Dronedaron (Multaq)

• by golden_snitch
• 2009-09-15 02:09:20
• Conditions, Meds & Tests
• 4534 views
• 0 comments

Hi there!

Since "Dronedarone" (Multaq) has been subject to some postings here lately, I wanted to post an article I got yesterday. It's from theheart.org, and I think one has to be logged in to read it. I'm posting it here so that you don't have to register for reading it. The baseline of the article is: Dronedarone is not as effective as Amiodarone, but it's much safer. I don't want to open another discussion on this, just thought the article might be of interest for some of you.

Best wishes,
Inga

Dronedarone in atrial fib trades efficacy for safety in meta-analysis
September 11, 2009 | Steve Stiles

Durham, NC - Patients taking dronedarone (Multaq, Sanofi-Aventis) for prevention of recurrent atrial fibrillation (AF) are about half as likely to remain in sinus rhythm as patients on amiodarone, but they're also far less likely to go off antiarrhythmic therapy due to adverse effects, concluded the authors of a meta-analysis primarily of studies comparing one or the other drug with placebo [1].

Their report, published online September 8, 2009 in the Journal of the American College of Cardiology, supports the common perception that dronedarone, recently approved by the FDA for reducing the risk of CV hospitalization in high-risk patients with AF or atrial flutter, likely trades efficacy for safety compared with the much older drug, which has a particularly daunting side-effect profile.

So whether dronedarone is an appropriate treatment, even for a patient who meets the indications, likely depends on the patient, the report's first author, Dr Jonathan P Piccini (Duke Clinical Research Institute, Durham, NC), told heartwire.

The evidence behind the drug's approval, primarily the results of the ATHENA trial [2], "is very, very sound," he said; that trial didn't look at AF recurrence rates. The drug's approved indication is for reduction of CV hospitalization risk, and the drug is contraindicated for patients in NYHA class 4 heart failure and those in class 2-3 if they've recently been hospitalized for decompensation. "That again is well supported by the evidence," Piccini said, referring to the ANDROMEDA trial.

Less clear, he said, is what to do with a patient already doing well on amiodarone, which is notable for its toxicities involving the thyroid, lungs, and other organ systems. "Do you switch the patient to dronedarone? At this time, I think the answer would be no. If they're tolerating amiodarone and have not developed any adverse effects, and they've received a good rhythm response, the available evidence suggests that dronedarone is not as good as amiodarone at maintaining sinus rhythm. But that has to be balanced against the fact that dronedarone is associated with fewer adverse events that cause the drug to be discontinued. I think that's a gray area that requires more refinement."

Not a conventional meta-analysis

Piccini cautions that his group's analysis is an "indirect meta-analysis," one that makes comparisons between two drugs based on studies that pit each individually against placebo, and so has limitations. But with a dearth of information from large head-to-head trials, he noted, the analysis consolidates the existing evidence in a way that can help fill in the knowledge gap.

What it doesn't show, Piccini said, is that dronedarone can prolong survival. But there was a trend: an increased all-cause mortality risk with amiodarone, at an OR of 1.61 (95% CI 0.97-2.68), fell short of significance (p=0.066). "We did a power calculation and estimated that if you recruited a population like those in the ATHENA trial, you would need 14 000 patients to identify a robust reduction in mortality."

In an accompanying editorial [3], Dr Paul S Chan (Mid America Heart Institute and the University of Missouri, Kansas City) and colleagues consider other limitations of the analysis that make it only hypothesis-generating and in need of "confirmation from direct comparisons in adequately powered clinical trials."

For example, they write, its number of dronedarone recipients was overwhelming compared with those who received amiodarone, and the vast majority of those came from one trial, ATHENA. Quality-of-life issues are prominent in AF treatment consideration, but the analysis doesn't provide insights in that area.

In addition, the eight trials enrolled different populations, potentially introducing bias into the analysis. "It is noteworthy that all four dronedarone studies excluded patients with permanent AF, whereas two of the four amiodarone studies excluded patients with paroxysmal AF," the group writes. Also, "only one of the four amiodarone trials and none of the dronedarone trials enrolled patients with highly symptomatic AF."

Because elimination of symptoms is often the main reason to go with a rhythm-control strategy in AF, Chan et al contend, "we need to question whether the indications for chronic antiarrhythmic therapy in the patients evaluated in this meta-analysis are relevant to contemporary practice."

