- Email: [email protected]
Control of heart rate during transition from intravenous to oral diltiazem in atrial fibrillation or flutter
Control of Heart Rate During Transition from Intravenous to Oral Diltiuzem in Atrial Fibrillation or Flutter Joseph L. Blackshear, MD, Bruce S. Stambler, MD, William E. Strauss, MD, Denis Roy, MD, Virgil C. Dias, PharmD, C.L. Beach, PharmD, and M. Kathleen Ebener, RN We tested whether patienk presenting with atrial fibrillation (AF) or flutter (AFI) with a rapid ventricular response could maintain control of heart rate while transferring from a bolus and continuous infusion of intravenous diltiazem to oral diltiazem. Forty patients with AF or AFI and sustained ventricular rate 2 120 beak/min received intravenous diltiazem “bolus” (20 to 25 mg for 2 minutes) and “infusion” (5 to 15 mg/ hour for 6 to 20 hours). Oral long-acting diltiazem (diltiazem CD 180,300, or 360 mg/24 hours) was administered in patients in whom stable heart rate control was attained during constant infusion. intravenous diltiazem infusion was discontinued 4 hours after the first oral dose, and patients were monitored during 48 subsequent hours of “transition” to oral therapy. Response to diltiazem was defined as heart rate < 100 beats/min, ~20% decrease in heart rate from baseline, or con-
version to sinus rhythm. Other rate control or antiar rhythmic medications were not allowed during the study period. Thirty-seven of 40 patients maintained heart rate control during the bolus, and 35 of the remaining 37 maintained control during the infusion of intravenous diltiazem. Of the 35 patients achieving heart rate control with intravenous diltiazem who entered the transition to oral ther apy, 27 maintained heart rate control (response rate of 77%, 95% confidence interval 63% to 91%). The median infusion rate of intravenous diltiazem was 10 mg/hour, and the median dose of oral diltiazem CD was 300 ‘mg/ day. Oral long-acting diltiazem was 77% effective in controlling ventricular response over 48 hours in patients with AF or AFI in whom ventricular response was initially cono I996 by Excerpta trolled with intravenous diltiazem. Medica, Inc. (Am J Cardiol 1996;78: 1246- 1250)
and oral diltiazem have been demonstrated to be effective therapies for the control of Iheartntravenous rate in patients with rapid atria1 fibrillation
tients gave written informed consent before enrollment. Patients: Eligible study subjects were men and nonlactating women (age 2 18 years) of non-childbearing potential, with AF or AFl of established or fixed duration (224 hours) with a persistent resting ventricular rate 2 120 beats/min for at least 15 minutes. Exclusion criteria were as in revious investigations of intravenous diltiazem.** P Use of digoxin, p blockers, diltiazem, verapamil, or antiarrhythmic drugs was not allowed within 6 hours before the baseline period or during the study protocol. Study design: This was an open-label therapeutic trial. In the prestudy phase (Table I), informed consent was obtained, a history and physical examination were completed, entry criteria were satisfied, and 12-lead electrocardiogram, chest x-ray, and laboratory work were obtained. A digoxin level was obtained at least 6 hours after the last of dose of digoxin in patients who were receiving digoxin. During baseline and all study periods, heart rate, blood pressure, and cardiac rhythm were assessedafter at least 5 minutes of supinerest. After baseline measurements, a bolus of 20 mg of intravenous open-label injectable diltiazem was administered over 2 minutes. If a therapeutic response ( ~20% reduction in heart rate, or heart rate < 100 beats/min assessedby l-minute electrocardiogram rhythm strip) was not achieved within 17 minutes from the end of the diltiazem bolus or if additional heart rate reduction was deemed advisable
(AF) or atria1 flutter ( AFl) .‘m7In a previous study of intravenous diltiazem pharmacokinetics, plasma concentrations of 79, 172, and 294 rig/ml were predicted to slow rapid ventricular rates in patients with AF and AFl by 20%, 30%, and 40%, respectively.8 Pharmacokinetic simulation of dose and plasma levels (taking into account the nonlinear pharmacokinetics of diltiazem) suggests that oral diltiazem CD doses of 180 to 360 mg/day are likely to produce plasma concentrations in the range of 80 to 300 ng/ ml. The object of this study was to explore the safety and efficacy of transferring patients in AF and AFl to 1 of 3 oral doses of diltiazem CD after initial heart rate control with intravenous diltiazem.
