Consider rate control, individualized care for patients with AF

In the second part of Cardiology Today’s Round Table on Atrial Fibrillation, an expert panel describes the challenges of treatment decision related to AF.

“Have more respect for AF,” participant Albert L. Waldo, MD, advised cardiologists.

Carl J. Pepine, MD, moderated the November discussion that also included Peter Kowey, MD; Bernard Gersh, MB, ChB, DPhil; Andrew Epstein, MD; and Douglas P. Zipes, MD, during the American Heart Association’s Scientific Sessions in New Orleans. Here, in part two, the participants discuss the importance of anticoagulation, rate vs. rhythm control and drugs available and in the pipeline.

“A treatment plan takes time and thought, and no two patients are exactly alike … don’t sell rhythm control short,” Waldo said.

Part one, which appeared in last month’s issue, considered the prevalence of AF, research, treatment strategies and new drug development.

Carl J. Pepine, MD, Professor of Medicine, University of Florida, Gainesville: Recently, I was at a meeting on drug development for a new factor 10a inhibitor and the group leader said, ‘AF is too difficult a target.’ Why is there this perception?

Peter Kowey, MD, Chief, Division of CVDs, Lankenau Hospital and the Main Line Health System: First, they would have to go against warfarin using a non-inferiority design with a relatively low number of events. The inferiority margins that the FDA requests are very narrow. Second, we are all concerned about safety especially for direct thrombin inhibitors, where liver toxicity has been an issue. The intensity of liver monitoring during the course of these trials needs to be very high. Thirdly, there’s the dose issue, which usually comes from noncardiac experience like deep vein thrombosis. Venous thromboembolism is different than arterial thromboembolism and extrapolating the dose from this situation to AF can be problematic.

Pepine: Who you anticoagulate is a critically important question for practice. How comfortable are we with CHADS?

Kowey: The HRS is doing this initiative called AF 360. At the American College of Cardiology 2008 Scientific Sessions, we asked 300 to 400 people about CHADS since it is in the current guidelines. The number of incorrect answers was amazing. Even though I’m not very comfortable with CHADS, my fear is that if we go into anything more complicated people will not know what to do.

Douglas P. Zipes, MD, Distinguished Professor, Indiana University School of Medicine: There was an epidemiologic study in Heart Rhythm (Bennett and Walker, October 2008) examining more than 100,000 patients ≥40 years old with an insurance claim for AF or atrial flutter between 1999 and 2005. Warfarin was prescribed in only 45% of cases and 48% of cases had no claim for any anticoagulant or antiplatelet agent.

Pepine: What criteria do you think they use?

Albert L. Waldo, MD, Walter H. Pritchard Professor of Cardiology, Professor of Medicine and Biomechanical Engineering at Case Western University School of Medicine: CHADS₂.

Bernard Gersh, MB, ChB, DPhil, Professor of Medicine, Mayo Clinic, Rochester, Minn.: The ACC, American Heart Association and European Society of Cardiology guidelines endorse CHADS … I don’t really believe that you can draw up guidelines that apply from Bulgaria to Alaska. But why did they change the age cutoff from 65 to 75 years old? When I treat physician colleagues I say look, we originally said 65 years old, but we didn’t really have much data and now they’ve changed it to 75 years and you’re in that gray zone between 65 and 75. What do you think about taking warfarin? My colleagues still choose to go on warfarin.

Waldo: You should use warfarin. But you know, the European survey also confirmed exactly what Peter said earlier, not only don’t physicians use it when it’s indicated, they often use it when it’s not indicated.

Pepine: Yes, there are a lot of misperceptions not only about rate vs. rhythm, but also about anticoagulation.

Gersh: We also have to realize that it depends on the nature of the population comprising the bulk of a given physician’s practice. If you are practicing in an area where most of your patients wear a steel hat and that’s their occupation, you may anticoagulate a lot less people than if you’re taking care of a bunch of physicians.

Pepine: So, let’s discuss the currently approved drugs that we have and the new ones on the way.

Zipes: The most exciting drug is dronedarone (Multaq, Sanofi Aventis).

Gersh: It looks like amiodarone without some of the baggage.

Waldo: But it may not have quite the efficacy of amiodarone.

