Dronedarone a Hazard in High Risk Patients With Permanent AF

November 14, 2011

Updated November 14, 2011 (Orlando, Florida) — The latest chapter in the uneasy history of dronedarone (Multaq, Sanofi-Aventis) became official with today's publication of the international Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study and its presentation here at the American Heart Association 2011 Scientific Sessions [1].

As heartwire reported in July 2011, the randomized test of dronedarone in high-CV-risk patients with permanent atrial fibrillation (AF) was halted early at an enrollment of 3236 out of a planned >10 000 patients. An interim analysis showed a significant increase in CV events in patients receiving dronedarone.

With the PALLAS data now detailed in the New England Journal of Medicine, it's apparent that the dronedarone-related CV events over a median follow-up of 3.5 months consisted largely of stroke, heart failure, CV death, and arrhythmic death. Those events contributed to significant increases, by a factor of about two, in the trial's pair of co–primary end points: stroke, MI, systemic embolism, or CV death; and death or unplanned CV hospitalization. The significant effect of dronedarone on those end points held regardless of NYHA functional class or LVEF.

Dr Stuart J Connolly

The findings are in contrast to those of the ATHENA trial, which included somewhat lower-CV-risk patients with recent paroxysmal or intermittent AF and had a 24% drop in the primary end point of death or CV hospitalization over 21 months. ATHENA was the basis for the FDA approval of dronedarone in July 2009.

On the other hand, CV mortality went up in patients at increased CV risk due to heart failure who received dronedarone in the ANDROMEDA trial. PALLAS patients were at increased CV risk due to age (>65 years), with permanent AF for at least six months and at least one other CV risk factor, such as coronary artery disease, prior cerebrovascular event, history of heart-failure hospitalization, LV systolic dysfunction, or diabetes with advanced age.

"Our data show that dronedarone is hazardous in such patients," write the publication's authors, led by Dr Stuart J Connolly (Population Health Research Institute and McMaster University, Hamilton, ON). "It is reasonable to conclude that dronedarone should be avoided in patients with heart failure and other advanced cardiovascular disease, particularly when they also have permanent atrial fibrillation."

Who Should Get Dronedarone?

At a briefing on PALLAS for the media, Dr Mark Estes III (Tufts University Medical Center, Boston, MA), who wasn't involved in the trial, observed that current guidelines state that dronedarone is a reasonable option for maintaining sinus rhythm in paroxysmal or persistent atrial fibrillation in the absence of structural heart disease and for those with coronary disease but no heart failure. "I think that those guidelines still apply with a couple of caveats." Estes was the invited formal discussant following Connolly's live presentation of PALLAS.

Dr Mark Estes III

A major question following PALLAS, Estes said, is whether dronedarone should be used even in the lower-risk ATHENA-type patients for whom it is currently approved. "Personally, I think patients taking dronedarone who fit the ATHENA profile should be monitored regularly, at least every six months, to ensure that they remain within the approved indication and don't progress to permanent atrial fibrillation or new or worsening heart failure. And if clinicians do elect to initiate or continue dronedarone in ATHENA-type patients, they should be sure that the patients maintain in that profile."

To heartwire , Connolly said that avoiding the use of dronedarone in patients at risk for heart failure "pushes us toward a more limited population in which we can use it safely: symptomatic patients with intermittent atrial fibrillation." Even patients with asymptomatic LV systolic or diastolic dysfunction, he speculated, should probably not receive dronedarone. Clinicians, he said, "will want to be pretty careful about that."

But in the appropriate patients, he agreed, "a six-month follow-up of some sort, [perhaps] checking the ECG, would seem to be a reasonable way to monitor whether or not patients have gone into permanent atrial fibrillation."

