Intravenous Plus Oral Amiodarone, Atrial Septal Pacing, or

Both Strategies to Prevent Post-Cardiothoracic Surgery

Atrial Fibrillation: The Atrial Fibrillation Suppression
Trial II (AFIST II)
C. Michael White, PharmD; Michael F. Caron, PharmD; James S. Kalus, PharmD; Heidi Rose, RN;
Jessica Song, PharmD; Prabashni Reddy, PharmD; Robert Gallagher, MD; Jeffrey Kluger, MD

Background—The effect of a hybrid intravenous and oral prophylactic amiodarone regimen on postcardiothoracic surgery
(CTS) atrial fibrillation (AF) is unknown. The impact of active atrial septal pacing on post-CTS AF has not been well
characterized. In addition, the effect of using both amiodarone and atrial septal pacing together to prevent atrial
fibrillation is unknown.
Methods and Results—Patients (n⫽160) were randomized to amiodarone or placebo and then to pacing or no pacing using
a 2⫻2 factorial design. All therapies began within 6 hours post-CTS. Amiodarone was given by intravenous infusion
for the first 24 hours (1050 mg total) followed by oral therapy for 4 postoperative days (4800 mg total). Atrial septal
pacing was given for 96 hours. Amiodarone reduced the risk of AF by 43% and the risk of symptomatic AF by 68%
(P⫽0.037 and P⫽0.019) versus placebo. Atrial septal pacing did not reduce AF or symptomatic AF incidence versus
no pacing. The risk of post-CTS AF in the patients receiving amiodarone⫹pacing was lower than the placebo⫹no
pacing and the placebo⫹pacing groups (57.9% and 60.5% reductions, P⫽0.047 and P⫽0.040, respectively).
Conclusions—Amiodarone given as both an intravenous and oral regimen is effective at reducing post-CTS AF but atrial
septal pacing is ineffective. Combining amiodarone and pacing is better than placebo with or without pacing but not
amiodarone alone. (Circulation. 2003;108[suppl II]:II-200-II-206.)
Key Words: atrial fibrillation 䡲 amiodarone 䡲 pacemaker 䡲 artificial
Downloaded from http://ahajournals.org by on January 16, 2023

O ver 750,000 cardiothoracic surgeries (CTS; ie, bypass

and heart valve surgery) are performed annually in the
United States.1 Without prophylaxis, atrial fibrillation (AF)
develops in up to 65% of post-CTS patients with two-thirds
of cases arising on postoperative days 2 and 3.2 Clinical
consequences of AF can include hemodynamic instability,
ventricular arrhythmias, and stroke.2
Beta-blocker prophylaxis reduces the incidence of AF
post-CTS.3,4 Despite beta-blocker use, the incidence of AF
remains approximately 30% and could be due to inadequate
dosing clinically and the withdrawal of beta-blockade before
postoperative day 3.2,5–7 Amiodarone, sotalol, and biatrial
pacing are acceptable alternative strategies.3
In the Atrial Fibrillation Suppression Trial (AFIST), we
compared oral amiodarone to placebo.7 Amiodarone was
given in either a 5- or 1-day preoperative loading regimen
followed by therapy for 5 postoperative days (delivering 7g
or 6g total, respectively). The risk of atrial fibrillation was
reduced by 41% and the risk of ventricular arrhythmia or
stroke was reduced by 76% in amiodarone treated patients.
When each amiodarone dosing strategy was evaluated sepa-
rately, there were qualitatively better effects in the 5-day
loading group as compared with the 1-day group in atrial
fibrillation parameters.8 Whether the differences reflect the
higher dose or longer duration of therapy is not known.
Intravenous (IV) amiodarone has better bioavailability than
oral (100% versus 50%) amiodarone, has a rapid onset of
action, and does not produce nausea in higher doses.9 In a
small study of 77 patients undergoing CTS, IV amiodarone
reduced the incidence of post-CTS AF (5% versus 21%,
respectively, P⬍0.05).10 Whether an IV and oral hybrid
regimen begun after CTS and delivering the equivalent to 7 g
of oral amiodarone in our AFIST trial would provide efficacy
among patients already receiving beta-blockade as part of a
clinical pathway is unknown.
Seven trials evaluated prophylactic temporary epicardial
bi-atrial pacing to prevent post-CTS atrial fibrillation.3 In a
meta-analysis of these trials, bi-atrial pacing reduced the risk

