PALLAS Trial Demotes Dronedarone for Atrial Fibrillation

ORLANDO – A giant question mark now surrounds the antiarrhythmic agent dronedarone because of the drug’s surprisingly poor performance in a major randomized trial involving patients with permanent atrial fibrillation.

The hypothesis in the study known as PALLAS (Permanent Atrial fibriLLAtion Study) was that dronedarone (Multaq) would reduce major vascular events in patients with high-risk permanent atrial fibrillation (AF). Quite the opposite occurred. As a result, the international trial came to a screeching halt for safety reasons after only 30% of the planned 10,800 subjects were enrolled.

Prompting early termination of PALLAS was a disturbing 2.3-fold increase in the composite coprimary outcome consisting of stroke, MI, systemic embolism, or death from cardiovascular causes in the dronedarone group, compared with placebo-treated controls.

"It’s clear from our data that dronedarone should not be used in patients with permanent AF who have a high burden of vascular disease," Dr. Stuart J. Connolly, chair of the PALLAS steering committee, said in presenting the study results at the annual scientific sessions of the American Heart Association.

Dronedarone’s approved indication, based upon the results of the earlier ATHENA (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) trial, is to restore sinus rhythm and reduce hospitalizations for cardiovascular causes in patients with paroxysmal or persistent AF (N. Engl. J. Med. 2009;360:668-78). It is not approved for permanent AF.

The critical question now is whether the adverse results seen in PALLAS in patients with permanent AF apply to patients on dronedarone for the approved indication. Further data are needed in order to answer that question, but caution is appropriate, according to discussant Dr. Mark Estes III, professor of medicine at Tufts University and director of the cardiac arrhythmia center at Tufts Medical Center, Boston.

If physicians elect to initiate therapy with dronedarone, he said, they’d better make sure that patients possess the clinical profile of ATHENA-type patients: that is, paroxysmal or persistent AF and a low burden of vascular disease.

"Currently, I think patients taking dronedarone who fit the ATHENA profile should be monitored regularly – at least every 6 months – to ensure that they remain within the approved indication and don’t progress to permanent AF or new or worsening heart failure," Dr. Estes added.

Monitoring for progression from intermittent to permanent AF can be done quite easily by ECG, noted Dr. Connolly, chair of the PALLAS steering committee and professor of cardiology at McMaster University in Hamilton, Ont.

The impetus for organizing PALLAS was the finding in ATHENA that dronedarone not only decreased cardiovascular hospitalizations, it also reduced rates of death, MI, stroke, and systemic embolism in patients with intermittent AF, including the subgroup which developed permanent AF during the course of the study. These findings, along with dronedarone’s blood pressure–lowering and adrenergic blockade effects, encouraged investigators to think that the drug might also be beneficial in patients with permanent AF, a group for which there has been no effective therapy. And so PALLAS came about.

PALLAS participants had to be at least 65 years old and have had permanent AF for at least 6 months. They also had to have coronary artery disease, symptomatic heart failure, prior stroke or transient ischemic attack, peripheral arterial disease, and/or a left ventricular ejection fraction of 40% or less. Indeed, 69% of PALLAS participants had a history of symptomatic heart failure, compared with just 20% in ATHENA.

One possible contributor to the unfavorable outcomes in PALLAS was the fact that about one-third of study participants were on digoxin. Dronedarone increases the serum digoxin level, sometimes into a potentially toxic range. That could have played a causative role in the increased cardiovascular death rate, but it does not explain the puzzling increased risks of stroke and heart failure episodes, according to Dr. Connolly.

An important lesson provided by PALLAS, the cardiologist continued, is that the patient population with permanent AF is fundamentally different from others with AF.

"As cardiologists we’ve tended to think of AF as running along a continuum from short, intermittent episodes to more persistent episodes and finally to permanent AF, with some progression of vascular disease along the way. We think of it all as one disease process. This trial really makes us see that this is not the case. Something rather unique seems to have changed between the ATHENA-type population and the PALLAS population because of their dramatically different response to the same drug," he observed.

Simultaneous with Dr. Connolly’s presentation at the AHA meeting, the PALLAS results were published (N. Engl. J. Med. 2011 Nov. 14 [doi:10.1056/NEJMoa1109867]).

"It’s clear ... that dronedarone should not be used in patients with permanent AF who have a high burden of vascular disease."