METHODS Approval for the protocol was given by institutional review boards at each of the 6 medical centers that participated in the study (see Appendix); PaFrom the Mayo Clinic Jacksonville and St. Luke’s Hospital, Jacksonville, Florida; McGuire Veterans Administration Medical Center, Richmond, Virginia; West Roxbury Veterans Administration, Boston, Massachusetts; Montreal Heart Institute, Quebec, Canada; and Hoechst Marion Roussel, Inc., Kansas City, Missouri. This study was supported by a grant from Hoechst Marion Roussel, Inc. [formerly Marion Merrell Dow, Inc.), Kansas City, Missouri. Manuscript received March 1, 1996; revised manuscript received and accepted June 3, 1996. Address for reprints:Joseph L. Blackshear, MD, Mayo Clinicjacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224.
1246
01996 by Excerpta Medico, All rights reserved.
Inc.
0002.9149/96/S 15.00 PII SOOO2.9149(96)00604-2
TABLE I Study Schematic Baseline (15 min)
Before Study History, exam, ECG, CXR, informed consent, lab work
Heart rate 2 120 beats/min by 1 min; rhythm strips x 2, 15 min apart
B&s (20-40 min)
Infusion (2-20 h)
Transition (48 h)
After Study
0.25 mg/kg or 20 mg bolus i.v. diltiazem; if no response in 20 min, second bolus of 0.35 mg/kg or 25
10 mg/h i.v. diltiazem infusion. If response lost, 1O-mg bolus and increase infusion to 15 mg/h; if excessive slowing, decrease infusion to 5 mg/h; if additional rate control desired without loss of response, can increase to 15 mg/h.
After 2 h with stable response during infusion, oral diltiazem CD given. At final infusion rate of 5, 10, or 15 mg/h; transfer to oral diltiazem CD dose at 180, 300, or 360 mg, respectively. Infusion continued for 4 h after oral dose.
Exam, ECG, lab work
mg
CXR = chest x-ray;
ECG = electrocardiogram;
TABLE II Characteristics
i.v. = intravenous.
of the Study Group
(n = 40) 68L 10 31 (77.5) 832 18 13 (33)
Age (yd Men Weight (kg) Active pulmonary disease Angina Hypertension Congestive heart failure (NYHA class I or II) Coronary artery disease Prior coronary bypass or angioplasty Prior myocardial infarction Valvular heart disease Digoxin 548 h Any rate control medicine ~48 h Data ore presented NYHA
= New
as mean
York Heart
2 SD or number
8 (20) 27 (68) 10 (25) 11 (28) 5 If31
8 WI 6 (151 24 (60) 29 (73)
(%).
Association.
diogram strips, spaced 30 minutes apart, were considered nonresponders and exited the study. Patients who maintained a therapeutic response for at least 2 consecutive hours at a constant rate of infusion were eligible to receive long-acting oral diltiazem (Cardizem CD, Hoescht Marion Roussel, Inc., Kansas City, Missouri). The intravenous diltiazem infusion was abruptly discontinued 4 hours after oral diltiazem administration. The oral dose was determined by the final infusion rate. Patients receiving 5, 10, or 15 mg/ hour of intravenous diltiazem received 180, 300, or 360 mg of diltiazem CD per day, respectively, for the 2 days of the in-hospital study. Data collected after institution of oral therapy included: heart rate and rhythm; blood pressure; number of patients maintaining a therapeutic response at hours 4,6, 8, 12, 18, and 24 of the first 24 hours; and number of patients maintaining a therapeutic response at hours 6, 12, and 24 of the second 24 hours. Efficacy: The primary measure of efficacy was the time to loss of therapeutic response during the transition to oral therapy. Time of loss of response was designated as that time halfway between the last time in which response was maintained and the first of the 2 times of absent therapeutic response. Thus, if the patient responded at hour 6 of the transition period but lost response at hours 8 and 9, then the time to loss of response for that patient was 7 hours. The proportion of patients maintaining responseat each time in the 48hour period was plotted over time using Kaplan-Meier methods. Logistic regression methods were used to assessthe association between the odds of responding to diltiazem CD and subgroups of entrants based on age, arrhythmia type, baseline heart rate, and cumulative dose of diltiazem given. Adverse events: Adverse events were assessedby physician investigators and assigned a probability score for relation to study medication.