Results consistent with existing evidence

To arrive at the eight studies, Piccini et al screened the literature for randomized, controlled trials that assigned patients with AF to either drug or placebo, had followed them for more than six months, and included recurrent AF or all-cause mortality as end points. They found four that compared dronedarone (usually 800 mg/day) with placebo (total n=5967) and another four pitting amiodarone (200 mg/day) against placebo (total n=669).

In the indirect meta-analysis, amiodarone bested dronedarone in preventing AF recurrence; the odds ratio (OR) for AF in patients treated with the older drug compared with the newer one was 0.49 (95% CI 0.37-0.63; p<0.001). On the other hand, the amiodarone OR for adverse events leading to drug withdrawal was significantly increased at 1.81 (95% CI 1.33-2.46; p<0.001).

Piccini et al say their findings are consistent with a ninth study, an 504-patient direct comparison of the two drugs in "persistent" AF called DIONYSOS whose preliminary results were released by the sponsor publicly in December 2008 [4] and to an FDA advisory panel convening a few months later [5], although they have yet to appear in the literature.

Piccini et al interpreted their findings in the context of those from DIONYSOS to derive some numbers physicians may find helpful when deciding whether to prescribe dronedarone. "If the indirect meta-analysis results are given the same approximate weight as the DIONYSOS direct comparison," they write, "we estimate that for every 1000 patients treated with dronedarone instead of amiodarone, there would be 228 more recurrences of AF at one year in exchange for 9.6 fewer deaths and 62 fewer adverse events requiring discontinuation of drug."


The one major randomized comparison

Sanofi-Aventis announced the DIONYSOS results in a press release last year [4] and disclosed them in more detail to the March 18, 2009 FDA advisory panel considering whether dronedarone was worthy of approval [5]. But the study hasn't been published nor, as far as heartwire has determined, has it been formally presented at a scientific meeting.

Carried out in 23 countries across Europe and Asia, the Americas, and Australia, DIONYSOS randomized 504 patients with documented AF (but no AF continuously for >12 months) and "a need for cardioversion and antiarrhythmic treatment" who were on anticoagulants and who, at the start of the trial, did not have "clinically overt" NYHA class 3-4 heart failure.

As it turned out at baseline, of the 249 assigned to dronedarone and 255 who received amiodarone, 16.5% had lone AF, 21.6% were experiencing their first AF episode, about 28.5% had structural heart disease, 22% were in heart failure, about 63% were on conventional beta blockers, and about 37% were taking digoxin or other drug in the digitalis family.

After a mean of seven months, the company reported, 184 patients who received dronedarone (73.9%) and 141 treated with amiodarone (55.3%) reached the primary end point of "AF recurrence or premature drug discontinuation for intolerance or lack of efficacy" (p<0.001). The hazard ratio at 12 months for dronedarone vs amiodarone was 1.589 (95% CI 1.275-1.980).

The respective absolute rates of recurrent AF were 63.5% and 42.0% and of going off the assigned drug due to intolerance or lack of efficacy were 10.4% (10.0% for intolerance only) and 13.3% (all because of intolerance).

The two groups didn't differ significantly (p=0.1291) in a broad predefined safety end point encompassing multiple end-organ toxicities and withdrawal due to adverse events, according to a company press release. But gastrointestinal side effects were more common with the new drug; gauged by a second prespecified safety end point that excluded such GI effects, dronedarone's adverse-event rate was a significant 39% lower than that of amiodarone (p=0.0021), according to Sanofi-Aventis.

DIONYSOS was not openly discussed much when the FDA panel met to consider dronedarone's approvability. ATHENA and ANDROMEDA were the main drivers behind its decision to recommend approval with a vote of 10 to 3, as covered by heartwire.

"Piccini is supported by an American College of Cardiology Foundation/Merck Award." Of the editorialists, Dr Hakan Oral (University of Michigan, Ann Arbor) reports being a founder of Ablation Frontiers and receiving research grants from Boston Scientific, St Jude Medical, and GlaxoSmithKline.

Sources

1. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089-1095.
2. Hohnloser SH, Crijns HJGM, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668-678.
3. Chan PS, Nallamothu BK, Oral H. Amiodarone or dronedarone for atrial fibrillation: too early to know the winner? J Am Col Cardiol 2009; 54:1096-1098.
4. Sanofi-Aventis. DIONYSOS study results showed the respective profiles of dronedarone and amiodarone [press release]. December 28, 2008. Available here.
5. Sanofi Aventis. Multaq (dronedarone) briefing document. March 18, 2009. Available here.