From the Divisions of Cardiology, Drug Information, and Cardiac Surgery at Hartford Hospital, Hartford, CT, and the School of Pharmacy, University
of Connecticut, Storrs, CT.
Correspondence to Jeffrey Kluger, MD, Director, Arrhythmia Service, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102-5037. Phone:
860-545-2883; Fax: 860-545-2756; E-mail: Jkluger@harthosp.org.
This study was sponsored by the Hartford Hospital Research Foundation in Hartford, CT. Pacerone and matching oral placebo tablets were donated
by Upsher-Smith Pharmaceuticals, Minneapolis, MN, while external pacemaker boxes were donated by Medtronic Corporation, Minneapolis, MN.
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.cir.0000087445.59819.6f

II-200
 White et al
of atrial fibrillation significantly (OR 0.46, 95% CI 0.30 to
0.71). However, therapy required the placement of two
epicardial pacing wires rather than the one.3 In 1 trial, there
was no benefit from right atrial or bi-atrial pacing in the total
population but in the subset on beta-blockers, there was a
trend toward lower post-CTS atrial fibrillation in post-hoc
analysis.11 The reason for this effect was not known and if it
relates to other antiadrenergic drugs such as amiodarone is
not known. Whether pacing through a single epicardial wire
placed in the atrial septum, the electrical connection between
the atria, can prevent post-CTS atrial fibrillation and the
impact of concurrent adjunctive amiodarone on efficacy is
unknown. Preliminary investigations in patients with atrial
fibrillation unrelated to CTS found 74% of patients free from
chronic atrial fibrillation post-implantation versus only 47%
in those receiving right atrial appendage pacing (P⫽0.01).12
The Atrial Fibrillation Suppression Trial II was designed to
evaluate the prophylactic use of a hybrid intravenous and oral
amiodarone regimen, atrial septal pacing, or both strategies in
post-CTS patients.
Methods
Study Design
This was a 2⫻2 factorial design study evaluating two active
treatments, amiodarone and atrial septal pacing in post-CTS patients
(n⫽160). Patients were randomized to amiodarone or placebo and
were then randomized to active atrial septal pacing or no active atrial
septal pacing. Using stratified allocation, CABG, and valve surgery
patients were randomized separately to ensure equal distribution
between groups. This study was designed as a management trial in
Downloaded from http://ahajournals.org by on January 16, 2023
that the recommended treatment regimens were established by study
investigators and available to clinicians but the patient’s physician
determined whether to adjust regimen intensity or to discontinue
therapy without investigator consultation. The Institutional Review
Boards of Hartford Hospital and the University of Connecticut
approved the study with written informed consent being obtained
prior to surgery.
Study Subjects
Patients over 50 years of age scheduled to undergo coronary artery
bypass grafting or heart valve surgery at Hartford Hospital were
screened. Patients could be excluded for the following reasons: (1)
chronic atrial fibrillation or flutter; (2) known amiodarone hypersen-
sitivity; (3) current use of class I or class III antiarrhythmics; (4)
current use of Implantable Cardioverter Defibrillators (ICD) or
implantable pacemakers; (5) cardiogenic shock or advanced conges-
tive heart failure (NYHA class IV); (6) marked sinus bradycardia
(HR ⬍50 bpm) or second or third degree AV block; (7) patients with
moderate to severe liver disease; or (8) current use of cyclosporine,
cimetidine, phenytoin, or cholestyramine.
Overall, 671 patients were screened and 511 patients were
excluded from participating for the following reasons: age (n⫽91),
amiodarone drug interaction (n⫽3), antiarrhythmic use (n⫽42),
atrial fibrillation (n⫽58), heart block/bradycardia (n⫽11), pac-
maker/ICD implantated (n⫽24), patient declined (n⫽102), physician
refusal (n⫽32), already enrolled in a competing study (n⫽129), or
shock/Class IV heart failure (n⫽3).
Experimental Regimens/Patient Management
Patients received a 1050 mg IV loading dose of amiodarone
(Cordarone, Wyeth Ayerst, Philadelphia, PA) as a continuous infu-
sion over 24 hours beginning within 6 hours postsurgery or matching
placebo. This was followed by 400 mg of oral amiodarone (Pac-
erone, Upsher-Smith, Minneapolis, MN) 3 times a day on postoper-
ative days 1 to 4 (4800 mg total oral drug) or matching placebo. This
Preventing Post-CTS Surgery AF II-201
Figure 1. Pacing protocol.
IV and oral regimen delivers the equivalent of 6900 mg of oral
amiodarone.
All patients in the study had epicardial pacemaker wires placed in
the atrial septum at Bachmann’s Bundle, the anatomical electrical
connection between the left and right atrium. A temporary PM
generator (TPM dual chamber, Medtronic, Minneapolis, MN) was
programmed to AAI mode and set up according to the protocol in
Figure 1. Atrial septal pacing was initiated within 6 hours of CTS
and continued for 96 hours.
As part of the institution’s CTS critical pathway, the preprinted
admission order sheet includes beta-blockers. Patients initially were
cared for within the cardiothoracic intensive care unit before transfer
to a monitored bed. The hospital telemetry equipment (Marquette,
Milwaukee, WI) saves all abnormal rhythms in the previous 24-
hours and a certified technician continuously monitored the alarm-
triggered equipment printing out abnormal strips. A study investiga-
tor obtained a 12-lead ECG daily (MAC500, Marquette, Wisconsin,
WI) on and off pacing, evaluated pacing threshold measurements,
and reviewed the previous 24-hours of recording with the study
physician for the occurrence of arrhythmias. Patient care was
provided by the patient’s hospital clinicians including the manage-
ment of atrial fibrillation, other arrhythmias, and hemodynamic
issues.
Trial Endpoints
The primary endpoint was the development of atrial fibrillation
within 30 days of CTS. For the purposes of this study the following
definitions were used: postoperative atrial fibrillation, any docu-
mented atrial fibrillation of more than 5 minutes duration; symptom-
atic atrial fibrillation, associated with hemodynamic compromise
(hypotension, heart failure) requiring treatment or feelings of sub-
jective discomfort (palpitations, chest pain, shortness of breath,
syncope); recurrent atrial fibrillation, atrial fibrillation occurring
more than 24 hours after resolution of a previous episode; and
cerebrovascular accident, development of a transient ischemic attack
(documented focal neurological deficit lasting less than 24 hours) or
stroke (documented focal neurological deficit lasting more than 24
hours with cerebral infarction confirmation via computed tomogra-
phy or magnetic resonance imaging). Patients received a phone call
from a study investigator at 1 week and 1 month postdischarge to
determine if an event occurred. If a post-discharge event was
suggested, the hospital record or the outpatient medical record from
the patient’s physician was garnered to confirm the event.
Post-CTS, side effects reported in the medical chart and side
effects elucidated by study investigators on discussion were
recorded.
 II-202 Circulation September 9, 2003

