Rate vs Rhythm for Post-op AF: Neutral Trial, Positive Message
John M. Mandrola, MD|April 19, 2016
Editor's Note: John M. Mandrola, MD, interviews A. Marc Gillinov, MD, who presented the Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery trial at the 2016 American College of Cardiology (ACC) scientific sessions on behalf of the Cardiothoracic Surgical Trials Network (CTSN).
John M. Mandrola, MD: Hi, everyone. This is John Mandrola from theheart.org on Medscape, here at the ACC meeting in Chicago. I'm pleased to have Dr Marc Gillinov, a heart surgeon at the Cleveland Clinic, lead investigator of the Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery trial, and a representative of CTSN. Welcome, Dr Gillinov.
A. Marc Gillinov, MD: Thank you.
Post-op AF Common
Dr Mandrola: Tell us about the impetus to do this study. I'm excited to learn why you did it.
Dr Gillinov: Postoperative atrial fibrillation (AF) in cardiac surgical patients is a huge pain. We know it's going to happen: 30%-50% of people get it.[2,3] We also know we probably cannot prevent it. It's like the sun rising in the morning; it's going to happen. The question is, if we can't reliably prevent it, how are we going to treat it?
As an electrophysiologist, you know better than I do that we have two broad options: rate control or rhythm control. Practice within my own group, within our hospital, around the country, and around the world varies enormously. We had no good guidance about how to choose between rate or rhythm control.
Dr Mandrola: The reason that postoperative AF is such a problem is that it does have an influence on outcomes, doesn't it?
Dr Gillinov: Yes. It's not innocuous. It is temporary, but people who get postoperative AF have greater morbidity, mortality, and resource utilization. It is associated with higher cost. They have readmissions. It's definitely an undesirable event.
Dr Mandrola: How did you go about answering this question? How did you even think about studying rate control, because it seems to me that most of the preventive measures have been rhythm control strategies.
Dr Gillinov: We said that most of the people going into heart surgery are going to be on beta-blockers anyway. So they already have some measure of rate control, but they still get AF afterward. We recognized that the two broad strategies, rate control and rhythm control, really can be simplified to beta-blockers vs amiodarone. The challenge, logistically, was that we don't know for sure who is going to get postoperative AF. We actually had to enroll and consent more than 2000 patients, wait to see what happened, and randomize them only when they did develop AF.
Dr Mandrola: You randomized them before the surgery?
Dr Gillinov: No. We consented and enrolled them before, but then they had their surgery. Then, for example, if at 2 AM they got AF, one of our stellar research nurses had to be available to randomize them at that point.
Dr Mandrola: Tell us more about the methodology. This was a true randomized controlled trial, wasn't it?
Dr Gillinov: Right. Of the 523 people who developed postoperative AF and were randomized, there was almost exactly half-and-half distribution of rate control vs rhythm control, meaning beta-blockers vs amiodarone, with or without cardioversion.
Dr Mandrola: Multiple centers?
Dr Gillinov: Yes, more than a couple dozen centers around the world, including Canada.
Dr Mandrola: What kinds of surgeries were performed?
Dr Gillinov: Forty percent were coronary artery bypass grafting or bypass surgery alone. The other 60% had valve surgery, which was either isolated or combined with coronary artery bypass grafting.
Dr Mandrola: That's an important thing, because you can then generalize the results to all of the different kinds of heart surgery.
Dr Gillinov: Right. Basically anyone undergoing heart surgery would fall into this group of patients.
Dr Mandrola: What were you looking at for the primary and secondary outcomes?
Dr Gillinov: The primary outcome was the number of days in hospital from the date of randomization until 60 days post-randomization. We chose that outcome because it captures the initial index hospital length of stay and also captures admissions and emergency department visits, and in a broad sense it serves as a surrogate for morbid events. We really couldn't power this to look at stroke, death, thromboembolism, bleeding. That would require thousands of patients.
Dr Mandrola: Why would it require thousands of patients? Because the event rates are pretty low with postoperative AF?
Dr Gillinov: Yes; thankfully, the serious complications and mortality have low event rates.
Dr Mandrola: What about some important secondary outcomes?
Dr Gillinov: We looked at virtually every kind of morbidity you can imagine. Mortality was 1% or less in both groups during the entire trial. All morbid complications, including bleeding in those who were anticoagulated and those who weren't, systemic thromboembolism, and cerebrovascular thromboembolism were all the same between groups.
Dr Mandrola: Tell us how the primary outcome and results ended up.
Dr Gillinov: It turned out that primary outcome, days in hospital, was exactly the same for rate control vs rhythm control. To my mind, since there was no cost to rate control, it's simpler, and it avoids the intolerance associated with amiodarone, it's pretty reasonable to say that rate control is a good first choice.
Dr Mandrola: There was some talk about the crossover. Tell us about that.
Dr Gillinov: About 25% of people in each group were, let's say, "nonadherent." The reason I'm not using the word "crossover" is because if you were in the rhythm-control arm and you did receive amiodarone, that's still there; that's still on board. If you were intolerant of amiodarone, did not complete the therapy because we stopped it, and switched to rate control, it wasn't a complete crossover because you still have the amiodarone on board.
