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2 decades of AF
A Cardiology Today Editorial Board member discusses progress in the management and treatment of atrial fibrillation.
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Editor’s Note: Cardiology Today is celebrating its 20th anniversary in 2017. We are reaching out to experts in cardiology for their take on changes in CV medicine since the publication launched in 1997. In this issue, Albert L. Waldo, MD, PhD (Hon.), focuses on atrial fibrillation.
There have been some very important studies concerning AF that were initiated and completed in the last 20 years. Perhaps foremost is the AFFIRM trial, which started in 1995 but it ended in the 21st century. It was the first study that prospectively compared trying to maintain sinus rhythm in people with AF and risk for stroke vs. a strategy of anticoagulation and ventricular rate control. Until that time, the approach had always been to prioritize keeping the patient in sinus rhythm, with rate control as a fallback option.
Rhythm control vs. rate control
The AFFIRM trial showed for the first time that there is no difference in all-cause mortality between the two strategies. In fact, presumed benefits of rhythm control over rate control treatment strategies — fewer symptoms, better exercise tolerance, a lower risk of stroke, eventual discontinuation of long-term anticoagulant therapy, better quality of life, and better survival — if sinus rhythm could be maintained were not realized, leading to the conclusion that rate control was a legitimate primary therapeutic option. This was very important, and was confirmed by RACE and several small studies.
Another important study was AF-CHF, which examined whether there was a difference in CV mortality between the rhythm control and rate control strategies in patients with AF and congestive HF. The hypothesis (and expectation) was that in patients with congestive HF, restoring and maintaining sinus rhythm would reduce CV mortality by 25% compared with a rate control strategy, ie, that it would be far better to be in sinus rhythm. When the trial ended, again there was no difference between strategies.
And again, it showed that even in patients with HF, rate control was a legitimate primary therapeutic option. Why did that happen? In large measure, it’s because in the 21st century we learned how to treat HF so much better. We learned to use beta-blockers; we learned to use afterload reduction. The comorbidities were remarkably well-treated. The great majority of patients were taking the appropriate medications, including warfarin. That made such a big difference in outcomes.
An AFFIRM substudy compared the efficacy of all the known antiarrhythmic drugs against each other to see which, at the end of 1 year, was best for maintaining sinus rhythm. At 80 of the 213 sites, all patients randomly assigned to the rhythm control arm were further randomly assigned to amiodarone, sotalol or a class 1A or 1C antiarrhythmic drug. Amiodarone easily beat out all the others in terms of patients who remained in sinus rhythm on their assigned drug and without cardioversion at 1 year. But the lesson learned was that 80% of patients were still in sinus rhythm at 1 year and still did well even if they required cardioversion or were switched to a different antiarrhythmic drug. This suggested that occasional AF recurrence is not ipso facto failure. The bigger concern is frequent recurrence. Similarly, in AF-CHF, for those assigned to the rhythm control arm, there was no difference in outcomes between those who were in sinus rhythm the vast majority of the time vs. those who were in AF the vast majority of the time. The lesson learned is that if you maintain anticoagulation and treat the comorbidities well, most patients with AF will have similar outcomes with either a rhythm or a rate control treatment strategy.
New oral anticoagulants
The trials that led to the approval of four non-vitamin K oral anticoagulants — dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Janssen Pharmaceuticals), apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and edoxaban (Savaysa, Daiichi Sankyo) — showed that these the drugs were as good as or better than warfarin, which is very important. When initiating oral anticoagulant therapy in patients with AF and stroke risk, it can take as long as 5 weeks to get a patient in therapeutic range on a stable dose of warfarin. And then it is hard to maintain therapeutic range, whereas the newer drugs offer protection against stroke within 2 to 4 hours of administration. In addition, management of warfarin is difficult because it interacts with so many foods and drugs. That is not the case for these newer drugs, which represent a very important advance in most respects.
Some new antiarrhythmic drugs have been approved in the past 20 years, including dofetilide (Tykosin, Pfizer) and dronedarone (Multaq, Sanofi). They are good additions, but AF still tends to recur. If recurrence is infrequent, I am willing to leave my patients on these drugs even if they require an occasional cardioversion.
Mechanisms of AF
We have also learned much about the mechanism of AF in the past 20 years. In 1998, it was shown that AF is usually preceded by triggers primarily coming from the pulmonary veins. To this day, the only AF ablation technique that is universally accepted is isolation of the pulmonary veins, because if the triggers can’t get out to the atria to incite the AF, sinus rhythm has a reasonably good chance of being maintained, sometimes with the help of antiarrhythmic drug therapy.
But understanding AF mechanism(s) remains a challenge because most mapping technologies don’t have sufficient recording resolution to sort this out. There is a lot of ongoing research, and a lot more to be learned. It is generally believed that AF is due to one or more drivers, either focal or re-entrant. Recently, our group has done intraoperative mapping of the atrial epicardium in patients with persistent and long-standing persistent AF, and found a new paradigm of AF due to multiple atrial focal and breakthrough sites (four to six per patient) generating atrial activation at very fast, but different rates, resulting in collision and fusion of wave fronts which maintain AF. When we well understand its mechanism(s), improved AF treatment, especially AF ablation, will follow.
AF ablation
The current status of AF ablation is that it is largely empiric. The technology is far ahead of the science. As of now, ablation seems to work best in patients with new-onset AF, especially if they are young and have no comorbidities. AF recurrence rates at 1 year are about 40% for patients with paroxysmal AF and about 70% for patients with persistent or long-standing persistent AF.
The biatrial maze surgical ablation procedure is also largely empiric. It has evolved and grown in use as a treatment for AF during the past 20 years. AF recurrence rates are similar to that following catheter ablation, although more recent data indicate the AF recurrence rate is about 30% to 35%. However, of interest is a study published in 2015 in The New England Journal of Medicine. Patients with AF requiring mitral valve surgery were randomly assigned to AF maze ablation or no ablation during the procedure. Those in the ablation group were further randomly assigned to pulmonary vein isolation alone or the biatrial maze procedure, which included pulmonary vein isolation plus other lesion sets. There was no significant difference in the rate of freedom from AF between patients who underwent pulmonary vein isolation alone and those who underwent the biatrial maze procedure. In the end, we get back to the notion that understanding AF mechanism(s) is key.
– Albert L. Waldo, MD, PhD (Hon.)
Cardiology Today Editorial Board Member
Case Western Reserve University
University Hospitals Cleveland Medical Center
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Disclosure: Waldo reports consulting and/or speaking for Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Pfizer and St. Jude Medical.