In an accompanying editorial, Dr. Stanley Nattel of the Montreal Heart Institute referred to dronedarone in AF as a "Jekyll and Hyde" drug (N. Engl. J. Med. 2011 Nov. 14 [doi:10.1056/NEJMe1111997]). He said that exactly why dronedarone was so harmful in PALLAS and yet so beneficial in ATHENA may never be known for certain. Was the key factor in PALLAS the permanent AF, the high burden of vascular disease overall, the substantial prevalence of heart failure, or something else? Regardless, the PALLAS experience warrants a revised, far more limited role for dronedarone moving forward, according to Dr. Nattel.

Not only should dronedarone absolutely be avoided in patients with permanent AF, it should also be avoided in high-risk patients with intermittent AF, particularly if they have heart failure. If dronedarone is to be prescribed in patients on digoxin, dose adjustment of the digoxin is now clearly mandatory, he continued.

And the major guidelines for management of AF need to be reexamined. Since receiving marketing approval, dronedarone has figured prominently in the treatment algorithms for patients with paroxysmal or persistent AF. Now, however, it seems appropriate to reserve the antiarrhythmic for selected low-risk patients, and perhaps only those in whom other antiarrhythmic drugs have failed, Dr. Nattel said.

Dr. Estes disagreed. The latest AHA/American College of Cardiology guidelines characterize dronedarone as a reasonable drug for maintaining sinus rhythm in patients with recurrent paroxysmal or persistent AF who have no structural heart disease, or who have hypertension without left ventricular hypertrophy, or in those with CAD without heart failure (Circulation 2011;123:104-23).

"I think that these guidelines still apply," he said.

Dr. Connolly disclosed having received research grants and honoraria from Sanofi-Aventis, which sponsored PALLAS. Dr. Estes and Dr. Nattel reported no relevant financial interests.

ORLANDO – A giant question mark now surrounds the antiarrhythmic agent dronedarone because of the drug’s surprisingly poor performance in a major randomized trial involving patients with permanent atrial fibrillation.

The hypothesis in the study known as PALLAS (Permanent Atrial fibriLLAtion Study) was that dronedarone (Multaq) would reduce major vascular events in patients with high-risk permanent atrial fibrillation (AF). Quite the opposite occurred. As a result, the international trial came to a screeching halt for safety reasons after only 30% of the planned 10,800 subjects were enrolled.

Prompting early termination of PALLAS was a disturbing 2.3-fold increase in the composite coprimary outcome consisting of stroke, MI, systemic embolism, or death from cardiovascular causes in the dronedarone group, compared with placebo-treated controls.

"It’s clear from our data that dronedarone should not be used in patients with permanent AF who have a high burden of vascular disease," Dr. Stuart J. Connolly, chair of the PALLAS steering committee, said in presenting the study results at the annual scientific sessions of the American Heart Association.

Dronedarone’s approved indication, based upon the results of the earlier ATHENA (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) trial, is to restore sinus rhythm and reduce hospitalizations for cardiovascular causes in patients with paroxysmal or persistent AF (N. Engl. J. Med. 2009;360:668-78). It is not approved for permanent AF.

The critical question now is whether the adverse results seen in PALLAS in patients with permanent AF apply to patients on dronedarone for the approved indication. Further data are needed in order to answer that question, but caution is appropriate, according to discussant Dr. Mark Estes III, professor of medicine at Tufts University and director of the cardiac arrhythmia center at Tufts Medical Center, Boston.

If physicians elect to initiate therapy with dronedarone, he said, they’d better make sure that patients possess the clinical profile of ATHENA-type patients: that is, paroxysmal or persistent AF and a low burden of vascular disease.

"Currently, I think patients taking dronedarone who fit the ATHENA profile should be monitored regularly – at least every 6 months – to ensure that they remain within the approved indication and don’t progress to permanent AF or new or worsening heart failure," Dr. Estes added.

Monitoring for progression from intermittent to permanent AF can be done quite easily by ECG, noted Dr. Connolly, chair of the PALLAS steering committee and professor of cardiology at McMaster University in Hamilton, Ont.

The impetus for organizing PALLAS was the finding in ATHENA that dronedarone not only decreased cardiovascular hospitalizations, it also reduced rates of death, MI, stroke, and systemic embolism in patients with intermittent AF, including the subgroup which developed permanent AF during the course of the study. These findings, along with dronedarone’s blood pressure–lowering and adrenergic blockade effects, encouraged investigators to think that the drug might also be beneficial in patients with permanent AF, a group for which there has been no effective therapy. And so PALLAS came about.

PALLAS participants had to be at least 65 years old and have had permanent AF for at least 6 months. They also had to have coronary artery disease, symptomatic heart failure, prior stroke or transient ischemic attack, peripheral arterial disease, and/or a left ventricular ejection fraction of 40% or less. Indeed, 69% of PALLAS participants had a history of symptomatic heart failure, compared with just 20% in ATHENA.