TABLE 1. Baseline and Surgical Characteristics

Amiodarone Placebo P- Nonpacing Pacing P-
(n⫽77) (n⫽83) Value (n⫽87) (n⫽73) Value
Gender (% male) 76.8 74.7 0.921 75.9 75.3 0.914
Age (years) 66.8⫾9.0 64.9⫾8.3 0.155 66.2⫾9.2 65.3⫾8.1 0.544
AF Hx (%) 2.6 2.4 0.667 4.6 0 0.178
LVEF (%) 48.3⫾12.3 48.0⫾12.7 0.903 49.2⫾12.0 46.9⫾12.9 0.262
Pre-CTS beta-blockers (%) 70.1 74.7 0.639 72.4 72.6 0.880
Metoprolol dosing (mg)** 91.6⫾50.4 89.2⫾63.5 0.838 77.3⫾38.6 106.1⫾70.8 0.011
Hx MI (%) 24.7 26.5 0.933 23.0 28.8 0.514
MR Hx (%) 11.7 20.5 0.196 14.9 17.8 0.784
Valvular surgery (%) 19.5 22.9 0.739 21.8 20.5 0.996
Artery grafts (n) 1.8⫾1.1 1.5⫾1.3 0.071 1.6⫾1.2 1.7⫾1.3 0.471
Total grafts (n) 3.5⫾1.5 3.3⫾1.8 0.274 3.2⫾1.7 3.6⫾1.7 0.126
On-pump cases (%) 44.2 44.6 0.916 42.5 46.6 0.724
Cross clamp time (min) 93.6⫾40.3 98.7⫾45.5 0.622 87.2⫾38.4 107.0⫾45.9 0.049
CTS duration (min) 277.6⫾74.9 299.9⫾164.5 0.282 286.2⫾97.5 292.4⫾158.0 0.761
Fluid in (mL) 2732.9⫾1496.7 2988.9⫾2019.3 0.469 2904.1⫾2052.5 2762.2⫾1366.4 0.683
Fluid out (mL) 2066.3⫾1705.4 1701.2⫾1102.4 0.221 1918.2⫾1655.1 1854.4⫾1099.4 0.826
Net fluid balance (mL) 1107.6⫾1257.8 1322.5⫾1721.5 0.484 1274.4⫾1549.0 1152.6⫾1475.5 0.692
HR⬎100 bpm (%) 9.1 15.7 0.309 12.6 12.3 0.847
SBP⬎180 mm Hg (%) 7.8 19.3 0.06 13.8 13.7 0.831
SBP⬍90 mm Hg (%) 31.2 49.9 0.029 39.1 42.5 0.785
ST ⌬ (%) 2.6 3.6 0.943 4.6 1.4 0.485
Inotropes needed (%) 89.6 83.1 0.338 89.7 82.2 0.256
(n), number; LVEF, left ventricular ejection fraction; Dx, disease; Hx, history; MI, myocardial infarction; CCB, calcium channel
Downloaded from http://ahajournals.org by on January 16, 2023

