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Expert Interview
When treating atrial fibrillation, when do you attempt rate control, and when do you attempt rhythm control?
Dr. Ezekowitz: Five clinical trials have compared the two strategies, and these studies agree that rhythm control offers no mortality benefit, but does offer a benefit in improving quality of life for the patient. So, in the first group of candidates for rhythm control are those who are significantly symptomatic.
The next group is patients who have new-onset AF, particularly if left atrial size is normal or not very much enlarged. Those patients generally are more likely to be successful with cardioversion, or restoration to sinus rhythm, than patients who have long-standing chronic AF with a very large left atrium.
A second motivation for attempting to cardiovert patients and maintain them in sinus rhythm is to prevent remodeling of the atrium—the permanent histologic changes that occur in the left atrium in patients with AF. These histologic changes affect the mechanical contraction as well as the electrical properties of the left atrium and make our attempts to maintain patients in sinus rhythm less likely to succeed. However, if you are fortunate enough to identify a patient early in the course of the disease, you can prevent left atrial remodeling by early cardioversion and can restore sinus rhythm.
Which antiarrhythmic agent works best to prevent AF: amiodarone or dronedarone?
Dr. Ezekowitz: I think the general agreement is that, on the efficacy side, amiodarone is the best available antiarrhythmic agent. The problem is that over time patients develop important side effects related to this drug, which accumulates in the body and produces liver toxicity, skin hypersensitivity, neurotoxicity and so forth.
Dronedarone has a similar mechanism of action to amiodarone, but does not contain the iodine moiety and is not as effective at restoring patients back to sinus rhythm or reducing episodes of AF. But in the classic ATHENA trial, dronedarone reduced cardiovascular death and hospitalization compared with placebo, so the indication for dronedarone is to reduce these two important endpoints. That trial involved patients with paroxysmal AF and excluded patients with permanent AF. ATHENA also included patients at entry who were in sinus rhythm but did have episodes of AF in the past.
Now, dronedarone should not be used in patients with chronic AF, patients who have had AF for more than 6 months, or in patients who have episodes of heart failure. The regulators are debating whether all forms of heart failure should be excluded, or just the more serious forms—New York Heart Association classses III and IV. But in general, we advise caution in patients with all forms of heart failure with respect to dronedarone.
Also, progressive liver toxicity has occurred in two cases, leading to a liver transplant, and in both cases the patient was being prescribed was dronedarone. So in the United States, the FDA has made the determination that voluntary liver monitoring is advised in patients on dronedarone to ensure that they are not developing any forms of liver toxicity.
What are your thoughts on dabigatran vs. apixaban vs. warfarin for stroke prevention?
Dr. Ezekowitz: We have an evolving debate now with the completion of two clinical trials. The first was the RE-LY trial, which compared dabigatran with well-controlled warfarin. The 150-mg dose of dabigatran resulted in a significant reduction in stroke and systemic embolism by 35% and reduction in intracerebral and intracranial hemorrhages. Dabigatran was very close to showing a reduction in all-cause mortality. The only negative is that the 150-mg twice-daily dose showed an increase in GI bleeding rate of 6 cases per 1,000 patients treated for 1 year.
All in all, RE-LY far exceeded the expectations of the trial when it was designed. In general, using dabigatran is preferable to using warfarin provided the patient’s creatinine clearance is above 30, in which case you use 150 mg twice daily. If the creatinine clearance is between 15 and 30, then based on the FDA’s approval document, you can use 75 mg twice daily.
As for apixaban, the ARISTOTLE trial also showed superiority against well-controlled warfarin. The benefit was striking with respect to reduction in all forms of intracerebral bleeding against well-controlled warfarin. The rates of ischemic strokes were similar—bear in mind that warfarin is very effective in reducing ischemic strokes as compared with placebo—but all the other secondary parameters were either statistically significantly better or trended toward better for apixaban.
Comparing apixaban and dabigatran is difficult without a head-to-head clinical trial. However, both options are outstanding alternatives to warfarin, and physicians would have to make decisions for individual patients as to which of these two novel agents they would use in comparison to warfarin.
That doesn’t mean to say that warfarin will go away entirely. Patients who have mechanical heart valves, pregnant women, women of reproductive age, children and patients who have very poor renal function or who are on dialysis can’t be treated with these novel agents. And also, some patients are well-controlled with warfarin, and physicians need to make individual decisions concerning the advisability of switching them to a novel agent.
In general, going forward, for the first time in 60 years we will have options as to which medications to use for stroke prevention. The good news is that ultimately millions of patients will benefit from effective stroke prevention measures.
Do you think aspirin has any role to play in stroke prevention in patients with AF?
Dr. Ezekowitz: I think the role for aspirin alone is absolutely minimal. In terms of stroke prevention for AF, the worst you can do is not treat the patient. The next worst thing is to treat them with aspirin, which is the least effective agent, and probably not at all effective in patients who are at high or intermediate risk. Then, aspirin plus clopidogrel is better than aspirin alone, but aspirin plus clopidogrel is not as good as any of the forms of anticoagulation. Stroke prevention in AF has become almost entirely an anticoagulation story, and the role of antiplatelet agents should be minimal with respect to this particular indication.