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Dr. James Reiffel Discusses Afib Rhythm Control and Combining Ranolazine with Dronedarone

New Atrial Fibrillation Treatments and Rate vs. Rhythm Control for Afib — Video Interview with Dr. James Reiffel

Dr. James Reiffel Discusses Afib Rhythm Control and Combining Ranolazine with Dronedarone

By Mellanie True Hills

August 2, 2012

  • Summary:  Dr. James Reiffel discusses the treatment of atrial fibrillation with medications, including rate control vs. rhythm control, new drug combinations, and research into new afib drugs.
  • Reading and watching time is approximately 10 minutes

In this video interview at Heart Rhythm 2012, Dr. James Reiffel updates us on new directions in drug treatments for atrial fibrillation. He talks about the combination of ranolazine (Ranexa) and dronedarone (Multaq), both used in lower doses, and about other coming atrial-selective drugs. He also discusses the rate control vs. rhythm control decision, which varies by age and level of symptoms.

View the video interview with Dr. Reiffel (approximately 10 minutes)

About James Reiffel, MD:

Professor of Clinical Medicine
Columbia University College of Physicians & Surgeons

Attending Physician
New York Presbyterian Hospital

For more information, see Dr. Reiffel's profile

Video Transcript:

Mellanie True Hills: Dr. Reiffel, this is an honor to have you talking with us here at Heart Rhythm Society. You’re an expert in the use of medications for treating atrial fibrillation, and you’ve presented some very interesting ideas at some of the medical conferences lately. I appreciate you taking the time to share with us, the patient community. Let me just ask you, what are some of the interesting new directions in medications for treating atrial fibrillation?

Dr. Reiffel: Thank you for the opportunity, first of all. Second of all, there are interesting new opportunities. We know that, when we talk about antiarrhythmic medications to control atrial fibrillation — we need to either terminate it or prevent it — the current drugs are far from perfect. They work about half the time. They have side effects, which may or may not be well tolerated, may or may not be life threatening, so we’re looking for better agents. That search takes us in two directions.

One direction are agents that are brand-new in many respects. Agents that, for example, focus on channels in the atrium that are electrically active and play a role in fibrillation, either its development or its maintenance, that are not present or are relatively unimportant in the ventricle. So that if we develop agents that directed those channels and prevent them from contributing to atrial fibrillation, because they’re not present in the ventricle the drugs can’t have untoward effects in creating new rhythms in the ventricle, that we know is a process that many of our current drugs have.

The second is to combine drugs, perhaps in lower dose, to try to get additive efficacy but to reduce the risk or likelihood of adverse side effects because many of those are dose dependent. As an example, we can talk about two or three things. One, we have used off-label ranolazine, a drug that’s on the market for use in ischemic heart disease to control angina. It has properties that are antiarrhythmic, that are relatively atrial-selective, and we’ve used it for atrial fibrillation specifically, both for termination as a single large dose and for prevention in a small number of patients in a pilot study where its efficacy was as high as anything else that we use frankly. About 70% of patients with or without heart disease convert with a single dose of the drug, even in recent-onset atrial fibrillation. It’s an agent that has no significant organ toxicity, that does not promote ventricular arrhythmias, and so its safety profile is quite good. It’s currently being studied in a pilot study in combination, in lower dose, with dronedarone, in lower dose. Dronedarone is a drug — the brand is Multaq on the market — for atrial fibrillation specifically, but which in patients with advanced structural heart disease, with heart failure, has some significant detrimental and potentially life-threatening effects. So we’re looking at combinations of ranolazine and dronedarone to take advantage of additive potential efficacy. Now we’re in a pilot study, but with plans to move forward to a large phase three trial if the pilot is positive, and that currently is enrolling in several countries.

There are drugs, as I said, that are selective for the atrium. Those have been under development by a number of companies now for a while. One of them is available in Europe for intravenous cardioversion, and that’s a drug called vernakalant — that’s the generic name — and it is effective in atrial fibrillation, parenthetically not in flutter. It converts about half the patients with fibrillation of relatively recent onset — three hours to seven days or so, about half the time, with an average conversion time of between eight and 12 minutes, so that’s pretty rapid. It’s not yet available in the United States, but as a model of other drugs holds some promise. It, too, is going to be studied for oral preparations for long-term prevention, and its focus is on channels in the atrium that are not significant in the ventricle, and so should be at much lower risk of creating adverse ventricular arrhythmias than our current drugs.