blocker; FHx, family history; CTS, cardiothoracic surgery.

**Metoprolol dose or metoprolol equivalent dose of atenolol (atenolol dose⫻2⫽metop dose).

Length of Stay/Cost Analysis
This trial was not designed to be powered to detect significant
changes in length of stay or total costs. For each patient enrolled in
the trial, the total costs of care were determined from the time of
randomization through hospital discharge.
Statistical Analysis
Power analysis was for a 2⫻2 fixed effects analysis of variance. The
alpha-value was set at 0.05 and the analysis was set as 2 tails. With
40 cases per cell (4 cells total) and with an estimated effect size of
(f) 0.25, the power is 0.88.
Data are presented as means⫾SD or proportions and a probability
value ⬍0.05 is considered significant for all comparisons. Chi-
square analysis was used to compare categorical data. Student t-tests
were used for two group comparisons of continuous parametric data
while Mann-Whitney tests were used for nonparametric two group
comparisons. One way ANOVA with Bonferroni corrected t-tests
were used for multiple comparisons of parametric data.
Results
Amiodarone versus Placebo
The AFIST II population was 65.8⫾8.7 years of age, 75.6%
male, and 21.3% had valvular surgery. Baseline characteris-
tics in the amiodarone and placebo groups (regardless of
pacing randomization) were similar for all evaluated param-
eters (Table 1). Intraoperative parameters were similar except
for a higher incidence of perioperative hypotension in the
placebo group (Table 1).
The overall risk of atrial fibrillation was reduced by 42.7%,
the mean ventricular response rate was 7.0% slower, and
symptomatic atrial fibrillation was reduced by 68.3% in
amiodarone treated patients versus placebo (P⫽0.037,
P⬍0.0001, and P⫽0.019, respectively). This occurred even
though there was a trend toward higher beta-blocker dosing in
the placebo group (P⫽0.07) (Table 2). Therapy was well
tolerated with no differences in IV or oral consumption of
study drug (Table 2) and no significant differences in safety
endpoints were noted between groups in the trial (Table 3).
Pacing versus No Pacing
Baseline characteristics in the pacing and no pacing groups
(regardless of amiodarone randomization) were similar ex-
cept for greater preoperative beta-blocker dosing in the
pacing group (P⫽0.011) (Table 1). Surgical parameters were
similar except the pacing group had a higher cross clamp time
(P⫽0.049) (Table 1). Pacing was ineffective at preventing
post-CTS atrial fibrillation with no differences in safety
parameters as well (Tables 2 and 3).
Overall, 53.8% of patients in the atrial septal pacing group
discontinued active pacing for a portion of the postoperative
period. Thirty-nine percent of patients stopped active pacing
because their native heart rates exceeded 100 beats per
minute as suggested in our pacing protocol (Figure 1).
Deterioration of clinical status, development of atrial fibril-
 White et al Preventing Post-CTS Surgery AF II-203

TABLE 2. AF Endpoints and Drug Dosing

Amiodarone Placebo P- Nonpacing Pacing P-
(n⫽77) (n⫽83) Value (n⫽87) (n⫽73) Value
AF (%) 22.1 38.6 0.037 33.0 27.4 0.523
Symptomatic AF (%) 6.5 20.5 0.019 13.8 13.7 0.831
Recurrent AF (%) 10.4 13.3 0.753 14.9 8.2 0.287
Beta-blockers post-CTS (%) 80.5 83.1 0.823 78.2 86.3 0.260
Metoprolol dose post-CTS 67.7⫾35.2 78.3⫾31.4 0.070 75.4⫾33.8 71.2⫾34.4 0.493
(mg/day)
Total IV study drug (mg) 980.8⫾246.9 956.4⫾277.0 0.560 972.0⫾256.5 963.6⫾270.6 0.843
Total PO study drug (mg) 3584.4⫾1649.5 3366.3⫾1701.6 0.412 3441.4⫾1669.5 3611.0⫾1618.0 0.517
IV, intravenous; PO, oral; AF, atrial fibrillation; CTS, cardiothoracic surgery.