Kowey: Current therapy is limited and we have to deal with lots of issues with propafenone (Rythmol, GlaxoSmithKline), flecainide, sotalol, dofetilide (Tikosyn, Pfizer) and amiodarone. Each one has its limitations and niches. In each case we worry about safety. The most exciting thing we’ve seen for several years is what’s happened in ATHENA and the fact that dronedarone not only appeared to be a good atrial antiarrhythmic, but it had excellent safety as well.

Pepine: I was also impressed when I saw the decrease in ACS hospitalizations.

Gersh: What about the decrease in sudden death?

Kowey: That is interesting and needs to be explored further.

Pepine: Alright, let’s move to the newer, exciting drugs.

Kowey: There’s two major pathways that development has taken. One is to try to take amiodarone (Cordarone, Wyeth) and change it because it’s such an interesting drug and it has such interesting multichannel effects. The other, as you suggested, is to try to develop something that perhaps is a bit more atrial specific. Dronedarone is the first amiodarone congener. Vernakalant (Cardiome Pharma) is the lead compound for relative atrial specificity, although it’s not completely atrial-specific, and it’s multichannel. The IV formulation is still under regulatory review and the oral hasn’t entered phase-3 trials yet.

Zipes: It is not as multichannel as amiodarone or dronedarone. Vernakalant is an IKur blocker with sodium channel-blocking activity.

Kowey: Correct, but it has a substantial sodium channel effect in the atrial muscle.

Zipes: My argument for years is that to make a drug that blocks a single or two channels is wrong. You’re trying to create electrical homogeneity and the best way to create heterogeneity is to block one channel because it’s not going to be uniform in every cell in the same fashion. That’s why dirty drugs like amiodarone — and now its daughter dronedarone — appear to be effective.

Andrew Epstein, MD, Professor of Medicine, University of Alabama at Birmingham: Years ago I heard a drug discoverer for one of the pharmas talk about amiodarone as ‘a dirty drug for a dirty problem,’ referring to sudden death. It’s really the same thing in the atria. There is not just one channel or substrate to target, and any new drug has to be not only effective for a complex disease but it also has to be safe.

Pepine: If it were safer it may have greater efficacy, right?

Zipes: And a drug that specifically blocks IKur is going to shorten atrial refractoriness, which may promote AF.

Pepine: What about cilavarone? How’s that look?

Kowey: It’s in phase-2. It’s once-a-day and has simpler kinetics.

Waldo: A substudy of AFFIRM showed when you choose a rhythm control strategy and AF recurs, if you cardiovert your patient and keep the patient on it or change to drug B, at the end of one year about 80% will be in sinus rhythm. AF recurrence per se is not failure. It’s the frequency of recurrence and the seriousness of the symptoms during recurrence that are the measure of efficacy. If you’re willing to cardiovert your patient from time to time, you can do very well. Dronedarone is not going to have 98% efficacy, but it might be good enough so that occasional recurrence is well treated with cardioversion rather than abandonment of the drug or rhythm control treatment strategy.

Gersh: That’s a really good point. We’re not dealing with ventricular tachyarrhythmias and we’re not dealing with sudden cardiac death. We’re dealing with AF and if once a year you end up being cardioverted and you have sinus rhythm for 95% of the year, that’s good enough. The time to first recurrence doesn’t really answer the problem.

Pepine: What take-home message do you have for our audience — mostly the non-electrician cardiologist — relative to AF?

Epstein: Because AF is associated with tremendous morbidity and mortality, we should protect the brain, anticoagulate people who have risk factors for stroke and then go after symptoms. This may mean rate control or rhythm control, but we need to keep all options open to prevent stroke.

Waldo: Have more respect for AF. To dismiss its treatment as just ‘anticoagulated rate control’ is too simplistic. A treatment plan takes time and thought, and no two patients are exactly alike. Finally, don’t sell rhythm control short.

Zipes: It’s a diffuse bag and you have to take care of a specific patient who has AF. Generalizations may not be applicable.

Gersh: Management needs to be carefully individualized with one ear tuned to new developments. We are likely to see some of these come to fruition in the next few years.

Kowey: I tell our fellows that the initial interview with a patient with AF is everything; what their expectations are, what their symptoms are like, and how one might want to map out their treatment.

You begin to broker with them and negotiate what the plan of treatment is going to be. They are difficult-to-manage patients, but they can be helped if we take the time to do it right.