Pharmacology Update: Non-antiarrhythmic Medications for the Treatment of Atrial Fibrillation

In this interview we speak with Maya Guglin, MD, PhD, FACC about the possible uses of non-antiarrhythmic medications for atrial fibrillation (AF). Dr. Guglin is the Director of Heart Failure and Associate Professor of Medicine at the University of South Florida.

How often are antiarrhythmic medications used in the treatment of AF? Has there been any decrease in the use of antiarrhythmic medications? Do you think procedures such as ablation have been more commonly utilized for the treatment of AF in recent years? Antiarrhythmics in atrial fibrillation are still frequently used, though not as much as before. Just 5 or 6 years ago, the typical scenario in atrial fibrillation was as follows: Patient presents with new onset of atrial fibrillation. We admit him or her, perform an echocardiogram to make sure the heart is structurally normal, then restore normal sinus rhythm with electrical cardioversion and discharge the patient from the hospital. In a couple of years atrial fibrillation recurs, so the patient is admitted again and started on flecainide or propafenone; he or she converts back into normal sinus rhythm and is discharged. In a year this same person comes back with recurrent atrial fibrillation, so we discontinue antiarrhythmics, get the patient started on sotalol, then cardiovert and discharge. The cycle repeats with dofetilide, and finally with amiodarone. However, this almost does not occur anymore. We are more easily able to accept chronic atrial fibrillation and stop the attempts much sooner to keep patients in sinus rhythm at any cost, especially if the rate is well controlled. It took a while for the findings from the AFFIRM and RACE trials to sink in, but eventually the message came through: in giving antiarrhythmics for maintenance of sinus rhythm, we do not prolong life or make life better. However, it still seems counterintuitive, so we usually give it one or two tries, but we are not nearly as persistent as before. At the same time, ablations are becoming more and more common as electrophysiologists gain experience, confidence, and skill. However, there is a deep controversy between two main points. On one hand, treating atrial fibrillation with antiarrhythmics in order to restore and maintain sinus rhythm does not translate into a better quality or greater quantity of life. On the other hand, atrial fibrillation itself is associated with a worse prognosis and worse survival. Therefore, there are only two ways to explain this. Firstly, we treat atrial fibrillation by the wrong means. Antiarrhythmics cause side effects that offset the benefits of being in normal sinus rhythm, so the logical step is to try something different (e.g., ablation). Secondly, atrial fibrillation does not shorten life by itself, but is a marker of poor cardiovascular health, associated with higher morbidity and mortality. If this is true, then ablation is not going to help, although we do not know yet and we are hopeful.

What are some of the complications found when using antiarrhythmics? What antiarrhythmics are most commonly used in EP today? The most commonly used antiarrhythmic is amiodarone, and the list of complications is such that patients get scared when they look it up. It can adversely affect almost every system in the body, except for maybe the kidneys. Most of the side effects are dependant on the cumulative dose of amiodarone, so we try not to prescribe it chronically in patients younger than 75 years of age; the idea is that older people will not live long enough to develop complications from this drug. However, complications still happen, especially with the most severe and poorly reversible side effects of amiodarone, such as pulmonary fibrosis and hepatic failure. They do not occur often, but when they do, it is difficult to explain to patients why we insisted on this therapy if there are no data that it improves or prolongs quality of life. Dofetilide and sotalol prolong QT interval and increase the risk for torsades de pointes. These medications have to be started in the hospital. In addition, dofetilide has multiple interactions with other medications, and the dose has to be adjusted for kidney function. Not every physician can prescribe dofetilide, so if one does, they invariably will get several phone calls from the pharmacy with questions and suggestions…but this is “side effect” for doctors, not for patients.

