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anti-arrhythmic drug doubles death rate

Antiarrhythmic drug doubles death rate, yet still used.  The negative results occurred in a study using elderly, sicker population, testing for FDA occurred in an otherwise healthy, younger population.  Thus the PALLAS trial had negative results and the ATHEN results positive, because the weak and infirmed our the ones who principle die from arrhythmia , not the young and otherwise health, but is the former who are most like to be medicated for arrhythmia .  (Manufactured by Sanofi-Aventis, approved by FDA in July of 2009).   Approved in Canada for “treatment of patients with a history of, or current atrial fibrillation to reduce their risk of cardiovascular hospitalization due to this condition." [20] The NEJM 12/15/11 study exposed risk. 

FDA drug report:   http://www.fda.gov/Drugs/DrugSafety/ucm283933.htm

FDA Drug Safety Communication: Review update of Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events

Safety Announcement 

[12-19-2011] The U.S. Food and Drug Administration (FDA) has completed a safety review of the heart drug Multaq (dronedarone). This review showed that Multaq increased the risk of serious cardiovascular events, including death, when used by patients in permanent atrial fibrillation (AF). The review was based on data from two clinical trials, the PALLAS trial (Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy) and the ATHENA trial (which supported Multaq's approval for treatment of non-permanent AF).1,2 FDA is providing new information and recommendations for the use of Multaq to manage the potential serious cardiovascular risks with the drug. 

The Multaq drug label has been revised with the following changes and recommendations [see the revised Multaq label for all changes]:

  • Healthcare professionals should not prescribe Multaq to patients with AF who cannot or will not be converted into normal sinus rhythm (permanent AF), because Multaq doubles the rate of cardiovascular death, stroke, and heart failure in such patients.
  • Healthcare professionals should monitor heart (cardiac) rhythm by electrocardiogram (ECG) at least once every 3 months. If the patient is in AF, Multaq should be stopped or, if clinically indicated, the patient should be cardioverted.
  • Multaq is indicated to reduce hospitalization for AF in patients in sinus rhythm with a history of non-permanent AF (known as paroxysmal or persistent AF)
  • Patients prescribed Multaq should receive appropriate antithrombotic therapy.

Patients should contact their healthcare professional if they have any questions or concerns about Multaq. Patients should not stop taking Multaq without talking to their healthcare professional.

FDA is reviewing the risk evaluation and mitigation strategy (REMS) for Multaq to determine the changes necessary to ensure that the benefits of Multaq outweigh the risks of cardiovascular death, stroke, and heart failure.


Data Summary

The PALLAS (Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy) trial Description: disclaimer iconwas a large outcome trial intended to evaluate the effectiveness of Multaq in patients with permanent AF.1 This clinical trial was terminated early because of a significantly higher number of cardiovascular events in the Multaq-treated group compared to the group of patients given a placebo (i.e., with no active ingredient). FDA issued a Drug Safety Communication (DSC) in July 2011 when the study was terminated.


Table 1. Final results from PALLAS (provided by the manufacturer) showed the following:


Multaq (dronedarone) N=1619 N

Placebo N=1617   N

Hazard Ratio (95 % Confidence Intervals)

Total Deaths



1.94 (0.99 to 3.79)

Death from arrhythmia or Sudden Death



3.26 (1.06 to 10.0)




2.32 (1.11 to 4.88)

Hospitalization for Heart Failure



1.81 (1.10 to 2.99)

To determine whether the increased risks observed in the PALLAS study population apply to patients for whom the drug is indicated (i.e., patients with non-permanent AF), the FDA reassessed data from the ATHENA trial (the clinical trial supporting Multaq's approval for non-permanent AF), with special attention to arrhythmic death, stroke, and heart failure outcomes Description: disclaimer icon.2 The ATHENA trial showed a reduction in the risk of hospitalizations for AF in patients with non-permanent AF who were randomized to receive Multaq. Patients administered Multaq in the ATHENA trial did not have an increased risk of cardiovascular death, stroke or heart failure.

The FDA believes that Multaq provides a benefit for patients with non-permanent AF and recommends that healthcare professionals who prescribe Multaq follow the recommendations in the revised Multaq drug label. 

From approval in July 2009 through October 2011, a total of approximately 1.3 million Multaq® prescriptions were dispensed and approximately 278,000 patients received Multaq® prescriptions from U.S. outpatient retail pharmacies. 3


  1. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011. DOI: 10.1056/NEJMoa1109867.
  2. Hohnloser SF, Crijns HJGM, van Eickels M, et al. Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation. N Engl J Med 2009. DOI: 10.1056/NEJMoa0803778.
  3. Source: IMS, Vector One®: National (VONA) and Total Patient Tracker (TPT). July 2009 to October 2011. Extracted December 2011.


New England Journal of Medicine:  Dec. 15 2011 

Dronedarone in High-Risk Permanent Atrial Fibrillation


Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation.


We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death.


After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02).  {SAME AS FDA TABLE ABOVE}


Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.)



Atrial fibrillation (AF or A-fib) is the most common cardiac arrhythmia (abnormal heart rhythm). It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers (atria) of the heart result in the muscle fibrillating (i.e., quivering), instead of achieving coordinated contraction. The presence of AF can be confirmed with an electrocardiogram (ECG or EKG) by the absence of P waves and an irregular ventricular rate. Presence of AF in a population increases with age, with 8% of people over 80 having AF.

