Concern about Multaq is not new. We started writing about it in January, 2011. Since then, there have been a number of bulletins issued by the FDA and Health Canada concerning safety issues with Multaq (dronedarone), a drug used in treatment of atrial fibrillation.
These warnings stem from post-marketing surveillance ativities and the recent premature termination of Sanofi’s Phase IIIb PALLAS study in patients with permanent atrial fibrillation. The PALLAS study is not the first study to be terminated prematurely. Sanofi’s ANDROMEDA study was stopped due stopped due to a higher incidence in death in subjects on dronedarone compared to placebo (8.1% vs. 3.8%). Concerns have been raised by the regulatory agencies regarding cardiovascular risk including congestive heart failure, liver injury, interstitial lung disease and concomitant therapy with warfarin. This has prompted the FDA and Health Canada to review the overall safety of the drug.The Problem Multaq Is Intended to Tackle: Atrial Fibrillation
The most common abnormal heart rhythm is atrial fibrillation. Atrial fibrillation is the fibrillation (quivering) of the atrial heart muscles instead of coordinated contractions. It is commonly noticed through measurement of heart rate as heart beats do not occur at regular intervals and may be further investigated by ECG or EKG (electrocardiogram) in order to diagnose. It is estimated that 8% of the population over 80 years has atrial fibrillation.
There are three different types of atrial fibrillation: paroxysmal, persistent, and permanent. Paroxysmal atrial fibrillation goes away without intervention, usually within a week. Persistent atrial fibrillation has a longer duration than paroxysmal atrial fibrillation. Permanent atrial fibrillation, as the name suggest, does not go away.
So atrial fibrillation episodes may last minutes or weeks or even years. It can can cause many symptoms and injury, including palpitations, chest pain, shortness of breath, fatigue, heart failure and stroke.
Atrial fibrillation generally becomes a chronic condition. Chronic arterial fibrillation is estimated to increase the risk of death 1.5 to 1.9 times. Atrial fibrillation may result in fainting, palpitations, chest pain, or congestive heart failure. The risk of stroke is increased in patients with other cardiovascular risk factors.
Medications which slow the heart or alter the heart rate back to a normal rhythm, known as cardioversion, are used in the treatment of atrial fibrillation. Other treatments include surgical and catheter-based therapies or electrical cardioversion. Patients are sometimes prescribed warfarin or other blood thinning agents to prevent stroke. Cardioversion drugs include amiodarone, dronedarone, procainamide and others.Multaq (Dronedarone): An Overview
Multaq (the brand name for dronedarone) is a pharmaceutical manufactured by the French pharmaceutical company, Sanofi, and is used to reduce the risk of hospitalization due to atrial fibrillation. It is used in patients who have had atrial fibrillation in the previous six months. Multaq has received approval in various countries including the United States, Canada, and Europe, for use in patients with non-permanent atrial fibrillation. It is estimated that approximately 400,000 patients have been treated with Multaq worldwide, with 240,000 patients using Multaq in the US since its approval by the FDA and Health Canada in July 2009.
Dronedarone is a multi-channel blocker chemically related to amiodarone. Amiodarone is known to cause thyroid problems due to the presence of iodine functional groups. These functional groups are not present in dronedarone. Further, dronedarone has a methyl sulfonyl group which decreases its ability to dissolve in fats and lipids and shortens its half-life in blood, meaning that it does not stay present in the blood as long as amiodarone. It is believed that this in turn reduces organ toxicity. Although dronedarone may not be as efficacious as amiodarone, it is often the first-choice of antiarrhythmic drugs for patients with atrial fibrillation (Dagres et al., 2011 and Penugonda et al., 2011)Safety Profile and Concerns
Patients who have severe congestive heart failure, unstable hemodynamic (blood flow or circulation) conditions, second or third degree atrioventricular block or sick sinus syndrome, bradychardia (slow heart beat, <50bpm), sever hepatic impairment, are pregnant or lactating, or are on ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, ritonavir, phenothiazines, tricyclic antidepressants, some types of oral macrolyes and class I and II antiarrhythmics are advised not to take Multaq.