What non-antiarrhythmic medications were discussed in your article? What are these drugs normally prescribed for? Of the non-antiarrhythmic medications we reviewed (i.e., ACE inhibitors, spironolactone, statins), none are currently prescribed specifically to treat atrial fibrillation. ACE inhibitors or aldosterone antagonists are typically used for treatment of cardiomyopathy or cardiomyopathy with heart failure; they improve structure and function of the left ventricle, and indirectly reduce the burden of atrial fibrillation, in terms of primary prevention or recurrences. Statins are even more interesting, because they were initially introduced as cholesterol-lowering agents, but it appeared that they can accomplish much more…even prevent atrial fibrillation. I was interested to see that fish oil, oral steroids, and statins were studied for their anti-arrhythmic effects. Tell us about these findings. To date, there have been almost no trials or controlled studies specifically designed to test the effect of non-antiarrhythmic medications on atrial fibrillation. Most of the data represent retrospective subanalyses of trials with large subsets of patients with atrial fibrillation but which were initially designed and powered to study different outcomes. Steroids have been shown to have a protective benefit in the perioperative atrial fibrillation. For example, in a double-blind, randomized, multi-center trial at three university hospitals in Finland, steroids taken before and for three days after cardiothoracic surgery reduced postoperative atrial fibrillation by 30%. This proves that postoperative atrial fibrillation is a different species, where inflammation may play a major role. There has also been interest in fish oil for its potential effect on atrial fibrillation. However, studies have not shown fish oil to be beneficial. In a study following over 5,000 participants from the Rotterdam study for 6.4 years, no significant correlation was found between either fish intake or omega-3 fatty acid intake and occurrence of AF. In another trial, the quintile with the greatest intake of fish oils actually demonstrated significantly more episodes of atrial fibrillation than the lowest quintile. Statins are different. They appear to perform well in virtually all scenarios: primary prevention of atrial fibrillation, perioperative setting, and prevention of recurrence after cardioversion. To me, they are more promising than any other non-antiarrhythmic medication. Their effect seems to be completely unrelated to their cholesterol-lowering activity. In a large cohort of patients with chronic stable coronary artery disease but not in atrial fibrillation followed for 5 years, statin therapy was associated with a significantly reduced risk of developing atrial fibrillation, with an odds ratio of 0.48.1 This association remained significant after adjustment for age, hypertension, left ventricular dysfunction, occurrence of heart failure or acute ischemic events, and baseline cholesterol level. Patients taking non-statin cholesterol-lowering medications did not have any anti-arrhythmic benefit.

Were there any side effects found in the non-antiarrhythmics mentioned? There are no medications free of side effects. Placebo is the safest of all drugs, but even placebo causes side effects — look at any placebo-controlled clinical trial. ACE inhibitors can cause angioedema, hypotension, renal dysfunction, or cough; spironolactone causes gynecomastia and hyperkalemia, especially in people with compromised renal function; and statins cause myopathy and elevated liver enzymes. However, side effects develop in the minority of patients.

How many trials were looked at in your research? We looked at everything we could find on PubMed starting from the early 1970s (https://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed).

Why is it important to consider non-antiarrhythmics as a new course of treatment? Is there a need for a major revision in the types of anti-arrhythmics that are prescribed? At this time, non-antiarrhythmics cannot be considered as a new course of treatment for atrial fibrillation. They work too slowly and facilitate anti-arrhythmic effect in too small fraction of patients. If you look at the trials we cite, it took thousands of patients and years of follow-up to find the difference in new onset or recurrent atrial fibrillation. I consider the anti-arrhythmic effect of non-antiarrhythmics as a sign that we can have more luck if we improve geometry and function of the left ventricle, rather than attacking arrhythmia directly. If you remember, there was the Cardiac Arrhythmia Suppression Trial (CAST) years ago. It seemed to be such a straightforward and logical concept: patients with myocardial infarction have many premature ventricular beats, and if they develop sustained ventricular tachycardia, they will die. So the theory was to give antiarrhythmics, reduce the number of premature ventricular beats, prevent sustained ventricular arrhythmias, and reduce mortality. However, when antiarrhythmics were given, the number of ectopic beats decreased, but mortality rates went up instead of going down. The human body is more complex and less straightforward than we think. Tell us about some of the newer research being done in trials such as the ONTARGET/TRANSCEND trial and the ACTIVE trial.

When can the results of these trials be expected? Results of ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) were presented at the American College of Cardiology meeting this year. The trial results showed that telmisartan is a well-tolerated treatment in high-risk cardiovascular patients that is as effective as ramipril in preventing heart attacks, stroke and hospitalizations for heart failure and deaths. To my knowledge, no data on atrial fibrillation were released. Using the same outcomes, TRANSCEND compares telmisartan to placebo for individuals who are unable to take ACE inhibitors because of intolerable side effects. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) program consists of three randomized controlled trials designed to compare the rate of strokes in different antiplatelet regimens in the treatment of atrial fibrillation. Only one of three arms studying irbesartan can potentially demonstrate some anti-arrhythmic effect of this drug.

Which of the non-antiarrhythmic agents do you think seem most promising? In which AF patients will this most benefit? The effect of ACE inhibitors and angiotensin-receptor blockers was modest. Statins look more promising, especially in the perioperative setting, but also for prevention of new onset atrial fibrillation.