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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - Based on presentations from the Canadian Cardiovascular Congress 2010

Montreal, Quebec / October 23-27, 2010

Reviewed and edited by:

Paul Dorian, MD, FRCPC

Professor of Medicine, University of Toronto, Toronto, Ontario

The goal of the treatment of atrial fibrillation (AF) is to determine why a patient is presenting with AF, and why, specifically now—in other words, are there any potentially reversible causes behind the AF? If underlying structural heart disease is present, it should be addressed independently of what is required to treat the AF. For ventricular rate control, the goal of treatment should be to improve symptoms and quality of life which are attributable to excessive ventricular rates, according to the new guidelines.

However, perhaps the most important goal in the treatment of AF is to reduce the risk of adverse cardiovascular (CV) outcomes, as pointed out by Dr. Brent Mitchell, Libin Cardiovascular Institute of Alberta, Calgary.

Rate and Rhythm Control

The new guidelines do not favour one approach over the other; as they stated, the two strategies are simultaneous as rhythm control also requires good rate control if a patient goes back into AF. Features which favour rate control include the presence of persistent AF; age (>65); hypertension; no history of heart failure (HF); and previous antiarrhythmic agent failure. If rate control is chosen, the primary goal is to improve symptoms and prevent deterioration of cardiac function associated with excessively rapid ventricular rates during AF and atrial flutter (AFl).

In the past, emphasis was placed on slowing the heart rate <80 bpm at rest; following publication of the RACE II trial results, where outcomes using strict rate control (<80 bpm at rest, <110 bpm with submaximal exercise) were not different than a more lenient approach (<110 bpm), the guidelines now recommend that physicians aim for a resting heart rate of <100 bpm.

As Dr. Mitchell noted, rate control is easier to accomplish than rhythm control and there is also less risk of inducing antiarrhythmic agent pro-arrhythmia. On the other hand, patients experience fewer symptoms with rhythm control and they enjoy better exercise tolerance; rhythm control also accomplishes rate control. The guidelines recommend rhythm control for patients with AF who remain symptomatic with rate control therapy or in whom rate control treatment is unlikely to control symptoms.

Agents recommended for rate control include the beta-blockers (BBs) and non-dihydropyridine calcium channel blockers (CCBs). Digoxin and digitalis should be reserved for sedentary patients, those with left ventricular dysfunction and as second-line therapy. In rate control, dronedarone is recommended as second-line therapy in the new guidelines; as suggested by Dr. Mitchell, dronedarone may be added for additional rate control in patients with uncontrolled ventricular response rates despite treatment with BBs, the non-dihydropyridine CCBs and digoxin. Amiodarone should only be used for isolated rate-control under exceptional circumstances.

Features that favour rhythm control include the presence of paroxysmal or newly detected AF; age <65; no hypertension but a history of HF exacerbated by AF; no previous antiarrhythmic agent failure; and more symptoms. If rhythm control is chosen, therapy goals should again be to improve symptoms and clinical outcomes, although these goals do not necessarily imply elimination of all AF.

Oral Antiarrhythmic Drug Therapy

As noted by electrophysiologist, Dr. Atul Verma, Southlake Heart Rhythm Program, Southlake Regional Health Centre, Newmarket, Ontario, the guidelines committee recommended the use of maintenance oral antiarrhythmic agents as first-line therapy for patients with recurrent AF in whom long-term rhythm control is decided. In terms of regimen choice, physicians must first determine whether the patient has normal or abnormal ventricular function. For normal ventricular function, first-line agents may include dronedarone, flecainide, propafenone or sotalol, although flecainide and propafenone should be avoided in patients with coronary artery disease (CAD) and they should be combined with an AV-nodal blocking agent, i.e. BBs or non-dihydropyridine CCBs (Figure 1).

Figure 1.

When these agents are contraindicated or fail, then second-line therapy should be amiodarone; if drug therapy fails, catheter ablation may be considered. For patients with abnormal ventricular function, physicians need to stratify patients according to their ejection fraction (EF), either >35% or =35%. For patients with moderately depressed EF, the guidelines indicate that either amiodarone, dronedarone or sotalol may be used, although sotalol should be used with caution in patients with borderline EF and it is contraindicated in women >65 tak
2).

Figure 2.

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In patients with low EF, amiodarone is the only agent currently recommended and again, catheter ablation may be considered if amiodarone fails. For the first time, the guidelines committee also indicate that physicians may consider intermittent, “pill-in-pocket” antiarrhythmic drug therapy for symptomatic patients with infrequent, longer lasting episodes of AF/AFl as an alternative to daily therapy, using a single dose of either flecainide 200 to 300 mg or propafenone 450 to 600 mg, taken together with a short-acting BB.