by the investigator, a second dose of 25 mg of intravenous diltiazem was administered. Patients who did not achieve a therapeutic response within 17 minutes of a second intravenous diltiazem bolus were deemed not to have responded and were treated outside the study protocol. An open-label infusion period began immediately on documentation of a therapeutic response to the bolus injection. Diltiazem infusion was administered at 10 mg /hour through an infusion pump. Heart rate and rhythm were monitored every 30 minutes by l-minute rhythm strips. Manual or automated blood pressure was assessedevery 15 minutes for the first hour and every 30 minutes thereafter while the patient was awake and receiving the intravenous infusion of diltiazem. During the intravenous infusion, if the therapeutic effect was lost (heart rate 2 100 beatsknin or <20% decrease in heart rate from baseline) or if additional heart rate reduction was desired, an additional lo-mg bolus of intravenous diltiazem was given over 2 minutes, and the infusion was increased to 15 mg/ hour. If excessive slowing of heart rate was noted, a decreaseto 5 mg/hour was allowed. During the infu- RESULTS sion period, patients who had absence of heart rate Table II describes the characteristics of the study responsecriteria on 2 consecutive l-minute electrocar- population. Seventy-three percent of the patients had ARRHYTHMIAS
AND
CONDUCTION
DISTURBANCES/RATE
CONTROL
WITH
ORAL
DllTlAZEM
1247
40! 0
-
1-I.‘.‘*‘-‘.‘*““‘.“’ 4
2
6
8
10
12
14
16
18
20
22
24
Time from start of dlltiazem (hours) L
J
FIGURE1. Ventricular rate in a single patient with atrial fibrillation to long-acting
and the response to intravenous
oral diltiazem (diltiazem CD).
TABLE III Patients Who Maintained
Heart Rate Control
During
Each Phase [n = 40)* Phase
Number
Baseline
40 (100%) 37(92.5%) 35 (88%) 28 (70%) 27 (67.5%)
Bolus
Infusion Transition Transition * Twelve (marked during
day 1 day 2 had loss of response;
liver function infusion
1 had adverse
abnormalities);
and 5 during
transition
7 patients day
event during converted
transition
day
to sinus rhythm:
1 2
1.
received rate control medicines >6 but ~48 hours before study entry. Figure 1 describes the heart rate response of a single patient. Efficacy: Table III lists the numbers and percentages of patients who maintained heart rate control during each period of the study. BOLUS PERIOD: Of the 40 patients, 37 (92.5%, 95% confidence interval [CI] 84% to 100%) had a therapeutic response to bolus injectable diltiazem. Eight patients received a second bolus, and 5 of these 8 responded. No patient converted to sinus rhythm. INFUSION PERIOD: Two of 37 patients who entered the infusion phase of the study failed to maintain a therapeutic heart rate response. Two of 37 patients converted to normal sinus rhythm. Entry into the transition phase required a constant therapeutic response for 2 consecutive hours. Thirty-two of the 35 patients who achieved stable heart rate control during diltiazem intravenous infusion did so within the first 6 hours. During the infusion period, 6 patients received an additional lo-mg intravenous bolus of diltiazem injectable, 12 patients had their infusion rate increased from 10 to 15 mg/hour, and 3 patients 1248
(IV) bolus, infusion, and transition
THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 78
had their infusion rate decreased from 10 to 5 mg/ hour. The duration of the infusion period ranged from 2 to 19 hours (mean 3.5, median 2). ~a~.smoN PERIOD: Thirty-five patients (88%, 95% CI 77% to 98%) achieved heart rate control with bolus and infusion of diltiazem injectable and entered the transition period. Based on their final infusion rates, 1 patient received 180 mg/day, 23 patients received 300 mg/day, and 11 patients received 360 mg/day of oral diltiazem CD. Twenty-seven of the original 40 patients (67.5%, 95% CI 53% to 82%) maintained a therapeutic heart rate response through the 48-hour transition period. Figure 2 illustrates the timing of the loss of response for the 35 patients who entered the transition phase. For the 35 patients who responded to intravenous