We also have to focus on toxicity, so with our current agents, not only do we worry about creating ventricular arrhythmias, which can be dangerous, but toxicity. Amiodarone, which is pretty effective for atrial fibrillation, can affect the eyes, skin, liver, neurological system, thyroid, and many organ systems. Some of those can be quite debilitating, if not fatal. It slows the heart rate, requires pacemaker implantation in some patients. Our new agents, we’re hoping, are devoid of that kind of toxicity.

We know with dronedarone, for example, rare cases of liver involvement, but no lung, no thyroid, no eye. Ranolazine has had no organ toxicity at all. So that combination — again if a lower dose in combination is efficacious, free of ventricular arrhythmias, the combination we know will be essentially free of organ toxicity — that holds a lot of promise. So we look forward, in the next couple of years, to advancing this knowledge base substantially. There’s a company in Europe, called Zention Discovery, that’s been working on some atrial-selective drugs — very early in development, but it holds a great promise.

Hills: Awesome. So let me throw you a curveball and ask you,  when is the right time to consider moving to rhythm control drugs off of the typical first treatment, which is rate control.

Dr. Reiffel: That’s not such a curveball. There are a couple of considerations. First, in the patients who are symptomatic, rate control may reduce the symptoms. It usually doesn’t alleviate the symptoms to an adequate degree, so for many patients — those who remain symptomatic despite adequate rate control — rhythm control needs to be considered and pursued.

Then there’s the consideration of what about the younger patient who may or may not be symptomatic. Let’s take someone who’s tolerating atrial fibrillation, their heart is normal, they have no structural heart disease. We know in any patient, the longer you let fibrillation persist, the more there are changes in the atria, called remodeling, that actually facilitate the maintenance of atrial fibrillation, and there comes a time when you can no longer reverse it if you would like to, by any means. We know patients in their 30s, 40s, or 50, who may be asymptomatic now, may not be asymptomatic if they should develop structural heart disease, when they develop hypertension, when they have angina, when they have their first heart attack. Things happen to patients as they get older. Many of us attempt rhythm control, even if the symptoms are minimal, in the younger patient because we’re concerned that if we don’t control fibrillation, they may become symptomatic as they age and get the cardiac disorders that come with age, and at that time, it will be too late to revert the fibrillation. So we do it sometimes in anticipation.

Now, if you were an 80-year old who came in with incidentally-detected atrial fibrillation and no symptoms, frankly I would let the fibrillation persist. I would rate control, I would anticoagulate, but I’m not worried about how it will be tolerated 40 years from now. I can’t say that about the 30 or 40 year old.

Hills: So do you consider things like shortness of breath while walking up stairs to be a symptom or is that, as people often think, just a sign that they’re getting older?

Dr. Reiffel: There’s only one way to know. Patients complain of palpitations. When we monitor them, roughly half the time there’s no rhythm disturbance, so even palpitations aren’t specific. That’s been known for a long time — the correlation between arrhythmias and palpitations isn’t very good because people sometimes feel their own heart beating when it’s beating normally, for whatever reasons — too much caffeine, anxiety, what have you. Shortness of breath, dizziness, fatigue, chest discomfort, are all non-specific — there are many things that can cause them, including atrial fibrillation. The only way you know whether the fibrillation is a cause or a bystander is to stop the fibrillation and see if the symptom gets better. If you put them in sinus rhythm and the symptom persists, they weren’t related. So I will always, in the symptomatic patient, pursue normal rhythm to determine whether the symptoms are mechanistically linked to the fibrillation. If they’re not, the impetus to control the fib may not be quite as strong. Again, age dependent, co-morbid disease dependent, but that’s an important consideration.

Hills: Thank you so very much taking the time to share this with us, and with the patient community. From Heart Rhythm Society’s 2012 convention, this is Mellanie True Hills for

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Last Modified August 2, 2012

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