In AF, the normal electrical impulses that are generated by the sinoatrial node are suddenly or gradually overwhelmed by disorganized electrical impulses that often originate in the roots of the pulmonary veins, leading to irregular conduction of impulses to the ventricles which generate the heartbeat. AF may occur in episodes lasting from minutes to weeks, or be permanent in nature. The natural tendency of AF over time is to become a chronic condition. Chronic AF leads to a small increase in the risk of death.[1][2]

Some people are asymptomatic despite having frequent episodes, while others experience symptoms that are troubling or incapacitating. Whilst AF is not immediately life-threatening, it may result in palpitations, fainting, chest pain, or congestive heart failure. People with AF have an increased risk of stroke because blood tends to form clots in the poorly contracting atria - especially in the left atrial appendage (LAA). The degree of stroke risk can be up to seven times that of the average population, depending on the presence of additional risk factors[3]. In the absence of other risk factors, the risk of stroke in AF patients is similar to that of the general population.[4]

Atrial fibrillation may be treated with medications to either slow the heart rate or revert the heart rhythm back to normal. Synchronized electrical cardioversion can be used to convert AF to a normal heart rhythm. Surgical and catheter-based therapies may be used to prevent recurrence of AF in certain individuals. People with AF often take anticoagulants such as warfarin to protect them from stroke.


Chemically, dronedarone is a benzofuran derivative related to amiodarone, a popular antiarrhythmic the use of which is limited by toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease.

Mechanism of action

Dronedarone has been termed a “multichannel blocker” however it is unclear which channel(s) play a pivotal role in its success.[9] Thus dronedarones actions at the cellular level are controversial with most studies suggesting an inhibition in multiple inward potassium currents including rapid delayed rectifier, slow delayed rectifier and Ach-activated inward rectifier.[10] It is also believed to reduce inward rapid Na current and L-type Ca channels. The reduction in K current in some studies was shown to be due to the inhibition of K-Ach channel or associated GTP-binding proteins.[11] Reduction of K+ current by 69% lead to increased AP duration and increased effective refractory periods, thus shown to suppress pacemaker potential of the SA node and return patients to a normal heart rhythm.[12] In a European trial, the average time to recurrence of an arrhythmia was 41 days in the placebo group vs. 96 days in the dronedarone group (similar results obtained in the non-European trial, 59 and 158 days respectively).[13]


  • NYHA (New York Heart Association) Class IV heart failure or NYHA Class II or III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.
  • Second or third degree atrioventricular (AV) block or sick sinus syndrome (exception in patients with a functional pacemaker)
  • Bradycardia less than 50 beats per minute
  • QT interval corrected for rate of 500 msec or greater
  • PR interval exceeding 280 msec
  • Use of cytochrome P-450 (CYP) 3a isoenzyme inhibitors (includes: clarithromycin, cyclosporine, itraconazole, ketoconazole, nefazodone, ritonavir, telithromycin, voriconazole)
  • Use with drugs or herbal supplements that prolong QT interval or increase risk of torsades de points (Class I or III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, certain oral macrolides, ephedra)
  • Hepatic impairment. In Jan 2011 the FDA advised about cases of rare, but severe, liver injury, including two cases of acute liver failure leading to liver transplant in patients treated with dronedarone (Multaq). It is not known whether routine periodic monitoring of serum liver enzymes (ALT, AST, and alkaline phosphatase) and bilirubin in patients taking dronedarone will prevent the development of severe liver injury[5].
  • Women who are or may become pregnant
  • Nursing women

·         linical trials have compared dronedarone to placebo and to amiodarone, for its ability to reduce atrial fibrillation, to reduce mortality overall and from cardiac causes, and for its adverse effects, including excess mortality.[2] [14] Dronedarone is a non-iodinated class III anti-arrhythmic drug which helps patients return to normal sinus rhythm. This treatment for AF is also known to reduce associated mortality and hospitalizations compared to other similar antiarrhythmic agents.[15]

·         In the EURIDIS and ADONIS trials in atrial fibrillation (2007), dronedarone was significantly more effective than placebo in maintaining sinus rhythm, with no difference in lung and thyroid function in the short term.[16]

·         However, in the ANDROMEDA study (2007), dronedarone doubled the death rate compared to placebo, and the trial was halted early.[3] ANDROMEDA enrolled patients with moderate to severe congestive heart failure, a relatively sicker patient population.

·         In a more recent atrial fibrillation trial, ATHENA, with 4628 subjects, dronedarone was significantly more effective than placebo in reducing the composite endpoint of first hospitalization due to cardiovascular events or death.[17] There was a significant reduction in the rate of cardiovascular death, but not in the rate of death from any cause.[2] Later post-hoc analysis of the ATHENA-results showed a significant reduction in the rate of stroke.[18]

·         Patients randomized to dronedarone were more likely to develop bradycardia and QT-interval prolongation (but only 1 case of Torsades). Nausea, diarrhea, rash, and creatinine elevation also were more common in the dronedarone arm.


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