bolus and infusion diltiazem and entered the transition period, this represents a 77% (95% CI 63% to 91%) response rate to oral long-acting diltiazem. Five patients converted to normal sinus rhythm during the transition period, all during the first 24 hours. Figure 3 shows the values of heart rate and blood pressure of responders at the end of each study period, with the number of patients who responded. By logistic regression analysis, patient age, arrhythmia type (AF vs AFl), and baseline heart rate did not predict treatment failure. Adverse events: Only 1 patient was discontinued from study medication prematurely. This patient, a 68-year-old man, was found to have markedly abnormal liver function tests. The event abated spontaneously but did result in prolonged hospitalization. Other events not requiring discontinuation of study medication included hypotension (2 patients) and new chest rales on examination after the study (1 patient). DECEMBER 1, 1996
5 '5
60-
*0 I 6
50 0
1 12
I 18
, 24
I 30
1 36
I 42
I 46
Time after oral diltiazem CID (hr) FIGURE 2. Kaplan-Meier survival curve of maintenance of thempeutic heart rare response after oral diltiazem CD in 35 patients initially controlled with intravenous diltiazem infusion. QD = daily.
160
F E
% k r^
140
120 100
%l $30 60
1
Baseline n=40
Bolus n=37
Infusion n=35
Transition n=27
FIGURE 3. Heart rate (HR) (solid line) and systolic (dashed line) and diastolic (doffed and dashed line) blood pressure (BP) response to intravenous followed by oral diltiazem in mpid atrial fibrillation or flutter. Values depicted are from the end of each study period. The dumtion of each period was bolus (20 to 40 minutes), infusion (2 to 20 hours), and transition (48 hours).
DISCUSSION The objectives of rate control therapy in AF and AFl include control of the resting heart rate and control of the exercise heart rate individualized to patient activity level and co-morbidities.’ In this study, intravenous diltiazem was 88% effective in rapidly controlling heart rates in AF and AFl, as shown previously.2*5-7 This study extends prior experience by demonstrating that, among patients with heart rate initially controlled using intravenous diltiazem, an oral dose of diltiazem determined by the effective infusion rate was 77% effective in maintaining resting heart rate control over 48 hours. For asymptomatic patients, those in whom rapid control of heart rate is not urgently required on a clinical basis, and perhaps for those with left ventricular systolic dysfunction, digoxin is either the drug of choice or, at least, is acceptable first-line ARRHYTHMIAS AND CONDUCTION
therapy.’ Its effect is complementary when used in combination with other rate control medications, such as p blockers, diltiazem, or verapamil. lo-l5 However, the obligatory use of digoxin for all patients with AF or AFI is being reassessed.16,17Its disadvantages include a slow onset of response in the acute setting with frequent loss of heart rate control, inadequate exercise rate control during chronic therapy, and failure to provide adequate rate control during episodes in patients with paroxysmal AF.9*16,18 Potential advantages of the strategy tested in this study over digoxin-based monotherapy are quicker attainment of control of rapid heart rates, shortened hospital stay or even avoidance of hospitalization, as well as the use of an agent that is indicated therapy for comorbid conditions. More than half of patients with AF require antihypertensive therapy, and approximately one quarter have angina.‘+23 Medications such as diltiazem may serve a dual purpose in such patients. This study evaluated the control of resting heart rates over 48 hours in hospitalized patients. Many patients may require additional therapy to reduce heart rate increases during activity. Edema, which has been associated with high doses of oral diltiazem, was not noted in this study, but is a potential adverse effect of long-term therapy. These limitations aside, a strategy of intravenous and oral diltiazem monotherapy was safe and effective over 48 hours in two thirds of patients with rapid AF or AFl.