One possible contributor to the unfavorable outcomes in PALLAS was the fact that about one-third of study participants were on digoxin. Dronedarone increases the serum digoxin level, sometimes into a potentially toxic range. That could have played a causative role in the increased cardiovascular death rate, but it does not explain the puzzling increased risks of stroke and heart failure episodes, according to Dr. Connolly.

An important lesson provided by PALLAS, the cardiologist continued, is that the patient population with permanent AF is fundamentally different from others with AF.

"As cardiologists we’ve tended to think of AF as running along a continuum from short, intermittent episodes to more persistent episodes and finally to permanent AF, with some progression of vascular disease along the way. We think of it all as one disease process. This trial really makes us see that this is not the case. Something rather unique seems to have changed between the ATHENA-type population and the PALLAS population because of their dramatically different response to the same drug," he observed.

Simultaneous with Dr. Connolly’s presentation at the AHA meeting, the PALLAS results were published (N. Engl. J. Med. 2011 Nov. 14 [doi:10.1056/NEJMoa1109867]).

"It’s clear ... that dronedarone should not be used in patients with permanent AF who have a high burden of vascular disease."

In an accompanying editorial, Dr. Stanley Nattel of the Montreal Heart Institute referred to dronedarone in AF as a "Jekyll and Hyde" drug (N. Engl. J. Med. 2011 Nov. 14 [doi:10.1056/NEJMe1111997]). He said that exactly why dronedarone was so harmful in PALLAS and yet so beneficial in ATHENA may never be known for certain. Was the key factor in PALLAS the permanent AF, the high burden of vascular disease overall, the substantial prevalence of heart failure, or something else? Regardless, the PALLAS experience warrants a revised, far more limited role for dronedarone moving forward, according to Dr. Nattel.

Not only should dronedarone absolutely be avoided in patients with permanent AF, it should also be avoided in high-risk patients with intermittent AF, particularly if they have heart failure. If dronedarone is to be prescribed in patients on digoxin, dose adjustment of the digoxin is now clearly mandatory, he continued.

And the major guidelines for management of AF need to be reexamined. Since receiving marketing approval, dronedarone has figured prominently in the treatment algorithms for patients with paroxysmal or persistent AF. Now, however, it seems appropriate to reserve the antiarrhythmic for selected low-risk patients, and perhaps only those in whom other antiarrhythmic drugs have failed, Dr. Nattel said.

Dr. Estes disagreed. The latest AHA/American College of Cardiology guidelines characterize dronedarone as a reasonable drug for maintaining sinus rhythm in patients with recurrent paroxysmal or persistent AF who have no structural heart disease, or who have hypertension without left ventricular hypertrophy, or in those with CAD without heart failure (Circulation 2011;123:104-23).

"I think that these guidelines still apply," he said.

Dr. Connolly disclosed having received research grants and honoraria from Sanofi-Aventis, which sponsored PALLAS. Dr. Estes and Dr. Nattel reported no relevant financial interests.

ORLANDO – A giant question mark now surrounds the antiarrhythmic agent dronedarone because of the drug’s surprisingly poor performance in a major randomized trial involving patients with permanent atrial fibrillation.

The hypothesis in the study known as PALLAS (Permanent Atrial fibriLLAtion Study) was that dronedarone (Multaq) would reduce major vascular events in patients with high-risk permanent atrial fibrillation (AF). Quite the opposite occurred. As a result, the international trial came to a screeching halt for safety reasons after only 30% of the planned 10,800 subjects were enrolled.

Prompting early termination of PALLAS was a disturbing 2.3-fold increase in the composite coprimary outcome consisting of stroke, MI, systemic embolism, or death from cardiovascular causes in the dronedarone group, compared with placebo-treated controls.

"It’s clear from our data that dronedarone should not be used in patients with permanent AF who have a high burden of vascular disease," Dr. Stuart J. Connolly, chair of the PALLAS steering committee, said in presenting the study results at the annual scientific sessions of the American Heart Association.

Dronedarone’s approved indication, based upon the results of the earlier ATHENA (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) trial, is to restore sinus rhythm and reduce hospitalizations for cardiovascular causes in patients with paroxysmal or persistent AF (N. Engl. J. Med. 2009;360:668-78). It is not approved for permanent AF.

The critical question now is whether the adverse results seen in PALLAS in patients with permanent AF apply to patients on dronedarone for the approved indication. Further data are needed in order to answer that question, but caution is appropriate, according to discussant Dr. Mark Estes III, professor of medicine at Tufts University and director of the cardiac arrhythmia center at Tufts Medical Center, Boston.