lation, and technical difficulties such as loss of capture or
problems with pacing wire placement accounted for 28.5%,
26.8%, and 16.7% of the discontinuations, respectively. A
few patients had more than 1 reason to discontinue active
pacing.
In a subgroup analysis, patients in the pacing group were
divided in to those with premature discontinuation and those
continuing pacing until postoperative day 4. There were no
differences in atrial fibrillation between the two subgroups
(34.7% versus 34.3%, P⫽0.838), respectively.
AmiodaroneⴙNo Pacing, PlaceboⴙNo Pacing,
Both Therapies, and PlaceboⴙPacing
Baseline characteristics were similar except for the history of
myocardial infarction which was higher in the
Downloaded from http://ahajournals.org by on January 16, 2023
the placebo⫹pacing group versus the amiodarone⫹pacing
group (P⫽0.078) (Table 6).
No difference in any efficacy parameter was noted between
the amiodarone⫹pacing and amiodarone⫹no pacing groups.
However, the patients receiving amiodarone⫹pacing showed
a trend toward receiving a higher dose of amiodarone than
those receiving amiodarone without pacing (oral dosing
equivalent [(2*IV dose)⫹oral dose] of 5871.3⫾1600.4 ver-
sus 5145.5⫾2205.2, P⫽0.10, respectively).
Length of Stay and Hospital Costs
The index hospitalization length of stay trended lower among
patients receiving amiodarone than those receiving placebo
(7.88⫾6.16 versus 11.36⫾16.83 days, P⫽0.08) but pacing

was not different than no pacing (10.01⫾16.86 versus

placebo⫹pacing group versus the placebo⫹no pacing group
(P⫽0.033). Surgical characteristics were similar between
groups. Table 4 contains selected baseline and surgical
characteristics for the 4 groups.
The risk of post-CTS atrial fibrillation in the amiod-
arone⫹pacing group was lower than the placebo⫹no
pacing and the placebo⫹pacing groups (57.9% reduction,
P⫽0.047 and 60.5% reduction, P⫽0.040, respectively).
Amiodarone⫹pacing reduced the risk of symptomatic
atrial fibrillation by 89.9% as compared with the
placebo⫹pacing group (P⫽0.038) and exhibited a trend
toward lower symptomatic atrial fibrillation versus the
placebo⫹no pacing group (P⫽0.071) (Table 5). Safety
endpoints were similar in the 4 groups for all parameters.
A trend toward less symptomatic bradycardia was noted in
9.41⫾8.43 days, P⫽0.77). Similarly, there was a trend
toward lower costs in the amiodarone treated patients versus
placebo treated patients ($20 737⫾13 878 versus
$29 911⫾45 203, P⫽0.08) but no difference in the pacing
versus no pacing group ($25 970⫾42 546 versus
$25 098⫾25 333, P⫽0.87).
Among the four groups, no significant differences in length
of stay (P⫽0.16) or total costs (P⫽0.27) were found. Qual-
itatively, amiodarone⫹pacing had the lowest length of stay
and hospital costs (6.76⫾3.79 days, $18 697⫾8174) fol-
lowed by: amiodarone ⫹ no pacing (8.97⫾7.71 days,
$22 725⫾17 661), placebo⫹no pacing (9.77⫾9.04,
$27 026⫾30 226), and finally placebo⫹pacing (13.54⫾23.7
days, $33 868⫾60 309).

TABLE 3. Safety Endpoints

Amiodarone Placebo P- Nonpacing Pacing
(n⫽77) (n⫽83) value (n⫽87) (n⫽73) P-Value
CVAs (%) 0 3.6 0.271 2.3 1.4 0.878
Myocardial infarction (%) 2.6 3.6 0.932 2.3 4.1 0.842
Symptomatic bradycardia (%) 11.7 6.0 0.324 10.3 6.8 0.618
Symptomatic hypotension (%) 49.4 37.3 0.170 43.7 42.5 0.995
In house mortality (%) 1.3 2.4 0.948 3.4 0.0 0.309
Nausea (%) 24.7 19.3 0.526 24.1 19.2 0.573
Treatment postponement from nausea (%) 7.8 3.6 0.422 8.0 2.7 0.268
Treatment discontinuation from nausea (%) 5.2 1.2 0.320 4.6 1.4 0.476
CVA, cerebrovascular accidents.
 II-204 Circulation September 9, 2003