The safety profile of Multaq is based on ATHENA, EURIDIS, ADONIS, ERATO and DAFNE studies (total number of patients = 6285; 3282 of which were on dronedarone). The most common adverse events were gastrointestinal (3.2% versus 1.8% in placebo), namely, diarrhea, nausea and vomiting, abdominal pains and dyspepsia. Other adverse reactions occurring at greater incidence than placebo included fatigue and asthenia, bradycardia, rashes, itchiness, loss of taste and distortion of taste. To date there have been 14 human clinical studies sponsored by Sanofi, conducted with Multaq. Eight of these studies have been completed and reported on. A summary of each trial highlighting findings of efficacy and safety is provided below.
A recent review of the studies on dronedarone reported to date advised that consideration prior to initiating treatment in an individual should be given to the underlying disease, current medications (e.g. anti-coagulants, amiodarone, etc.) and length of the QT interval (Schweizer et al., 2011).Post-marketing Surveillance and Regulatory Warnings – Congestive Heart Failure, Interstitial Lung Disease and Liver Injury
Post-marketing surveillance has demonstrated a possible link of Multaq with congestive heart failure and hepatic (liver) injury. Cases of new onset and worsening heart failure have been reported in patients treated with Multaq. Signs and symptoms to be aware of are weight gain, dependent edema and increasing shortness of breath, which may be a symptom of heart failure. Any patients having these symptoms are advised to consult a physician. Hepatocellular (liver cell) injury has been reported in some patients on Multaq. There have also been cases requiring acute liver transplants. Symptoms of hepatic injury include anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine or itching.
Due to the concerns raised in the post-marketing surveillance, in January 2011, Sanofi, the US FDA and Health Canada issued an advisory, warning of reports of acute liver injury in patients using Multaq (dronedarone).
In March 2011, the FDA approved labelling changes regarding the possible interaction of dronedarone with warfarin, a commonly prescribed anti-coagulant (blood thinner). In the ATHENA trial it was noted that a higher proportion of subjects experienced a clinically significant elevation in INR (International Normalized Ratio, a blood test to a measure how much active warfarin is present in the blood) within 1 week of starting treatment. Post-marketing cases of increased INR have been reported in patients on warfarin when initiated on dronedarone. Sanofi and the FDA advise on monitoring INR after initiating dronedarone in patients taking warfarin.
In June 2011, FDA approved label warning changes in response to post-marketing cases of respiratory illness, specifically interstitial lung disease including pneumonitis (inflammation of lung tissue) and pulmonary fibrosis (scarring or thickening of the lungs) in patients prescribed Multaq.
In July of this year, Sanofi terminated its PALLAS study on more than 3,000 patients due to the significantly higher death rate (32 deaths in the dronedarone arm versus 14 in the placebo group), significantly higher combined endpoint of death or unplanned hospitalization (118 versus 81 in the placebo group) and significantly greater rate of strokes (17 versus 7 in the placebo group).
On August 4, 2011, Health Canada issued an advisory that recognizing the possible relationship of Multaq with congestive heart failure as seen during the PALLAS study. Sanofi is currently revising product monographs (documents which physicians use as a guide when prescribing Multaq) to include this information for patients with permanent atrial fibrillation.
The FDA is currently investigating the relationship of the results of the PALLAS study and how they apply to patients using Multaq for the approved indications. Further both the US FDA and Health Canada are reviewing the overall safety of Multaq. Health Canada has stated that it would "take appropriate regulatory action as necessary once the review is complete."
Both the FDA and Health Canada are encouraging healthcare professionals and patients to report adverse events/side effects related to the use of Multaq (dronedarone). Such reporting can be made electronically at www.fda.gov/MedWatch/report.htm and www.healthcanada.gc.ca/medeffect for FDA and Health Canada, respectively.Clinical Research Supporting Efficacy and Safety – Summary by Trial - ATHENA Study
Multaq for the use in patients with non-permanent atrial fibrillation is supported by the ATHENA study. ATHENA was a multi-national, multi-center double-blind, randomized placebo controlled study in 4268 patients with paroxysmal or persistent atrial fibrillation / atrial flutter and is the largest trial in single antiarrhythmic drug trial conducted to date. The study was conducted to investigate the effectiveness of Multaq for the prevention of cardiovascular hospitalization or death from any cause. The study population had an inclusionary age of 75 years (with no additional risk factors) or 70 years (with additional risk factors). Initially, the study design had allowed for the inclusion of younger patients with additional risk factors. The change in study design to include an older population at higher risk occurred in response to the observation that overall mortality (death) was lower than expected.
