Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy - PALLAS

Nov 14, 2011
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi-Aventis
Date Presented:
01/01/2011
Date Published:
01/01/2011
Date Updated:
11/14/2011
Original Posted Date:
11/14/2011
References

Description:

The goal of this trial was to evaluate treatment with dronedarone compared with placebo among elderly patients with permanent atrial fibrillation.

Hypothesis:

Dronedarone will prevent major adverse cardiovascular events.

Study Design

  • Randomized
  • Blinded
  • Placebo Controlled
  • Parallel

Patient Populations:

  • Patients at least 65 years of age with permanent atrial fibrillation (at least 6 months) and at least one additional high-risk criteria: coronary artery disease, prior stroke or transient ischemic attack, symptomatic heart failure (except NYHA class II or III), left ventricular ejection fraction <40%, peripheral artery disease, age >70 years with hypertension and diabetes

    Number of enrollees: 3,236
    Median follow-up: 3.5 months

Exclusions:

  • Paroxysmal or persistent atrial fibrillation
  • Use of a defibrillator
  • Bradycardia (<50 bpm)
  • Prolonged QTc interval (>500 msec)

Primary Endpoints:

  • Time to the first occurrence of stroke, systemic arterial embolism, myocardial infarction, or cardiovascular death
  • Time to the first occurrence of unplanned cardiovascular hospitalization, or all-cause death

Secondary Endpoints:

  • Death from cardiovascular causes
  • Death from arrhythmia
  • Recurrent hospitalization for cardiovascular reasons
  • Total nights in the hospital for cardiovascular reasons
  • Acute coronary syndrome
  • Stroke or systemic embolism
  • Hospitalization for heart failure
  • Heart failure episode without hospitalization
  • Hospitalization for heart failure episode
  • Death from any cause 

Drug/Procedures Used:

Patients at least 65 years of age with permanent atrial fibrillation and risk factors for a major vascular event were randomized to dronedarone 400 mg twice daily (n = 1,619) versus placebo twice daily (n = 1,617).

Concomitant Medications:

All patients received antithrombotic and antiarrhythmic medications as appropriate. Drugs known to prolong the QT interval were prohibited.

Principal Findings:

The trial was terminated early due to an increase in adverse cardiovascular events among dronedarone-treated patients. Overall, 3,236 patients were randomized. The mean age was 75 years, 35% were women, 41% had coronary artery disease, 27% had prior stroke or transient ischemic attack, mean heart rate was 77 bpm, mean systolic blood pressure was 133 mm Hg, mean CHADS2 score was 2.8, and 69% of participants had atrial fibrillation for >2 years.

At 4 months, sinus rhythm was present in 3.5% of the dronedarone group versus 1.4% of the placebo group.

The first co-primary outcome of stroke, systemic arterial embolism, myocardial infarction, or cardiovascular death occurred at a rate of 8.2 events per 100 patient-years in the dronedarone group versus 3.6 events per 100 patient-years in the placebo group (p = 0.002).

The second co-primary outcome of unplanned cardiovascular hospitalization or all-cause death occurred at a rate of 25.3 events per 100 patient-years versus 12.9 events per 100 patient-years (p < 0.001), respectively.

Frequencies of the following individual outcomes are reported as events per 100 patient-years. All-cause mortality: 4.7 versus 2.4% (p = 0.049), cardiovascular death: 4.0 versus 1.9 (p = 0.046), death from arrhythmia: 2.5 versus 0.8 (p = 0.03), any stroke: 4.4 versus 1.9 (p = 0.02), myocardial infarction: 0.6 versus 0.4 (p = 0.64), and heart failure hospitalization: 8.3 versus 4.6 (p = 0.02), respectively.

Interpretation:

Among elderly patients with permanent atrial fibrillation and risk factors for a vascular event, the use of dronedarone was associated with a highly significant increase in major adverse cardiovascular events. This was due to an increase in cardiovascular death, stroke, and heart failure. The mechanism for the increase in adverse events is unclear; however, dronedarone increased levels of digoxin from 1.1 to 1.5 ng/ml. Digoxin levels >1.2 ng/ml have previously been associated with harm. Dronedarone was also associated with increased mortality in the ANDROMEDA trial, which enrolled patients with moderate to severe heart failure.

Dronedarone is currently approved for use among patients with nonpermanent atrial fibrillation (ATHENA trial), and this study does not change that indication. Management of permanent atrial fibrillation centers on rate-control and stroke prevention. It is unclear why the use of a long-term antiarrhythmic medication in patients with permanent atrial fibrillation was hypothesized to reduce adverse cardiovascular outcomes. In fact, most dronedarone-treated patients remained in atrial fibrillation.

References:

Connolly SJ, Camm AJ, Halperin JL, et al., on behalf of the PALLAS Investigators. Dronedarone in High-Risk Permanent Atrial Fibrillation. N Engl J Med 2011;Nov 14:[Epub ahead of print].

Presented by Dr. Stuart Connolly at the American Heart Associatioin Scientific Sessions, Orlando, FL, November 14, 2011.

U.S. Food and Drug Administration. FDA Drug Safety Communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm. July 21, 2011.

Keywords: Myocardial Infarction, Stroke, Ischemic Attack, Transient, Follow-Up Studies, Digoxin, Peripheral Arterial Disease, Blood Pressure, Risk Factors, Heart Rate, Heart Failure, Stroke Volume, Embolism, Hypertension, Diabetes Mellitus


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