TABLE 4. Selected Baseline and Surgical Characteristics with Regard to Drug and Pacing
Group Designation
Placebo⫹No Amiodarone⫹No Placebo⫹Pacing Amiodarone⫹Pacing
Pacing (n⫽48) Pacing (n⫽39) (n⫽35) (n⫽38)
Gender (% male) 72.9 79.5 77.1 73.7
Age (years) 64.8⫾9.1 67.9⫾9.1 65.0⫾7.3 65.7⫾8.9
AF Hx (%) 4.2 5.1 0 0
LVEF (%)
Pre-CTS beta-blockers (%) 77.1 66.7 71.4 73.7
Metoprolol dose (mg)** 77.2⫾37.6 89.4⫾48.6 112.5⫾79.1 103.0⫾60.2
Hx MI (%) 16.7 30.8 66.7* 22.6
MR Hx (%) 20.8 7.7 20 15.8
Valvular surgery (%) 25.0 17.9 20.0 21.1
Artery grafts (n) 1.5⫾1.2 1.9⫾1.1 1.7⫾1.4 1.8⫾1.1
Total grafts (n) 3.0⫾1.8 3.5⫾1.4 3.7⫾1.7 3.6⫾1.6
On-pump cases (%) 41.7 43.6 48.6 44.7
Cross clamp time (min) 89.9⫾36.5 85.5⫾42.2 109.5⫾53.8 101.7⫾37.9
CTS duration (min) 290.3⫾109.5 281.0⫾80.9 312.0⫾216.5 274.3⫾69.2
Fluid in (mL) 2884.3⫾2267.3 2962.7⫾1727.5 3202.2⫾1490.7 2526.5⫾1254.6
Fluid out (mL) 1462.5⫾1114.6 2498.7⫾2065.0 2014.0⫾1013.2 1660.2⫾1193.7
Net fluid balance (mL) 1372.1⫾1706.3 1141.2⫾1332.8 1248.2⫾1785.9 1079.1⫾1217.3
HR⬎100 bpm 14.6 10.3 17.1 7.9
SBP⬎180 mm Hg 16.7 10.3 22.9 5.3
SBP⬍90 mm Hg 47.9 28.2 51.4 34.2
ST ⌬ intra-op 6.3 2.6 0.0 2.6
Inotropes needed 89.6 89.7 74.3 89.5
Downloaded from http://ahajournals.org by on January 16, 2023

*Denotes P⫽0.033 for pacing⫹placebo, versus neither therapy. No other significant differences or trends found.
**Metoprolol dose or metoprolol equivalent dose of atenolol (atenolol dose⫻2⫽metop dose). Neuro Dz⫽history of
neurological disease.

Discussion were done in addition to the hospital’s standard of care

We found that a hybrid intravenous and oral amiodarone
regimen was effective at reducing post-CTS atrial fibrillation
and symptomatic atrial fibrillation but atrial septal pacing was
ineffective. Patients receiving both amiodarone and pacing
had significantly lower atrial fibrillation rates than those
receiving placebo with or without pacing. The groups with
the lowest rate of atrial fibrillation had the lowest length of
stay and total hospital costs. These experimental interventions
therapy, beta-blockade. Beta-blockade was utilized post-CTS
in over 80% of study patients.
We evaluated a hybrid regimen with intravenous ami-
odarone being given initially after surgery followed by oral
therapy for post-CTS atrial fibrillation prevention. Studies
have previously evaluated solely intravenous or oral ami-
odarone regimens. Using intravenous therapy for the first
24-hours post-CTS has several advantages over oral dosing