The patient population included in the ATHENA trial were higher risk than those included in the EURIDIS/ADONIS studies. Patients were included in the study provided they had atrial fibrillation or atrial flutter and sinus rhythm. Patients were treated with Multaq (400mg) or placebo twice daily with a mean follow-up period of 21 months and maximum follow-up period of 2.5 years. Results of this study demonstrated a significantly lower rate of hospitalization in the Multaq group compared to the placebo group (29.3% vs. 36.9%). With respect to safety measures, adverse events were more frequent in the Multaq group than the placebo group (12.7% vs. 8.1%). Events were predominantly gastrointestinal in nature. Other adverse events included increase serum creatinine, bradycardia, QT prolongation, rash, nausea and diarrhea.
- 2013 Study Showing Elevated Liver Enzymes
The European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and American-Australian Trial with Dronedarone in Atrial Fibrillation of Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS) study were designed to investigate the effectiveness of dronedarone in maintaining normal sinus rhythm after electrical, pharcological or spontaneous conversion from paroxysmal or persistent atrial fibrillation or atrial flutter. The EURIDIS/ADONIS study was a multi-national, multi-centered, double-blind placebo controlled phase III trial which included a total of 1237 patients. The study was conducted in patients over the age of 21. This study found that Dronedarone significantly increased the time to recurrence compared to placebo (116 days vs 53 days) and reduced the rate during atrial fibrillation recurrence (-16.7 beats per minute).
Side effects were similar between the placebo and dronedarone group. Dronedarone induced increases in serum creatinine which was reversed when treatment was stopped. Creatinine in the blood indicates deficiency in kidney filtration. Sanofi has stated that an increase in creatinine levels is expected with Dronedarone and has been reported for similar drugs such as amiodarone. Though creatinine levels increased, no changes have been reported in eGFR, another renal function marker. This result was similar to that reported in the ATHENA study. It is recommended that creatinine be monitored, but as of yet no indications of renal injury have been linked directly to dronedarone.DAFNE Study
The Phase II Dronedarone Atrial Fibrillation study after Electrical cardioversion (DAPHNE) trial was designed to determine the appropriate dose of Multaq in patients with persistent atrial fibrillation to prevent recurrence of atrial fibrillation after cardioversion. Patients were randomly assigned to receive either dronedarone (400mg, 600mg or 800mg) or placebo twice daily for six months. The most efficacious results were demonstrated with 400mg dronedarone twice daily. Further this dose demonstrated fewest adverse effects. The most frequent adverse events were gastrointestinal in the dronedarone groups. Patients receiving 800mg twice daily reported gastrointestinal problems and showed QT prolongation. This study provided the basis to select 400mg twice daily dose for subsequent Phase III studies.ERATO Study
The European Study of Dronedarone in Atrial Fibrillation (ERATO) study was conducted in 174 patients with permanent arterial fibrillation using other medications (i.e. b-blockers, calcium channel blockers, digoxin). The study was a multi-center, double-blind, placebo-controlled 6 month study to investigate the efficacy of dronedarone in the control of 24hour ventricular rate. Dronedarone significantly reduced 24 hour ventricular rate by 11.7 beats per minute. Though not statistically significant, serious adverse events (side effects that caused hospitalization or worse) occurred to a greater extent in patients on dronedarone compared to placebo (17% vs. 14%). Also not significant, but noteworthy, patients on dronedarone experienced greater incidence of infection (31% vs 25%) and gastrointestinal side effects (20% vs 14%).ANDROMEDA Study
The ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease) study was a phase II multi-center, randomized, placebo controlled trial in high risk patients with heart failure. 25% of the 627 patients enrolled had atrial fibrillation. Patients were randomized to receive either 400mg dronedarone or placebo. The study was designed to assess the effectiveness of dronedarone in this patient base to reduce the occurrence of death or hospitalization for worsening heart failure. The study was prematurely stopped due to excessive death rates. 8.1% of patients in the dronedarone group and 3.8% of patients on placebo died. Death was due to worsening heart failure in 10 of 25 patients on dronedarone and 2 of 12 patients on placebo. This study, like EURIDIS/ADONIS and ATHENA studies demonstrated a higher incidence in increased creatinine (kidney function marker) in patients on dronedarone compared to patients on placebo.DIONYSOS Study