APPENDIX Sites (number of patients enrolled), Principal and Associate Investigators, and Study Coordinators: Mayo Clinic Jacksonville, Jacksonville, FL (15): Joseph L. Blackshear, Randall C. Thompson, Robert E. Safford, and M. Kathleen Ebener; VA Medical Center, Richmond, VA (11): Bruce S. Stambler, Kenneth A. Ellenbogen, Mark Wood, Alan Cyan, and Donna Sergeant; VA Medical Center, West Roxbury, MA (8): William E. Strauss, William D&y, David Martin, and Diane Lapsley; Montreal Heart Institute, Montreal, Quebec, Canada (4): Denis Roy, Mario Talajic, and David Radzik; Hennepin County Medical Center, Minneapolis, MN (1): David M. Salerno, David Dunbar, and Adrienne Ettinger; St. Joseph’s Heart Institute, Tampa, FL (1): Peter Alagona, Dennis Cassidy, and Carol Riggio; and Hoechst Marion Rowe1 (formerly Marion Merrell Dow, Inc.), Kansas City, MO: Virgil C. Dias, C. L. Beach, Robert Reynolds, Lisa Vaughan, Diane LaFontaine, and Christine Bugos.
1. Roth A, Harrison E, Mitani G, Cohen J, Rahimtoola SH, Elkayam U. Efficacy and safety of medium- and high-dose diltiazem alone and combination with dig&n for control of heart rate at rest and during exercise in patients with chronic atria1 fibrillation. Circulation 1986;73:316-324. 2. Salerno DM, Dias VC, Kleiger RE, Tschida VH, Sung RJ, Sami M, Giorgi LV, for the Diltiazem-Atrial Fibrillation/Flutter Study Group. Efficacy and DISTURBANCES/RATE CONTROL WITH ORAL DllTlAZEM
1249
safety of intravenous diltiazem for treatment of atria1 fibrillation and atria1 Autter. Am J Cardiol 1989;63: 1046- 105 1. 3. Huycke EC, Sung RJ, Dias VC, Milstein S, Hariman RJ, Platia EV, and the Multicenter Diltiazem PSVT Study Group. Intravenous diltiazem for termination of reentrant suptwenticular tachycardia: a placebo-controlled, randomized, double-blind multicenter study. JAm Coil Cardiol 1989; 13538-544. 4. Lundstrom T, Ryden L. Ventricular rate control and exercise performance in chronic atrial fibrillation: effects of diltiazem and verapamil. JAm Coil Cardiol 1990;16:86-90. 5. Ellenbogen KA, Dias VC, Plumb VJ, Heywood JT, Mirvis DM. A placebocontrolled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atria1 fibrillation and atria1 flutter: a multicenter study. JAm Coil Cardiol 1991;18:891-897. 6. Goldenberg IF, Lewis WR, Dias VC, Heywood JT, Pedersen WR. Intravenous diltiazem for the treatment of patients with atria1 fibrillation or flutter and moderate to severe congestive heart failure. Am J Cardiol 1994;74:884-889. 7. Ellenbogen KA, Dias VC, Card&o FP, Strauss WE, Simonton CA, Pollak SJ, Wood MA, Stambler BS. Safety and efficacy of intravenous diltiazem in atria1 fibrillation or atrial flutter. Am J Cardiol 1995;75:45-49. 8. Dias VC, Weir SJ, Ellenbogen KA. Pharmacokinetics and pharmacodynamits of intravenous diltiazem in patients with atria1 fibrillation or atrial flutter. Circulation 1992;86:1421-1428. 9. Falk RH. Control of the ventricular rate in atrial fibrillation. In: Falk RH, Podrid PJ, eds. Atrial Fibrillation: Mechanisms and Management. New York: Raven Press, 1992:255-282. 10. David D, Segni ED, Klein HO, Kaplinsky E. Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta adrenergic blocking agent. Am .I Cmdiol 1979;44:1378-1382. 1 I. Schwartz JB, Keefe D, Kates RE, Kirsten E, Harrison DC. Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atria1 fibrillation. Circulation 1982;65:1163- 1170. 12. Mitchell LB, Jutzy KR, Lewis SJ, Schroeder JS, Mason JW. Intracardiac electrophysiologic study of intravenous diltiazem and combined diltiazem-digoxin in patients. Am Heart J 1982;103:57-66.
