Download Acute Ventricular Rate Control in Atrial Fibrillation

Acute Ventricular Rate Control in Atrial
Fibrillation*
IV Combination of Diltiazem and Digoxin vs IV
Diltiazem Alone
Norrapol Wattanasuwan, MD; Ijaz A. Khan, MD; Nirav J. Mehta, MD;
Pratheep Arora, MD; Narpinder Singh, MD; Balendu C. Vasavada, MD; and
Terrence J. Sacchi, MD
Objective: To analyze the efficacy of an IV combination of diltiazem and digoxin vs IV diltiazem
alone for acute ventricular rate control in patients with atrial fibrillation.
Design: Prospective, randomized, open-label study.
Patients and methods: Fifty-two patients with atrial fibrillation and uncontrolled ventricular rates
were randomized to receive either an IV combination of diltiazem and digoxin or IV diltiazem
alone and were observed for 12 h. The successful rate control was defined as a ventricular rate
< 100 beats per minute (bpm) persisting for 1 h or conversion to sinus rhythm. The loss of rate
control was defined as an increase in the ventricular rate to > 100 bpm persistently for > 30 min
or rebound to atrial fibrillation.
Results: In both treatment arms (n ⴝ 26 each), all patients achieved successful and comparable
ventricular rate control at 12 h. The mean (ⴞ SD) time taken to achieve successful rate control
was shorter in the combination arm (15 ⴞ 16 vs 22 ⴞ 22 min). Six patients in the combination arm
and 11 in the diltiazem-alone arm experienced episodes of loss of rate control. This loss in
the combination arm was less than that in the diltiazem-alone arm (14 vs 39 episodes; p ⴝ 0.05).
The loss of rate control per patient in the combination arm was also less than that in the
diltiazem-alone arm (2.0 ⴞ 1.0 vs 3.5 ⴞ 1.9 episodes per patient; p ⴝ 0.04).
Conclusions: This study demonstrates that in patients with atrial fibrillation who have a rapid
ventricular response, the IV combination of diltiazem and digoxin results in a more efficacious
ventricular rate control with fewer fluctuations than that achieved by therapy with IV diltiazem
alone.
(CHEST 2001; 119:502–506)
Key words: acute ventricular rate control; atrial fibrillation; atrioventricular node-blocking agents; combination
treatment; diltiazem; digoxin; loss of ventricular rate control
Abbreviation: bpm ⫽ beats per minute
fibrillation is the most common chronic type
A trial
of arrhythmia. The prevalence of atrial fibrillation in the adult population is 4% and rises with age,
from ⬍ 0.5% in patients 25 to 35 years of age to
⬎ 5% in patients ⬎ 69 years of age.1 The treatment
objectives for atrial fibrillation include ventricular
rate control, conversion to sinus rhythm, maintenance of sinus rhythm, and prevention of thromboembolic events.2,3 Ventricular rate control is the
*From the Division of Cardiology (Drs. Wattanasuwan, Mehta,
Arora, Singh, Vasavada, and Sacchi), Department of Medicine,
Long Island College Hospital, Brooklyn, NY; and Creighton
University School of Medicine (Dr. Khan), Omaha, NE.
Manuscript received April 4, 2000; revision accepted August 3,
2000.
Correspondence to: Ijaz A. Khan, MD, Creighton University
Cardiac Center, 3006 Webster St, Omaha, NE 68131-2044;
e-mail: [email protected]
primary goal in the short-term management of atrial
fibrillation because the patient’s symptoms are
chiefly governed by the rapid ventricular rate.2,4
Ventricular rate control is usually achieved by using
atrioventricular node-blocking agents including
digoxin, calcium-channel blockers, ␤-adrenergic
blockers, and amiodarone.5,6
Digoxin has been the mainstay treatment for
slowing ventricular rates in atrial fibrillation for
⬎ 200 years and had remained so until 1992.7 Currently, diltiazem and other atrioventricular nodeblocking agents have been recommended as a firstline therapy for ventricular rate control in most
patients with atrial fibrillation, with digoxin being
used as a second-line therapy.8 –10 Nevertheless,
digoxin still is being used for ventricular rate control
in the short-term management of atrial fibrillation,
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Clinical Investigations
either as a first-line therapy or as an addition to other
atrioventricular node blockers for synergistic effect.