At the same time, the committee stressed that rhythm control does not replace the need for anticoagulation as there is no evidence that a reduction in AF with antiarrhythmic drug therapy reduces the risk of stroke or thromboembolic events, and patients must continue on antithrombotic therapy according to their individual thromboembolic risk.

ATHENA Findings

Exploring the evidence supporting dronedarone in the new AF treatment guidelines, Dr. Stuart Connolly, Professor of Medicine, McMaster University, the Population Health Research Institute, Hamilton, Ontario, reminded CCC delegates that suppression of AF with antiarrhythmic agents such as amiodarone and, less effectively, propafenone and sotalol has never been shown to improve CV outcomes. In fact, most of the class I antiarrhythmic agents have been associated with an increase in mortality.

Using agents available prior to 2009, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial findings also showed there was no effect of rate control on stroke risk. The AF-CHF trial of rate vs. rhythm control in HF and CHF showed that there was no benefit from rhythm control on CV outcomes either. With this as a background, the ATHENA (A Placebo-Controlled, Double-Blind Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d. for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter) study was an important trial because it was the first study of a single antiarrhythmic drug to suggest physicians can do more than improve symptoms in patients with AF/AFl. Patients randomized in the ATHENA study were typical of elderly AF/AFl patients seen in arrhythmia clinics across the country, most of who were in sinus rhythm at the time of randomization.

Some 4700 patients with non-permanent AF were randomized either to dronedarone 400 mg b.i.d. on top of standard therapy or to placebo, again on top of standard therapy. At a mean follow-up of 21 months, approximately 40% of placebo patients had had their first hospitalization for a variety of reasons including AF, HF, angina, and the need for a pacemaker. The addition of dronedarone to standard therapy reduced the primary end point of unplanned CV hospitali
% relative to controls (P<0.001) (Figure 3).

Figure 3.

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For the secondary end point of CV death, the same antiarrhythmic agent reduced CV death by 29% relatively to placebo, most of that benefit coming from a reduction in arrhythmic death by 45%. Overall, dronedarone reduced non-AF related hospitalizations by 14% and its safety profile was clearly demonstrated with no increase in total mortality relative to placebo.

ATHENA investigators also evaluated a small subgroup of patients with symptomatic HF (approximately 200 patients) as well as patients with EF<35% (approximately 175 patients). Importantly, these patients were stable and had not been recently hospitalized for HF, as Dr. Connolly emphasized.

Results showed that these patients also benefitted from the addition of dronedarone (although results were not statistically significant) and there was no hint of excess mortality as was observed in an earlier study of dronedarone involving patients with severe HF who had recently been hospitalized. Although not a secondary end point, investigators also observed about a 30% reduction in stroke among the dronedarone group, a finding that requires replication.

Thus, as Dr. Connolly concluded, unlike previous antiarrhythmic drugs, dronedarone reduced unplanned CV hospitalization or death along with several other important CV outcomes including CV death and arrhythmic death. The mechanisms by which the agent confers these benefits likely include suppression of AF, rate control, blood pressure-lowering effects, anti-adrenergic effects and coronary vasodilation.

Greater Emphasis on Stroke Prevention

Although stroke prevention has been a major component in AF management, efforts to that end have been suboptimal. This may have been partly due to warfarin itself, still the only available systemic anticoagulant approved for stroke prevention, which is a difficult and inconvenient drug to use. However, dabigatran, a direct thrombin inhibitor (DTI), has now been approved for stroke prevention as well. Compared to warfarin, dabigatran has the potential to cause fewer drug-drug interactions, there are no dietary restrictions governing its use and most importantly, it does not require regular international normalized ratio (INR) monitoring. Other emerging strategies include the factor Xa inhibitors such as rivaroxaban and apixaban, both of which are showing considerable promise in stroke prevention.

The 2010 guidelines place a greater emphasis on stroke prevention than ever before. Among their key recommendations was that physicians must first assess individual stroke and bleeding risk using a predictive index for stroke—the CHADS₂ is recommended—and a predictive index for blee
imilarly recommended. Once stratified, most patients require antithrombotic therapy (Figure 4).

Figure 4.

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Patients at very low-risk for stroke (CHADS₂ 0) should receive low dose ASA, while those at low risk (CHADS₂ 1) should receive either warfarin or dabigatran; although ASA is an option. Patients at moderate risk (CHADS₂ 2) should receive either warfarin or dabigatran. Most patients should receive dabigatran in preference to warfarin, generally at a dose of 150 mg b.i.d.

