PAPABEAR: Prophylactic Amiodarone for the Prevention of Arrhythmias That Begin Early After Revascularization

Luis Gruberg, MD, FACC

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: L. Brent Mitchell, University of Calgary (Alberta, Canada)

Atrial fibrillation (AF) and atrial flutter (AFL) are the most common complications in patients who undergo cardiac surgery. Known to occur in ~30% of coronary artery bypass graft (CABG) surgeries, 40% of valvular surgeries, and 50% of combined procedures, these supraventricular arrhythmias are not completely benign and have been associated with adverse events, comorbidities, and prolonged hospitalization. Furthermore, they are difficult to prevent, as no widely available therapy has been shown to be effective.

Aim

The Prophylactic Amiodarone for the Prevention of Arrhythmias That Begin Early After Revascularization (PAPABEAR) study was designed to evaluate whether the prophylactic use of amiodarone is an effective, well-tolerated, and safe therapy for the prevention of postoperative AF and AFL in young and old patients undergoing CABG or valvular surgery with or without concomitant beta-blocker therapy.

Study Design

Patients of either sex undergoing nonemergent CABG or valvular repair or replacement were included in the study. Patients with the following characteristics were excluded from the study:

  • Prior sustained AF/AFL

  • Ongoing antiarrhythmic or amiodarone treatment in the past 3 months

  • NYHA heart failure class IV

  • Recent myocardial infarction (< 2 weeks)

  • Awake sinus rate < 50 bpm, QTc ≥ 480 ms, PR > 220 ms

  • Second- or third-degree atrioventricular block

  • Chronic lung disease

  • Clinical neuropathy

  • Thyroid disease

Patients who met the inclusion/exclusion criteria underwent randomization to either amiodarone (10 mg/kg/day divided in 2 doses) or placebo 1-6 days before and after the procedure. Patients were stratified by age < or > 65 years, CABG only or CABG plus valvular surgery, and the use or absence of preoperative beta-blocker therapy.

The primary endpoint of the study was AF/AFL during the postoperative period (0 to 6 days).

Secondary endpoints included AF/AFL characteristics, time to arrhythmia and burden of AF/AFL, duration of hospitalization, and potential side effects from amiodarone.

Investigators projected that the use of amiodarone would reduce the incidence of AF/AFL to 30% and that the overall results would detect an absolute 10% reduction in primary AF/AFL.

Results

A total of 600 patients were randomized to amiodarone (n = 299) or placebo (n = 301). Baseline clinical characteristics were similar between the 2 groups, and there were no significant differences in the length of the procedures, duration of pump use, or cross clamp time (Table).

Table. PAPABEAR: Baseline Clinical and Procedural Characteristics
  Amiodarone
(n = 299)
Placebo
(n = 301)
Age (yrs) 61 62
Male (%) 83 82
Coronary artery disease (%) 75 74
Hypertension (%) 52 53
Diabetes (%) 25 21
CHF (%) 25 25
CVA/TIA (%) 9 7
Preoperative beta-blocker (%) 59 56
Procedural time (hour) 2.64 2.68
Pump time (hour) 1.23 1.29
Cross clamp time (hour) 0.89 0.94
CHF, congestive heart failure; CVA/TIA, cerebrovascular accident/transient ischemic attack

There was a significantly higher incidence of AF/AFL in patients randomized to the placebo arm (Figure 1). In the amiodarone-treated patients, ventricular response was significantly slower than in patients in the placebo arm (105 bpm vs 131 bpm, respectively; P < .001). However, there were no significant differences between the groups with regard to the day of arrhythmia onset, longest duration of arrhythmia, or AF/AFL burden. In addition, there was no significant difference in the postoperative complication rates or in all-cause mortality between the 2 groups (Figure 2).

Figure 1. PAPABEAR: incidence of AF/AFl.
Figure 2. PAPABEAR: postoperative complications.

The benefit from amiodarone treatment was maintained across all of the subgroups analyzed (Figure 3). However, the rate of any adverse event was higher in the amiodarone group (Figure 4). There was no difference in the length of hospital stay between the 2 groups, but a favorable trend in hospital discharge ≤ day 6 was noted in the amiodarone-treated group compared with placebo (54% vs 48%, respectively).

Figure 3. PAPABEAR: subgroup analyses.
Figure 4. PAPABEAR: adverse events.
Conclusions

On the basis of the PAPABEAR study results, investigators concluded that the use of perioperative amiodarone therapy:

  • Effectively prevents postoperative AF/AFl in young and old patients undergoing CABG, or CABG plus valvular surgery, with or without the concomitant use of beta-blockers

  • Slows ventricular response

  • Fosters early patient discharge

  • Has a low adverse-effect profile and is not associated with postoperative complications or mortality

Discussant

Douglas P. Zipes, MD, Krannert Institute of Cardiology at Indiana University (Indianapolis, Indiana), commented that various studies have been conducted to determine pharmacologic approaches to preventing postoperative AF in cardiac surgery patients. In addition to the benefits shown in these smaller drug studies, biatrial AAI pacing has also been demonstrated to reduce the incidence of postoperative AF.

Dr. Zipes noted that PAPABEAR is the largest study conducted to date that supports the findings of the smaller studies, and added that the present study was very well performed, with appropriate inclusion and exclusion criteria, appropriate randomization, and appropriate endpoints.

Unexpectedly, there was no difference between the amiodarone and placebo groups with regard to the day of onset of AF, the number of patients, or the longest AF episode. He questioned why amiodarone reduced the total number of patients with AF but failed to show differences between the amiodarone and placebo groups with regard to these parameters.

Nevertheless, the findings of this study and others indicate that there is sufficient data to support the routine use of preoperative drugs to prevent postoperative AF in cardiac surgery patients.

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