TABLE 5. AF Endpoints and Drug Dosing With Regard to Drug and Pacing Group Designation
Placebo⫹No Amiodarone⫹No Placebo⫹Pacing Amiodarone⫹Pacing
Pacing (n⫽48) Pacing (n⫽39) (n⫽35) (n⫽38)
AF (%) 37.5† 28.2 40.0† 15.8
Symptomatic AF (%) 16.7‡ 10.3 25.7† 2.6
Recurrent AF (%) 16.7 12.8 8.6 7.9
Beta-blockers post-CTS (%) 81.3 74.4 85.7 86.8
Metoprolol dose post-CTS (mg/day)** 82.1⫾29.2 67.9⫾36.6 74.1⫾34.3 65.6⫾31.6
Total IV study drug (mg) 980.8⫾243.4 960.5⫾275.6 925.4⫾314.8 998.8⫾221.0
Total PO study drug (mg) 3462.5⫾1600.6 3410.5⫾1773.0 3325.7⫾1785.6 3873.7⫾1419.9
**Metoprolol dose or metoprolol equivalent dose of atenolol (atenolol dose⫻2⫽metop dose).
†denotes P⬍0.05 versus amiodarone⫹pacing group.
‡denotes P⬎0.05 but ⬍0.10 versus amiodarone⫹pacing group.
No other significant differences found.
 White et al
TABLE 6. Safety Endpoints With Regard to Drug and Pacing Group Designation
Placebo⫹No Pacing
(n⫽48)
CVAs (%) 4.2
Myocardial infarctions (%) 4.2
Symptomatic bradycardia (%) 10.4
Symptomatic hypotension (%) 37.7
In house mortality (%) 4.2
Nausea (%) 18.8
Treatment postponement from nausea (%) 4.2
Treatment discontinuation from nausea (%) 2.1
No significant differences or trends noted for any parameter. CVA, cerebrovascular accidents.
regimens. Patients are transferred to the surgical intensive
care unit post-CTS and initially receive drugs via nasogas-
tric tube; the percent absorption of oral amiodarone from
the gut of a post-CTS patient is unknown; and there is a
limit to how much oral amiodarone you can load a patient
with because of the risk of nausea. This is why previous
oral amiodarone trials have utilized preoperative loading.
Although preoperative loading reduces the amount of drug
needing to be delivered immediately after CTS, it excludes
patients who do not have the specified number of days
before CTS for oral loading. Having multiple oral amiod-
arone regimens for patients with varying numbers of days
from the day the surgery is scheduled until it takes place is
cumbersome clinically.
Downloaded from http://ahajournals.org by on January 16, 2023
If the a hybrid intravenous and oral regimen provides
similar efficacy as an all-intravenous regimen, there would be
cost advantages to the hybrid regimen. For example, supply-
ing all of the amiodarone utilized in this trial intravenously
would have an average wholesale cost of $2277.00 versus
only $748.00 with our hybrid regimen. In addition, we
utilized a bioequivalent and less expensive brand of amiod-
arone tablets (oral Pacerone®) rather than Cordarone®.
Previous trials of intravenous amiodarone and our original
AFIST trial suggest that the dose of amiodarone delivered
and not the duration of therapy is the important factor in
preventing post-CTS atrial fibrillation. A 4-day intravenous
amiodarone regimen was conducted with 2700 mg being
given over the first 2 days postcoronary artery bypass surgery
and 1800 mg being given over the next 2 days (equivalent to
9 g of oral drug).10 In that trial, patients experienced a 76%
reduction in the risk of atrial fibrillation in the amiodarone
group versus placebo. In another trial, patients undergoing
either coronary artery bypass or valvular surgery received 2 g
of intravenous amiodarone over 2 days (equivalent to 4 g
orally). The atrial fibrillation rate among amiodarone treated
patients was reduced by 25% versus placebo group.13 Our
AFIST II regimen delivered the equivalent of 7 g of oral
amiodarone with 43% reductions in atrial fibrillation falling
between those of the 2 previous IV amiodarone studies. These
results are also consistent with the 48% reduction in atrial
fibrillation from AFIST where 7 g of oral amiodarone was
given over 10-days beginning 5 days before CTS.8
We utilized atrial septal pacing to prevent post-CTS atrial
fibrillation. Historically, epicardial pacing wires were placed
Preventing Post-CTS Surgery AF II-205
Amiodarone⫹No Pacing Placebo⫹Pacing Amiodarone⫹Pacing
(n⫽39) (n⫽35) (n⫽38)
0.0 2.9 0.0
0.0 2.9 5.3
10.3 0.0 13.2
51.3 37.1 47.4
2.6 0.0 0.0
30.8 20.0 18.4
12.8 2.9 2.6
7.7 0.0 2.6
on the right atrium during CTS and used only in cases of
symptomatic bradycardia.3 Most of the clinical trial experi-
ence using active pacing to prevent atrial fibrillation is with
biatrial pacing in which an epicardial atrial pacing wire is
placed on each atria.3 However, placing 2 epicardial wires
requires additional work on behalf of the surgeons. We had
hoped that atrial septal pacing would provide efficacy similar
to that seen with biatrial pacing in post-CTS patients and
would provide efficacy as was seen previously in the chronic
atrial fibrillation setting.12