If physicians elect to initiate therapy with dronedarone, he said, they’d better make sure that patients possess the clinical profile of ATHENA-type patients: that is, paroxysmal or persistent AF and a low burden of vascular disease.

"Currently, I think patients taking dronedarone who fit the ATHENA profile should be monitored regularly – at least every 6 months – to ensure that they remain within the approved indication and don’t progress to permanent AF or new or worsening heart failure," Dr. Estes added.

Monitoring for progression from intermittent to permanent AF can be done quite easily by ECG, noted Dr. Connolly, chair of the PALLAS steering committee and professor of cardiology at McMaster University in Hamilton, Ont.

The impetus for organizing PALLAS was the finding in ATHENA that dronedarone not only decreased cardiovascular hospitalizations, it also reduced rates of death, MI, stroke, and systemic embolism in patients with intermittent AF, including the subgroup which developed permanent AF during the course of the study. These findings, along with dronedarone’s blood pressure–lowering and adrenergic blockade effects, encouraged investigators to think that the drug might also be beneficial in patients with permanent AF, a group for which there has been no effective therapy. And so PALLAS came about.

PALLAS participants had to be at least 65 years old and have had permanent AF for at least 6 months. They also had to have coronary artery disease, symptomatic heart failure, prior stroke or transient ischemic attack, peripheral arterial disease, and/or a left ventricular ejection fraction of 40% or less. Indeed, 69% of PALLAS participants had a history of symptomatic heart failure, compared with just 20% in ATHENA.

One possible contributor to the unfavorable outcomes in PALLAS was the fact that about one-third of study participants were on digoxin. Dronedarone increases the serum digoxin level, sometimes into a potentially toxic range. That could have played a causative role in the increased cardiovascular death rate, but it does not explain the puzzling increased risks of stroke and heart failure episodes, according to Dr. Connolly.

An important lesson provided by PALLAS, the cardiologist continued, is that the patient population with permanent AF is fundamentally different from others with AF.

"As cardiologists we’ve tended to think of AF as running along a continuum from short, intermittent episodes to more persistent episodes and finally to permanent AF, with some progression of vascular disease along the way. We think of it all as one disease process. This trial really makes us see that this is not the case. Something rather unique seems to have changed between the ATHENA-type population and the PALLAS population because of their dramatically different response to the same drug," he observed.

Simultaneous with Dr. Connolly’s presentation at the AHA meeting, the PALLAS results were published (N. Engl. J. Med. 2011 Nov. 14 [doi:10.1056/NEJMoa1109867]).

"It’s clear ... that dronedarone should not be used in patients with permanent AF who have a high burden of vascular disease."

In an accompanying editorial, Dr. Stanley Nattel of the Montreal Heart Institute referred to dronedarone in AF as a "Jekyll and Hyde" drug (N. Engl. J. Med. 2011 Nov. 14 [doi:10.1056/NEJMe1111997]). He said that exactly why dronedarone was so harmful in PALLAS and yet so beneficial in ATHENA may never be known for certain. Was the key factor in PALLAS the permanent AF, the high burden of vascular disease overall, the substantial prevalence of heart failure, or something else? Regardless, the PALLAS experience warrants a revised, far more limited role for dronedarone moving forward, according to Dr. Nattel.

Not only should dronedarone absolutely be avoided in patients with permanent AF, it should also be avoided in high-risk patients with intermittent AF, particularly if they have heart failure. If dronedarone is to be prescribed in patients on digoxin, dose adjustment of the digoxin is now clearly mandatory, he continued.

And the major guidelines for management of AF need to be reexamined. Since receiving marketing approval, dronedarone has figured prominently in the treatment algorithms for patients with paroxysmal or persistent AF. Now, however, it seems appropriate to reserve the antiarrhythmic for selected low-risk patients, and perhaps only those in whom other antiarrhythmic drugs have failed, Dr. Nattel said.

Dr. Estes disagreed. The latest AHA/American College of Cardiology guidelines characterize dronedarone as a reasonable drug for maintaining sinus rhythm in patients with recurrent paroxysmal or persistent AF who have no structural heart disease, or who have hypertension without left ventricular hypertrophy, or in those with CAD without heart failure (Circulation 2011;123:104-23).

"I think that these guidelines still apply," he said.

Dr. Connolly disclosed having received research grants and honoraria from Sanofi-Aventis, which sponsored PALLAS. Dr. Estes and Dr. Nattel reported no relevant financial interests.