The beneficial effect of administering an IV combination of digoxin and esmolol for acute ventricular
rate control in atrial fibrillation has been demonstrated.6 Several studies have compared and confirmed
the efficacy of IV digoxin and IV diltiazem used
individually for short-term ventricular rate control in
patients with atrial fibrillation.11–13 However, the
efficacy of an IV combination of diltiazem and
digoxin vs IV diltiazem alone for acute ventricular
rate control has not been investigated before.
Materials and Methods
Study Population
Fifty-two patients who presented to the Long Island College
Hospital with atrial fibrillation and rapid ventricular rates were
enrolled in the study. Informed consent was obtained from all the
participants. A rapid ventricular rate was defined as a ventricular
rate of ⬎ 100 beats per minute (bpm). Patients with systolic BPs
⬍ 90 mm Hg, acute congestive heart failure, acute coronary
syndromes, ventricular rates ⬎ 200 bpm, coexisting unstable
medical conditions (eg, fever, sepsis, acute renal failure, acute
hepatic failure, thyrotoxicosis, or ARDS), preexcitation syndrome, histories of allergy to diltiazem or digoxin, lack of consent
from the patient or the patient’s physician, and taking any
antiarrhythmic medications within 1 week before presentation
were excluded from the study. Atrial fibrillation of ⬍ 72 h
duration was considered as being of recent onset.
30 min before stopping the IV infusion. The loss of rate control
in patients who had already achieved a successful rate control was
defined as an episode of increase in ventricular rate to ⬎ 100
bpm persisting for ⬎ 30 min or as a rebound to atrial fibrillation
in cases where the atrial fibrillation had been converted to sinus
rhythm. The parameters examined included the number of
patients with successful rate control, the time taken to achieve
the successful rate control, and episodes of loss of rate control.
Echocardiography was performed within 24 h after ventricular
rate control had been achieved. The serum digoxin levels were
not measured routinely, but the study was designed to do so in
patients who displayed the symptoms or signs of digoxin toxicity.
Statistical Analysis
The continuous variables were expressed as mean ⫾ SD and
were analyzed by Student’s t test. The categorical variables were
expressed as percentages and were analyzed by ␹2 statistics or
Fisher’s Exact Test, as appropriate. A two-tailed p value of ⱕ 0.05
was considered to be significant. All the statistical analyses were
performed using computer software (SPSS, version 7.0; SPSS;
Chicago, IL).
Results
The baseline characteristics of the study population are summarized in Table 1. Twenty-one patients
(81%) in the combination-treatment arm of the study
and 22 patients (85%) in the diltiazem-alone arm had
recent-onset atrial fibrillation. The ventricular rates
before administration of the drugs were not significantly different between the treatment arms (combination treatment, 142 ⫾ 16 bpm; diltiazem alone,
Study Protocol
The study was conducted with a prospective randomized
open-label design and was approved by the Institutional Review
Board for Human Subjects Research of the Long Island College
Hospital. Patients were enrolled consecutively and were randomized to two treatment arms of equal numbers of patients, one
involving therapy with an IV combination of diltiazem and
digoxin and the other involving therapy with IV diltiazem only.
All the patients received IV diltiazem (Cardizem; Hoechst
Marion Roussel; Kansas City, MO), 0.25 mg/kg, at 0 h over 2 min
as an initial bolus followed by a maintenance continuous infusion
at a rate of 10 mg/h. At 15 min, a second bolus of diltiazem, 0.35
mg/kg was given if the ventricular rate was still ⬎ 100 bpm. The
patients in the combination treatment arm received a total of 1
mg IV digoxin (Lanoxin; Glaxo Wellcome; Research Triangle
Park, NC) in addition to IV diltiazem. An initial dose of 0.5 mg IV
digoxin was given at 0 h together with the first bolus dose of
diltiazem, followed by two doses of 0.25 mg IV digoxin at 2 h and
4 h. The second and third doses of digoxin were withheld if the
ventricular rate was ⬍ 55 bpm at the scheduled dose time.