Patients with AF/AFl with stable CAD should receive antithrombotic therapy based on their stroke risk: ASA for CHADS₂ 0; oral anticoagulation for CHADS₂=1 (here, warfarin is preferred over dabigatran for those at high risk of acute coronary events). Hemodynamically stable patient with AF/AFl =48 hours or uncertain duration for whom electrical or pharmacological cardioversion is planned should receive warfarin or dabigatran for 3 weeks before and at least 4 weeks’ post-cardioversion. If AF/AFl persists or recurs, antithrombotic therapy using either oral anticoagulants or ASA as appropriate should be continued indefinitely.

Committee members made 15 separate recommendations for stroke prevention which deserve careful and thorough consideration.

Summary

AF is the most prevalent sustained cardiac arrhythmia seen in clinical practice today, affecting an estimated one-quarter of a million Canadians. The great majority of patients who develop AF do so secondary to some underlying CV disease condition which must to be investigated and treated independently of the AF. Improvement in symptoms and quality of life remain the main goals of AF management, but prevention of CV events is arguably even more important. For the first time, physicians can reduce the risk of unplanned CV hospitalization or death in AF/AFl patients through the use of dronedarone. Appropriate antiarrhythmic drug use still does not obviate the need for anticoagulation and most patients with AF/AFl require antithrombotic therapy.

Questions & Answers

Questions and Answers with Dr. Stuart Connolly, Professor of Medicine, McMaster University, Hamilton, Ontario and electrophysiologist/cardiologist Dr. Jean Champagne, Institut Universitaire de Cardiologie et Pneumologie de Québec, and Clinical Professor of Medicine, Université Laval, Quebec City, Quebec.

Q: What do you believe are the key indications for dronedarone in patients with AF?

Dr. Connolly: I think the key indications are as labelled by Health Canada which is for the prevention of CV hospitalization, as that is the effect most clearly demonstrated with dronedarone and presumably the most important one. Dronedarone has also been shown to reduce the recurrence rate of AF and slow the rate down, so it’s also useful for symptomatic control of AF. But what is new and impressive about the drug which none of the other antiarrhythmic drugs have been shown to do is its demonstrated effect on CV hospitalization, and there is fairly strong evidence of it having other benefits as well.

Dr. Champagne: For me, any patient with a comorbid condition is the kind of patient I would treat with dronedarone. Patients with a history of MI, angina, cardiomyopathy or diabetes are the kinds of patients I personally would put on first-line dronedarone, at least in this kind of patient population. Part of this is because other antiarrhythmics, including flecainide, propafenone and sotalol, have limited efficacy in AF and they can be associated with some serious side effects, including an increase in mortality. These agents may be fine if you are treating AF in the absence of any other problem but even in these patients, if they are very symptomatic, catheter ablation needs to be considered. In patients with comorbidities, ablation is less effective so again, you need to consider dronedarone. We know at least that it does not increase mortality risk and it might even decrease mortality, so it is a safer option.

Q: Based on findings from ATHENA, do you feel the goals of AF management should be changed and go beyond symptom improvement?

Dr. Connolly: I think they are already changing. Some still say AF management is all about symptoms but I see it differently. I think reducing CV hospitalization, although not as impressive as reducing mortality, is nevertheless a big step in the right direction. We used to say, “We got rid of AF,” but now that we have shown dronedarone reduced unplanned CV hospitalizations or death, ATHENA has moved the goalpost further ahead and I think AF goals are shifting. I’m hopeful we will be able to demonstrate that dronedarone reduces other important CV outcomes more clearly in future studies which we are now carrying out. Dr. Champagne: It all goes together. When you see patients with AF, they are not feeling well, their quality of life is diminished and so the first step you need to take is to make your patients feel better. If they feel better, they are going to stay out of the hospital more, have fewer ER visits and mortality is decreased. Patients may want to live longer but they also want to feel well and have a better quality of life. If your patients are experiencing serious side effects because of the drugs you’ve put them on, that is impairing their quality of life so it all comes down to quality of life, which is your main goal in the treatment of AF.

Q: If treatments, such as dronedarone are recommended in the guidelines but are not currently reimbursed, should reimbursement be changed, in your opinion?

Dr. Connolly: I think it should, yes. I think Canada is out of step with the rest of many other countries where the drug is already on national and provincial formularies, and for a good reason: this drug has unique properties that other antiarrhythmic drugs do not have and there are patients who would benefit from treatment with it, but they can’t afford the drug so they are not getting it. I think formularies have a strong motivation to save money and we need them to be able to do that; at the same time, we can’t go too far and not allow a demonstrated useful drug with different properties and a different spectrum of activity to go unsupported.

Dr. Champagne: I would hope that it would, although I know Le Conseil du Médicament will also be looking at how much it will cost them to reimburse patients for this drug. It may come down to a need to have restricted access to dronedarone. The fact is, few patients over the age of 65 have private insurance, they only have public insurance, and with public insurance, I am not going to be able to give the drug to many patients.