Digoxin

IV Combination of Diltiazem and Digoxin vs IV Diltiazem Alone

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 [is less than] 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 [is greater than] 100 bpm persistently for [is greater than] 30 min or rebound to atrial fibrillation.

Results: In both treatment arms (n = 26 each), all patients achieved successful and comparable ventricular rate control at 12 h. The mean ([+or -] SD) time taken to achieve successful rate control was shorter in the combination arm (15 [+ or -] 16 vs 22 [+ or -] 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 = 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 [+ or -] 1.0 vs 3.5 [+ or -] 1.9 episodes per patient; p = 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

Atrial fibrillation is the most common chronic type of arrhythmia. The prevalence of atrial fibrillation in the adult population is 4% and rises with age, from [is less than] 0.5% in patients 25 to 35 years of age to [is greater than] 5% in patients [is greater than] 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 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, [Beta]-adrenergic blockers, and amiodarone.[5,6]

Digoxin has been the mainstay treatment for slowing ventricular rates in atrial fibrillation for [is greater than] 200 years and had remained so until 1992.[7] Currently, diltiazem and other atrioventricular node-blocking agents have been recommended as a first-line 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, 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 [is greater than] 100 beats per minute (bpm). Patients with systolic BPs [is less than] 90 mm Hg, acute congestive heart failure, acute coronary syndromes, ventricular rates [is less than] 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 [is less than] 72 h duration was considered as being of recent onset.

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 [is greater than] 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 [is less than] 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 [is less than] 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 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 [is greater than] 100 bpm persisting for [is greater than] 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 [+ or -] SD and were analyzed by Student's t test. The categorical variables were expressed as percentages and were analyzed by [chi square] statistics or Fisher's Exact Test, as appropriate. A two-tailed p value of [is less than or equal to] 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 [+ or -] 16 bpm; diltiazem alone, 145 [+ or -] 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 [+ or -] 16 min vs 22 [+ or -] 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 diltiazem-alone arm (14 vs 39 episodes; 0.5 [+ or -] 1.0 vs 1.5 [+ or -] 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 diltiazem-alone arm (2.0 [+ or -] 1.0 vs 3.5 [+ or -] 1.9 episodes per patient; p = 0.04) (Table 2). Twelve patients in the combination-treatment arm and 14 in the diltiazem-alone 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.

[Figure 1 ILLUSTRATION OMITTED]

Table 1--Comparison of Baseline Characteristics Between Combination and Diltiazem-Alone Treatment Arms(*)

(*) Values given as mean [+ or -] SD or No. of patients (%), unless otherwise indicated. Differences between treatment arms were not significant for all characteristics.

Table 2--Comparison of Ventricular Rate Control Results Between Combination and Diltiazem-Alone Treatment Arms(*)

(*) Values given as No. of patients (%) or mean [+ or -] SD, unless otherwise indicated.

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 [+ or -] 26 mm Hg; diltiazem alone, 131 [+ or -] 17 mm Hg; diastolic BP: combination treatment, 79 [+ or -] 15 mm Hg; diltiazem alone, 74 [+ or -] 12 mm Hg). The BPs remained comparable between the treatment arms throughout the study 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 combination-treatment 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 [Beta]-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 [Beta]-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 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 reported[22] 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 min[5,11]; 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, [is less than] 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

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[16] 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

[17] 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

(*) 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: ikhan@cardiac.creighton.edu

COPYRIGHT 2001 American College of Chest Physicians
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