All patients were continuously monitored for heart rate and
cardiac rhythm in the cardiac-care unit for 12 h. The heart rate
trend-meter was used to record hourly ventricular rates and
episodes of loss of ventricular rate control. A successful rate
control was defined as a ventricular rate ⬍ 100 bpm persisting for
1 h or conversion to sinus rhythm. The patients were evaluated on
an hourly basis. In patients who achieved a successful rate
control, therapy with IV diltiazem was switched to the oral form
at a dose of 60 mg every 6 h, and the first dose was administrated
Table 1—Comparison of Baseline Characteristics
Between Combination and Diltiazem-Alone Treatment
Arms*
Characteristics
CombinationTreatment Arm
Diltiazem-Alone Arm
68 (18–88)
61 ⫾ 21
66 (20–90)
64 ⫾ 18
14 (54)
12 (46)
16 (61)
6 (23)
6 (23)
6 (23)
8 (31)
2 (8)
21 (81)
5 (19)
46 ⫾ 8
54 ⫾ 14
7 (27)
15 (58)
11 (42)
11 (42)
7 (27)
6 (23)
4 (15)
3 (11)
3 (11)
22 (85)
4 (15)
42 ⫾ 8
47 ⫾ 16
6 (23)
Age, yr
Median (range)
Mean ⫾ SD
Gender
Male
Female
Hypertension
Congestive heart failure
Smoking
Alcohol abuse
Diabetes mellitus
Coronary artery disease
Recent-onset fibrillation
Chronic atrial fibrillation
Left atrial size, mm
Ejection fraction, %
Left ventricular
hypertrophy
*Values given as mean ⫾ SD or No. of patients (%), unless otherwise
indicated. Differences between treatment arms were not significant
for all characteristics.
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503
145 ⫾ 17 bpm; p ⫽ 0.50). All the patients had
achieved successful ventricular rate control at 12 h.
The ventricular rates were comparable in both treatment arms throughout the study period (Fig 1). The
time taken to achieve successful rate control was
shorter in the combination-treatment arm (15 ⫾ 16
min vs 22 ⫾ 22 min), but the difference was not
statistically significant. Six patients in the combination-treatment arm and 11 in the diltiazem-alone
arm had episodes of loss of ventricular rate control.
The loss of rate control in the combination-treatment
arm was significantly less than that in the diltiazemalone arm (14 vs 39 episodes; 0.5 ⫾ 1.0 vs 1.5 ⫾ 2.1
episodes per patient; p ⫽ 0.05). The loss of rate
control among the patients with episodes of the loss
of rate control was also significantly less in the
combination-treatment arm than in the diltiazemalone arm (2.0 ⫾ 1.0 vs 3.5 ⫾ 1.9 episodes per patient; p ⫽ 0.04) (Table 2). Twelve patients in the
combination-treatment arm and 14 in the diltiazemalone arm converted to sinus rhythm. Of these
patients, nine in the combination-treatment arm and
10 patients in the diltiazem-alone arm remained in
sinus rhythm throughout the study period.
Seven patients in the combination-treatment arm
and 11 in the diltiazem-alone arm received a second
bolus of diltiazem. In the combination-treatment
arm, 20 patients received a full dose of 1.0 mg
digoxin, 3 received 0.75 mg, and the other 3 received
0.5 mg. The pretreatment systolic and diastolic BPs
were not significantly different in both arms (systolic
BP: combination treatment, 131 ⫾ 26 mm Hg; diltiazem alone, 131 ⫾ 17 mm Hg; diastolic BP: combination treatment, 79 ⫾ 15 mm Hg; diltiazem alone,
74 ⫾ 12 mm Hg). The BPs remained comparable
between the treatment arms throughout the study
Figure 1. The ventricular rates in the IV combination of
diltiazem and digoxin and the IV diltiazem-alone treatment arms
(difference not significant).
period. The only adverse event noted during the
study was an episode of sinus pause for 2.5 s in a
31-year-old patient who was in the combinationtreatment arm, which occurred 3 min after the
administration of the initial bolus of diltiazem and
the initial dose of digoxin. None of the patients
displayed any symptom or clinical or ECG sign of
digoxin toxicity.