Dr Mandrola: Was there crossover in both groups?
Dr Gillinov: Yes. About 25% of the rate-control patients went to rhythm control, primarily because of ineffectiveness of the rate control. That was okay, because that almost always occurred during the index hospitalization. It's a patient who's still on your service who you're seeing, saying, "This is an easy switch; let's add some amiodarone." In contrast, more than half of the patients taking amiodarone who needed to switch had to do so after discharge, when it's a little more complicated for them and us.
Dr Mandrola: I was struck that the percentages of non-AF, or percentages of sinus rhythm, were pretty close.
Dr Gillinov: Yes. No matter what you do, rate control or rhythm control, by 7 days post-randomization, about 90% of people are no longer in AF. By 60 days post-randomization, it's 94% and 98%, with a very slight edge to the rhythm control.
Dr Mandrola: The take-home message for me, the really striking thing, was that more than 9 out of 10 patients with either strategy were in sinus rhythm.
Dr Gillinov: Right. So we chase our tails, we keep them in the hospital, we make them NPO, we cardiovert them. Don't do all that stuff; make it easy.
Dr Mandrola: Before we discuss that, tell us about some of the study's limitations.
Dr Gillinov: When I say don't do all that stuff, that applies to the hemodynamically stable patient. One of the limitations is that we did not include people who were highly symptomatic or hypotensive. They developed AF, their heart rate is 180 beats/min, their blood pressure is 80/60 mm Hg. We cardiovert those people and take them to the ICU.
In addition, we were not powered to detect anticoagulant-related hemorrhage, central thromboembolisms, and cerebrovascular thromboembolisms. Those things were, as we discussed, uncommon in both groups. We really could not discern a difference.
Dr Mandrola: Based on your results, do you think that those trials are necessary, or do you think that this should influence and change practice right now?
Dr Gillinov: I think this should influence practice right now. Again, this is opinion, because the data show that rate control and rhythm control are equal on the primary endpoint. But I think it's very reasonable to consider using rate control first, and if that doesn't work, there's rhythm control. I think the next step is to address the anticoagulation issue. Which agents to give? Who needs it? Those answers are not yet known.
Dr Mandrola: Since you brought that up, what are the anticoagulation results of this trial?
Dr Gillinov: Because we don't have any firm data to answer the question of who should be anticoagulated, as a consensus among investigators, we anticoagulated people who were in AF for 48 hours continuously after randomization and people who had recurrent AF. I should say that we recommended anticoagulation, which was received by 43% in both groups.
Dr Mandrola: Do you have plans to study that issue in the future with the CTSN?
Dr Gillinov: We're discussing two different questions related to anticoagulation. One would be a trial of anticoagulation for postoperative AF vs no anticoagulation. That would be a striking trial. There's a bit of resistance to the idea of taking someone who's in AF, who's been in AF for 3 consecutive days, and then discharging them on no anticoagulation, even if they have a high CHAD score.
That's a tough sell. It might be easier to compare warfarin anticoagulation with one of the newer anticoagulants, which are much easier for the patients to manage. The sort of subquestion there is, when can you start a novel oral anticoagulant drug after heart surgery? When is it safe?
Dr Mandrola: When is it safe?
Dr Gillinov: I don't know, but I'd like to do that trial.
Dr Mandrola: To close, you mentioned to me that one of your favorite treatments of post-op AF is time.
Dr Gillinov: Yes. It's going to go away almost no matter what. It's hard to do nothing, but be patient as the inflammation goes away along with whatever else heart surgery stirs up. It fades away. Just as your scar on your chest heals, the AF will more or less go away. Therefore, I'm not going to chase my tail cardioverting people and putting them through all kinds of procedures. I'm going to give them a beta-blocker and watch it go away.
Dr Mandrola: That's great. Thanks for joining us.
Dr Gillinov: My pleasure.
Dr Mandrola: That's it from the ACC sessions. This is John Mandrola from theheart.org on Medscape.
A. Marc Gillinov, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Abbott Cardiovascular Systems, Inc.; AtriCure, Inc.; Edwards Lifesciences; Onyx Pharmaceuticals, Inc.; ClearFlow Inc.
Serve(d) as a speaker or a member of a speakers bureau for: St. Jude Medical; Medtronic
Received research grant from: St. Jude Medical; Tendyne Holdings, Inc.
Received income in an amount equal to or greater than $250 from: Abbott Cardiovascular Systems, Inc; AtriCure, Inc.; Edwards Lifesciences; Onyx Pharmaceuticals, Inc.; ClearFlow Inc; St. Jude Medical; Medtronic; Tendyne Holdings, Inc.
Gillinov AM, Bagiella E, Moskowitz AJ, et al; CTSN. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. N Engl J Med. 2016 Apr 4. [Epub ahead of print]
Creswell LL, Schuessler RB, Rosenbloom M, Cox JL. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg. 1993;56:539-549. Abstract
Echahidi N, Pibarot P, O'Hara G, Mathieu P. Mechanisms, prevention, and treatment of atrial fibrillation after cardiac surgery. J Am Coll Cardiol. 2008;51:793-801. Abstract