillation patients receiving amiodarone should also receive oral anticoagulation therapy with warfarin or antiplatelet agents based on the CHA2DS2VASc score⁵.

The ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation provide the following anticoagulation recommendations for prevention of thromboembolism in patients with atrial fibrillation undergoing cardioversion.  Class 1 guidelines are as follows:

·         patients with atrial fibrillation of 48 hours or longer or for unknown duration of atrial fibrillation, anticoagulation is recommended at least 3 weeks prior to and 4 weeks after cardioversion regardless of electrical or chemical cardioversion method used (Level of Evidence B);

·         patients with atrial fibrillation more than 48 hours that require immediate cardioversion due to hemodynamic instability, heparin is to be administered concurrently by IV bolus and then a continuous infusion dose adjusted to prolong the aPTT 1.5 to 2x reference control, additionally, oral anticoagulation (INR 2.0 to 3.0) should be continue for at least for 4 weeks in patients with elective cardioversion (Level of Evidence: C); 

·         patients with atrial fibrillation less than 48 hours associated with hemodynamic instability (angina pectoris, MI, shock, or pulmonary edema), cardioversion should be performed immediately without delay for anticoagulation initiation (Level of Evidence: C) ⁶. 

Summary

Based on the limited evidence, it can be concluded that amiodarone cardioversion is associated with a risk of stroke though the risk can vary depending on patient factors.  Research studies and ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation recommend anticoagulation to prevent thromboembolism in patients with atrial fibrillation undergoing cardioversion.  As always, choice between anticoagulation should be continued to be based on patient factors.