Discussion
This study demonstrates that an IV combination of
diltiazem and digoxin results in more efficacious
ventricular rate control with fewer episodes of loss of
rate control than IV diltiazem alone. The combination regimen also enabled less frequent administration of the second bolus of diltiazem, an effect that
may be advantageous in patients with poor left
ventricular systolic function. In patients with atrial
fibrillation with a rapid ventricular response, the
primary and vital therapeutic aim is the control of
ventricular rates, since the patients’ symptoms are
frequently governed by the presence of rapid ventricular rates.2 The most popular form of administration of medications is IV due to rapid action, reliable
success rate, and well-known and acceptable side
effects.13,14 Short-term ventricular rate control is
conventionally achieved by using atrioventricular
node-blocking drugs, including digoxin, calcium
channel blockers, and ␤-receptor blockers. The digitalis glycosides had been the mainstay of the treatment for ventricular rate control in atrial fibrillation,
but they were replaced by two new major classes of
atrioventricular node-blocking drugs, calcium channel blockers (particularly, IV diltiazem) and ␤-receptor blockers.15,16
Since the atrioventricular node-blocking drugs
rarely provide sufficient ventricular rate slowing
when used alone, it is frequently necessary to use
several of them in different combinations.17,18 The
use of digoxin alone for this purpose results in a
delayed rate control response, possibly lower success
rates, and an easily inducible loss of rate control,
especially with physical activity.10 Although it
achieves ventricular rate control rapidly, diltiazem
also is associated with frequent episodes of loss of
rate control necessitating frequent dosage adjustments, which may result in deleterious hemodynamic fluctuations, particularly in patients with impaired left ventricular systolic function.19 Patients
with atrial fibrillation and rapid ventricular rates are
usually treated first with a single atrioventricular
node-blocking drug, and the second drug is added
later when the patients fail to respond to the first
drug or need higher dosages.17 Thus, it would seem
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Table 2—Comparison of Ventricular Rate Control Results Between Combination and
Diltiazem-Alone Treatment Arms*
Ventricular Rate Control Parameters
Successful rate control at 12 h
Time taken to rate control, min
Converted to sinus rhythm
Patients in sinus rhythm at 12 h
Patients with loss of rate control
Loss of rate control, No. of episodes
Loss of rate control episodes/patient
All patients
Patients with loss of rate control episodes
CombinationTreatment Arm
Diltiazem-Alone Arm
p Value
26 (100)
15 ⫾ 16
12 (46)
9 (75)
6 (23)
14
26 (100)
22 ⫾ 22
14 (54)
10 (71)
11 (42)
39
1.0
0.20
0.58
0.83
0.14
0.05
0.5 ⫾ 1.0
2.0 ⫾ 1.0
1.5 ⫾ 2.1
3.5 ⫾ 1.9
0.05
0.04
*Values given as No. of patients (%) or mean ⫾ SD, unless otherwise indicated.
reasonable to start treatment with an IV combination
of diltiazem and digoxin, which may result in an
efficacious ventricular rate control with fewer fluctuations. Various studies comparing the efficacy of
oral diltiazem alone or in combination with oral
digoxin for long-term ventricular rate control have
demonstrated that the use of a combination regimen
reduces ventricular rates more often than the use of
a single agent, both at rest and during exercise.20,21
The facts about the efficacy of this combination
regimen in an acute setting, however, were not
well-defined, and the present study establishes the
role of an IV combination of diltiazem and digoxin
for acute control of ventricular rates.
The length of time taken to achieve ventricular
rate control was shorter for patients in the combination-treatment arm of the study than that in patients
in the diltiazem-alone arm, but the difference did
not reach statistical significance, probably because
the study population was small. It was previously
reported22 that episodes of loss of rate control may
be associated with a longer median length of hospital
stay, but it was beyond the limit of this study to verify
this relationship. The average time to ventricular rate
control for patients receiving IV diltiazem is considered to be about 4 min5,11; in the present study, this
time is about 22 min in the diltiazem-alone arm and
15 min in the combination-treatment arm. This
difference is most likely due to the more rigid criteria
used to define ventricular rate control in present study
(ie, ⬍ 100 bpm persisting for at least 1 h).
Conclusion
This study demonstrates that in patients with atrial
fibrillation who have rapid ventricular rates, the IV
combination therapy of diltiazem and digoxin results
in a more efficacious acute ventricular rate control
with less frequent fluctuations than that achieved by
therapy with IV diltiazem alone. The beneficial
effects of this pharmacologic combination may be
applicable to the select group of atrial fibrillation
patients who meet the exclusionary criteria set forth
in the study.
ACKNOWLEDGMENT: The authors thank Kay L. Ryschon,
MS, for assisting in the statistical analysis.
References
1 Benjamin JE, Wolf PA, D’Agostino BR, et al. Impact of atrial
fibrillation on the risk of death: the Framingham heart study.