The DIONYSOS (Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm) was a multi-national, multi-center double-blind randomized controlled phase III study to compare safety and efficacy of dronedarone with amiodarone. The study compared the two drugs with respect to recurrence of atrial fibrillation and premature discontinuation of patients due to intolerance or lack of efficacy (i.e. the product was not working for them). The study included 504 patients on anti-coagulants (blood thinners) who had arterial fibrillation for greater than 72 hours. Patients received either 400mg dronedarone twice daily for 7 months or 600mg amiodarone daily for 28 days followed by 200mg/day amiodarone for the remainder of the 7 month study. Dronedarone was found to be less effective in respect to recurrence of atrial fibrillation than amiodarone (36.5% vs 58.0%), however, was found to have a lower incidence of side effects (10.4 % vs. 13.3%). Similar to previous studies with dronedarone, GI events were noted and occurred at a higher incidence than amiodarone. 9.2% of patients receiving dronedarone reported at least one episode of diarrhea compared to 3.1% receiving amiodarone.Recent Clinical Research
Since 2010, Sanofi has initiated 6 more human clinical studies on dronedarone, namely, the PALLAS study, the ARTEMIS AF study, the HESTIA study, the ODDYSEUS study, the AFRODITE study and the ELECTRA study.PALLAS STUDY
The PALLAS (Permanent atrial fibrillation outcome study using Dronedarone on top of standard therapy) study was a phase IIIb clinical study designed to be conducted in approximately 11,000 patients with permanent atrial fibrillation and additional risk factors. The study was to include 700 sites worldwide.
On July 07, 2011, Sanofi announced its discontinuation of its PALLAS trial in response to the observation of a significant increase in cardiovascular events in the treatment group as compared to the placebo group.
In a statement released by Sanofi, the manufacturer has stated that the population of patients currently using Multaq differs from the PALLAS study as the PALLAS study involved patients with permanent Atrial Fibrillation rather than those with non-permanent atrial fibrillation.ARTEMIS AF Study
The ARTEMIS AF study is being conducted as two studies, the ARTEMIS AF Loading study (A Randomized, international, multi-center, open-label study to document optimal timing of initiation of dronedarone treatment after conversion with loading dose of amioodarone in patients with persisten Atrial Fibrillation requiring conversion of Atrial Fibrillation (AF)) and the ARTEMIS AF Long Term study (A Randomized, international, multi-center, open-label study to document optimal timing of initiation of dronedarone treatment after conversion with loading dose of amiodarone in patients with persistent Atrial Fibrillation whatever the reason for the change of treatment). The objective of these two studies is to determine the optimal regimen for dronedarone initiation following discontinuation of amiodarone. Both studies are multi-centered, multi-national phase IV clinical trials and are currently ongoing and actively enrolling patients.
The ARTEMIS AF Loading study is a 12 week study designed to determine the rate of atrial fibrillation recurrences one month randomization according to different timings of initiation of dronedarone in 860 patients 18 years or older.
The ARTEMIS AF Long Term study will evaluate how different timings of the start of dronedarone treatment effect the way the drug acts in patients with paroxysmal or persistent atrial fibrillation on long-term amiodarone regimen up to 8 weeks in 165 patients 18 years or older.HESTIA study
The HESTIA study is currently recruiting patients to participate in a placebo-controlled, double-blind, randomized, multi-center study. The study is being conducted in 430 patients 21 years or older with permanent pacemakers to assess the effects of 400mg dronedarone twice daily for 12 weeks on the percentage of time in which a patient is in atrial fibrillation.ODDYSEUS study
September of 2010 is a placebo-controlled, multi-center study to assess the effects of dronedarone (400mg twice daily) on cardiac geometry and function in patients with atrial fibrillation and left atrial enlargement. The 12 month study is expected to enrol 330 subjects.AFRODITE study
The AFRODITE study to determine the effect of the addition of Dronedarone to conventional rate controlling medicine (ie. beta blockers, calcium channel blockers and digoxin) versus the increase of rate controlling medicine on ventricular rate during persistent atrial fibrillation has recently finished. The study enrolled 596 subjects 46 and older with persistent atrial fibrillation on one or two rate control medications. Results have not yet been published for this study.ELECTRA study
The objective of the ELECTRA study is to determine if treatment with dronedarone (400mg twice daily) 5-7 days before cardioversion is better than starting dronedarone (400mg twice daily) after cardioversion. The study assessed atrial fibrillation recurrence over 6 months in 500 patients 18 years or older with persistent atrial fibrillation. Results have not yet been published for this study.