Even though atrial septal pacing was ineffective overall, it
was effective at preventing post-CTS atrial fibrillation in
combination with amiodarone. This is similar to one study of
right atrial and biatrial pacing where therapy was ineffective
overall but efficacious in the subset of patients receiving
beta-blockade.11 In our trial the patients receiving amiodarone
with pacing received the oral equivalent of 726 mg in
additional amiodarone versus those receiving amiodarone
without pacing. This suggests that pacing may prevent
clinicians from reducing the dose or discontinuing anti-
adrenergic therapy.
Study Limitations
With a larger sample size, the impact of amiodarone, pacing,
and the combination of the two therapies on length of hospital
stay, total hospital costs, and cerebrovascular accident risk
could have been adequately explored. Greater investigator
control over the use of standard of care beta-blockade dosing,
post-CTS treatment of episodes of atrial fibrillation, and
when and whether to discontinue or postpone investigational
therapy would have increased the internal validity of the
study but would have done so at the expense of external
validity. We sought to explore the impact of these therapies as
they would be employed in the “real world” and feel we
achieved this aim. However, this meant that a large propor-
tion of patients (53.8%) did not receive continuous atrial
septal pacing which could have impacted the success of this
treatment. In our subgroup analysis of the patients receiving
pacing, premature discontinuation of pacing did not seem to
impact results versus sustained pacing for four postoperative
days.
Conclusions
A hybrid regimen with intravenous and oral amiodarone
given to post-CTS patients reduces the risk of atrial fibrilla-
 II-206 Circulation September 9, 2003
tion. Atrial septal pacing is ineffective as monotherapy but
when combined with amiodarone substantially reduces the
risk of post-CTS atrial fibrillation versus placebo based
regimens with or without pacing. However, combination
therapy with amiodarone and atrial septal pacing is not
substantially better than amiodarone alone and may add
unnecessary complexity to postoperative management.
References
1. Am Heart Association. 2002 Heart and Stroke Statistical Update. Dallas,
Texas: Am Heart Association, 2001 (accessed August 7, 2002).
2. Maisel WH, Rawn JD, Stevenson WG. Atrial Fibrillation after cardiac
surgery. Ann Intern Med. 2001;135;1061–1073.
3. Crystal E, Connolly SJ, Sliek K, Ginger TJ, Yusuf S. Interventions on
prevention of postoperative atrial fibrillation in patients undergoing heart
surgery: a meta-analysis. Circulation. 2002;106:75– 80.
4. Kowey PR, Taylor JE, Rials SJ, Marinchak K. Meta-analysis of the
effectiveness of prophylactic drug therapy in preventing supraventricular
arrhythmia early after coronary artery bypass grafting. Am J Cardiol.
1992;69:963–965.
5. Laurer MS, Eagle KA, Buckly MJ, et al. Atrial Fibrillation following
coronary artery bypass surgery. Prog Cardiol Dis. 1989;31:367–378.
Downloaded from http://ahajournals.org by on January 16, 2023
6. Crosby LH, Pifalo WB, Woll KR, Burkholder JA. Risk factors for atrial fibril-
lation after coronary artery bypass grafting. Am J Cardiol. 1990;66:1520–1522.
7. Giri S, White CM, Dunn AB, et al. Efficacy and safety of oral amiodarone
for the prevention of atrial fibrillation after open heart surgery in the
elderly: The Atrial Fibrillation Suppression Trial (AFIST). Lancet. 2001;
357:830 – 836.
8. White CM, Giri S, Tsikouris J, et al. A comparison of two individual
amiodarone regimens to placebo in open-heart surgery patients. Ann
Thorac Surg. 2002;74:69 –74.
9. United States Pharmacopoeia Convention. USPDI Drug Information for
the Health Care Professional. Micromedex, Inc, Englewood, CO, 2002.
10. Hohnloser SH, Meinertz T, Dammbacher T, et al. Electrocardiographic
and antiarrhythmic effects of intravenous amiodarone: results of a pro-
spective placebo-controlled study. Am Heart J. 1991;121:89 –95.
11. Gerstenfeld EP, Hill MR, French SN, et al. Evaluation of right atrial
pacing and biatrial pacing for the prevention of atrial fibrillation after
coronary artery bypass surgery. J Am Coll Cardiol. 1999;33:1981–1988.
12. Bailin SJ, Adler S, Guidici M. Prevention of chronic atrial fibrillation by
pacing in the region of Bachmann’s Bundle: results of a multicenter
randomized trial. J Cardiovasc Electrophysiol. 2001;12:912–917.
13. Guarnieri T, Nolan S, Gottlieb SO, Dudek A, Lowry DR. Intravenous
amiodarone for the prevention of atrial fibrillation after open heart
surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial.
J Am Coll Cardiol. 1999;34:343–347.