Circulation 1998; 98:946 –952
2 Mackstaller LL, Alpert JS. Atrial fibrillation: a review of
mechanism, etiology, and therapy. Clin Cardiol 1997; 20:
640 – 650
3 Tavel ME, Sopher SM, Camm AJ. Atrial fibrillation: problems in management. Chest 1996; 110:1089 –1091
4 Gardner MJ, Gilbert M. Heart rate control in patients with
atrial fibrillation. Can J Cardiol 1996; 12(suppl):21A–23A
5 Ellenbogen KA, Dias VC, Plumb VJ, et al. A placebocontrolled trial of continuous intravenous diltiazem infusion
for 24-hour heart rate control during atrial fibrillation and
atrial flutter: a multicenter study. J Am Coll Cardiol 1991;
18:891– 897
6 Shettigar UR, Toole JG, Appunn DO. Combined use of
esmolol and digoxin in the acute treatment of atrial fibrillation
or flutter. Am Heart J 1993; 126:368 –374
7 Sarter BH, Marchlinski FE. Redefining the role of digoxin in
the treatment of atrial fibrillation. Am J Cardiol 1992; 69:
71G– 81G
8 Stern EH, Pitchon R, King BD, et al. Clinical use of oral
verapamil in chronic and paroxysmal atrial fibrillation. Chest
1982; 81:308 –311
9 Atwood JE, Myers J, Quaglietti S, et al. Effect of betaxolol on
the hemodynamic, gas exchange, and cardiac output response
to exercise in chronic atrial fibrillation. Chest 1999; 115:1175–
1180
10 Falk HR, Leavitt IJ. Digoxin for atrial fibrillation: a drug
whose time has gone. Ann Intern Med 1991; 114:573–575
11 Salerno DM, Dias VC, Kleiger ER, et al. Efficacy and safety
of intravenous diltiazem for treatment of atrial fibrillation and
atrial flutter. Am J Cardiol 1989; 63:1046 –1051
12 The Digitalis in Acute Atrial Fibrillation (DAFF) Trial
Group. Intravenous digoxin in acute atrial fibrillation: results
CHEST / 119 / 2 / FEBRUARY, 2001
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21958/ on 05/02/2017
505
13
14
15
16
17
of a randomized, placebo-controlled multicenter trial in 239
patients. Eur Heart J 1997; 18:649 – 654
Schreck DM, Rivera AR, Tricarico VJ. Emergency management of atrial fibrillation and flutter: intravenous diltiazem
versus intravenous digoxin. Ann Emerg Med 1997; 29:135–
140
Shenasa M, Kus T, Fromer M, et al. Effect of intravenous and
oral calcium antagonist (diltiazem and verapamil) on sustenance of atrial fibrillation. Am J Cardiol 1988; 62:403– 407
Farshi R, Kistner D, Sarma JS, et al. Ventricular rate control
in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug
regimens. J Am Coll Cardiol 1999; 33:304 –310
Lang R, Klein HO, Weiss E, et al. Superiority of oral
verapamil therapy to digoxin in treatment of chronic atrial
fibrillation. Chest 1983; 83:491– 499
Yahalom J, Klein HO, Kaplinsky E. Beta-adrenergic blockade
as adjunctive oral therapy in patients with chronic atrial
fibrillation. Chest 1977; 71:592–596
18 Khalsa A, Edvardsson N, Olsson SB. Effects of metoprolol on
heart rate in patients with digitalis treated chronic atrial
fibrillation. Clin Cardiol 1978; 1:91–95
19 Heywood JR. Calcium channel blockers for heart rate control
in atrial fibrillation complicated by congestive heart failure.
Can J Cardiol 1995; 11:823– 826
20 Roth A, Harrison E, Mitani G, et al. Efficacy and safety of
medium- and high-dose diltiazem alone and in combination
with digoxin for control of heart rate at rest and during
exercise in patients with chronic atrial fibrillation. Circulation
1986; 73:316 –324
21 Lewis RV, Laing E, Moreland TA, et al. A comparison of
digoxin, diltiazem and their combination in the treatment of
atrial fibrillation. Eur Heart J 1988; 9:279 –283
22 Roberts SA, Diaz C, Nolan PE, et al. Effectiveness and costs
of digoxin treatment for atrial fibrillation and flutter. Am J
Cardiol 1993; 72:567–573
506
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