Hazard Ratio (95% CI) for Clinical End Points, Dronedarone vs Placebo, Over a Median of 3.5 Months in PALLAS

End point HR (95% CI) p
Co–primary end point: stroke, MI, systemic embolism, or CV death 2.29 (1.34–3.94) 0.002
Co–primary end point: death or unplanned CV hospitalization 1.95 (1.45–2.62) <0.001
Mortality 1.94 (0.99–3.79) 0.049
CV death 2.11 (1.00–4.49) 0.046
Arrhythmic death 3.26 (1.06–10.00) 0.03
Stroke 2.32 (1.11–4.88) 0.02
HF hospitalization 1.81 (1.10–2.99) 0.02
HF event or hospitalization 2.16 (1.57–2.98) <0.001

In an editorial accompanying the PALLAS report [2], Dr Stanley Nattel (Montreal Heart Institute and University of Montreal, QC) writes, "Patients with permanent atrial fibrillation have no reason to receive antiarrhythmic drugs, and on the basis of the PALLAS findings, they should certainly not receive dronedarone." He adds that the drug should also be avoided in "high-risk patients with nonpermanent atrial fibrillation," especially those with heart failure.

Given the addition of PALLAS to ATHENA and ANDROMEDA, he writes, "It will be necessary . . . to reserve dronedarone for selected low-risk patients with persistent or paroxysmal atrial fibrillation, possibly those in whom other antiarrhythmic drugs have failed."

Dr Peter Kowey

Dr Peter Kowey (Lankenau Medical Center, Wynnewood, PA), also addressing the media and also not with the PALLAS trial, agreed that such a low-vascular-risk population is the appropriate one for dronedarone. "It all comes down to making sure that if you treat somebody with atrial fib with this drug, in fact there's a prayer and potential for them to maintain sinus rhythm."

Connolly proposed that the difference between patients in ATHENA and PALLAS in type of atrial fibrillation might be greater than clinicians may appreciate. "I think as cardiologists, we tend to think of atrial fibrillation as running along a continuum from short intermittent episodes to more persistent episodes and finally to permanent, with some progression of their vascular disease along the way--we tend to think of it as one disease process," Connolly said.

"This trial [PALLAS] really makes us think that this is not the case, that something unique seems to have changed between the ATHENA population and the PALLAS population, because there was such a dramatically different response to exactly the same drug."

Why More Arrhythmic Deaths?

The increased CV death with dronedarone was driven by a jump in arrhythmic death, Connolly et al note. "This finding was surprising, since dronedarone had not been associated with proarrhythmic toxic effects in previous studies in animals, and in ATHENA, dronedarone significantly reduced the tertiary outcome of death from arrhythmia by 45%."They speculate on a possible explanation. "In our study, almost one-third of patients were receiving digoxin, and in these patients, dronedarone increased digoxin serum levels by 33%, from 0.9 to 1.2 ng/mL," they write. "It is therefore possible that digoxin toxicity induced by dronedarone played a role in the increased cardiovascular mortality."

According to editorialist Nattel, digoxin use in PALLAS was similar to that in ANDROMEDA, but in both trials it was still only about 30%. "It is hard to see how digitalis toxicity could explain the increased rates of stroke and heart failure."

Dronedarone was associated with a number of side effects. "Any serious adverse event leading to treatment discontinuation" occurred in 13.1% of dronedarone patients and 5% of controls (p<0.001). The most common adverse events were diarrhea, asthenia, nausea and vomiting, dizziness, dyspnea, and bradycardia, all of which were significantly increased in the dronedarone group.

PALLAS was supported by Sanofi-Aventis. Connolly discloses receiving a grant for his institution and a consulting fee or honorarium from Sanofi-Aventis. Disclosures for the coauthors are listed on the journal website. Nattel discloses being a board member for Merck and Pierre Fabre; having consulted for Bayer Pharma, Nyken Pharma, Pierre Fabre, and Cardiome; having received grants or grants pending from Pierre Fabre and AstraZeneca; being paid for lectures by Biosense Webster, Sanofi-Aventis, and Pfizer; and being listed as inventor for a European patent owned by the Montreal Heart Institute.


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