Safety of antiarrhythmic drugs

COPENHAGEN, DENMARK. A team of Danish researchers report the results of a very large study aimed at determining the safety of antiarrhythmic drugs in a group of atrial fibrillation (AF) patients. During the period 1995 to 2004, 141,500 patients were discharged from Danish hospitals with a diagnosis of AF. Of these, 40,823 (28.9%) filled one or more prescriptions for antiarrhythmic drugs (AADs) – more specifically, flecainide (2.4%), propafenone (2.6%), sotalol (16.5%), and amiodarone (7.3%). Average (mean) dosages of the four drugs were 206 mg/day for flecainide, 411 mg/day for propafenone, 123 mg/day for sotalol, and 287 mg/day for amiodarone.

By the end of 2004, 62,173 members of the study group had died with 11,080 deaths (27.1%) in the group receiving AADs as compared to 51,093 deaths (50.7%) in the group receiving no AAD therapy. The annualized mortality rates in the AAD group were 2.5% for flecainide, 4.25% for propafenone, 5.29% for sotalol, and 7.42% for amiodarone-treated patients. It is worth noting that most deaths occurring in the flecainide and propafenone groups happened after discontinuation of the AAD therapy. Patients treated with amiodarone had a substantially higher incidence (55.6%) of heart disease, congestive heart failure, and previous heart attack than did those treated with flecainide (12.1%), propafenone (20.6%), and sotalol (29.5%).

A multivariable Cox proportional hazard model adjusted for age, gender, comorbidity and concomitant medical treatment showed that AAD treatment was associated with lower mortality than no treatment. The relative risk (compared to no treatment) of therapy with flecainide was 0.38, propafenone and sotalol was 0.65, and amiodarone was 0.94. The researchers conclude that therapy with flecainide, propafenone, sotalol or amiodarone did not increase mortality in a large group of unselected AF patients. They do indicate though that this favourable outcome is likely associated with a careful matching of type of AAD therapy to the patient’s comorbidities and age.

In an accompanying editorial, Dr. Jean-Yves Le Heuzey of the Georges Pompidou Hospital in Paris emphasizes that Class 1C drugs (flecainide and propafenone) should be avoided in patients with congestive heart failure, complete left bundle branch block, and/or coronary artery disease. He points out that, while today’s cardiologists are perfectly aware of this, this was not the case 20 years ago. He also suggests that the routine prescription of a beta-blocker with Class 1C drugs reduces the risk of inducing 1:1 right atrial flutter.

In a second editorial, Drs. Krishnamoorthy and Lip from the University of Birmingham review a number of previous trials which have found AADs to be associated with increased mortality and conclude, “The currently available AADs are neither highly efficacious nor completely safe in the treatment of AF patients.” They also point out that the use of digoxin for rate control increases the risk of death by 42% in patients with persistent AF.

Andersen, SS, et al. Antiarrhythmic therapy and risk of death in patients with atrial fibrillation: a nationwide study. Europace, Vol. 11, 2009, pp. 886-91
Le Heuzey, JY. The risk of antiarrhythmic drugs in atrial fibrillation: 20 years of controversies. Europace, Vol. 11, 2009, pp. 840-41
Krishnamoorthy, S and Lip, GYH. How safe is the antiarrhythmic drug therapy in atrial fibrillation? Europace, Vol. 11, 2009, pp. 837-39

Editor’s comment: It is clear that the safety of AADs is still an area of controversy, although the Danish study goes a long way toward proving that AAD therapy is superior to no therapy in AF patients. Of course, in the case of lone AF (no underlying heart disease) there is no evidence that Class 1C drugs are dangerous, or associated with increased mortality.