[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 was
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
|
25
|
13
|
1.94 (0.99 to 3.79)
|
Death
from arrhythmia or Sudden Death
|
13
|
4
|
3.26 (1.06 to 10.0)
|
Stroke
|
23
|
10
|
2.32 (1.11 to 4.88)
|
Hospitalization
for Heart Failure
|
43
|
24
|
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 .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
References
- Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone
in high-risk permanent atrial fibrillation. N Engl J Med 2011. DOI:
10.1056/NEJMoa1109867.
- 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.
- Source: IMS, Vector One®: National (VONA) and Total
Patient Tracker (TPT). July 2009 to October 2011. Extracted December 2011.
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New England Journal of
Medicine: Dec. 15 2011
Dronedarone in High-Risk Permanent
Atrial Fibrillation
Background
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.
Methods
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.
Results
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}
Conclusions
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.)
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Wikipedia
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]
Cautions
- 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.
|