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THE AMERICAN JOURNAL OF CARDIOLOGY@
VOL. 78
13. DiBianco R, Morganroth J, Freitag JA, Ronan JA, Lindgren KM, Donahue DJ, Larca LJ, Chadda KD, Olukotun AY. Effects of nadolol on the spontaneous and exercise-provoked heart rate of patients with chronic atrial fibrillation receiving stable dosages of digoxin. Am Heart J 1984; 108: 112 1- 1127. 14. Atwood JE, Myers JN, Sullivan MJ, Forbes SM, Pewen WF, Froelicher VF. Diltiazem and exercise performance in patients with chronic atrial fibrillation. Chest 1988;93:20-25. 15. Shettigar UR, Toole JG, Appunn DO. Combined use of esmolol and digoxin in the acute treatment of atria1 fibrillation or flutter. Am Heart J 1993;126:368374. 16. Falk RH, Leavitt JI. Digoxin for atrial fibrillation: a dmg whose time has gone? Ann Intern Med 1991;114:573-575. 17. Sarter BH, Marchlinski FE Redefining the role of digoxin in the treatment of atrial fibrillation. Am J Cardiol 1992;69:716-81G. 18. Galun E, Flugelman MY, Glickson M, Eliakim M. Failure of long-term digitalization to prevent rapid ventricular response in patients with paroxysmal atria1 fibrillation. Chest 1991;99:1038-1040. 19. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebocontrolled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atria1 fibrillation. Lmcet 1989;1(8631): 175-179. 20. Stroke Prevention in Atria1 Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study: final results. Circulation 1991;84:527-539. 21. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505- 1511. 22. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C, for the CAFA Study Coinvestigators. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. JAm Coil Cardiol 1991;18:349-355. 23. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Coiling CL, Gomick CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992;327:1406- 1412.
DECEMBER 1, 1996
version to sinus rhythm. Other rate control or antiar rhythmic medications were not allowed during the study period. Thirty-seven of 40 patients maintained heart rate control during the bolus, and 35 of the remaining 37 maintained control during the infusion of intravenous diltiazem. Of the 35 patients achieving heart rate control with intravenous diltiazem who entered the transition to oral ther apy, 27 maintained heart rate control (response rate of 77%, 95% confidence interval 63% to 91%). The median infusion rate of intravenous diltiazem was 10 mg/hour, and the median dose of oral diltiazem CD was 300 ‘mg/ day. Oral long-acting diltiazem was 77% effective in controlling ventricular response over 48 hours in patients with AF or AFI in whom ventricular response was initially cono I996 by Excerpta trolled with intravenous diltiazem. Medica, Inc. (Am J Cardiol 1996;78: 1246- 1250)
and oral diltiazem have been demonstrated to be effective therapies for the control of Iheartntravenous rate in patients with rapid atria1 fibrillation
tients gave written informed consent before enrollment. Patients: Eligible study subjects were men and nonlactating women (age 2 18 years) of non-childbearing potential, with AF or AFl of established or fixed duration (224 hours) with a persistent resting ventricular rate 2 120 beats/min for at least 15 minutes. Exclusion criteria were as in revious investigations of intravenous diltiazem.** P Use of digoxin, p blockers, diltiazem, verapamil, or antiarrhythmic drugs was not allowed within 6 hours before the baseline period or during the study protocol. Study design: This was an open-label therapeutic trial. In the prestudy phase (Table I), informed consent was obtained, a history and physical examination were completed, entry criteria were satisfied, and 12-lead electrocardiogram, chest x-ray, and laboratory work were obtained. A digoxin level was obtained at least 6 hours after the last of dose of digoxin in patients who were receiving digoxin. During baseline and all study periods, heart rate, blood pressure, and cardiac rhythm were assessedafter at least 5 minutes of supinerest. After baseline measurements, a bolus of 20 mg of intravenous open-label injectable diltiazem was administered over 2 minutes. If a therapeutic response ( ~20% reduction in heart rate, or heart rate < 100 beats/min assessedby l-minute electrocardiogram rhythm strip) was not achieved within 17 minutes from the end of the diltiazem bolus or if additional heart rate reduction was deemed advisable
(AF) or atria1 flutter ( AFl) .‘m7In a previous study of intravenous diltiazem pharmacokinetics, plasma concentrations of 79, 172, and 294 rig/ml were predicted to slow rapid ventricular rates in patients with AF and AFl by 20%, 30%, and 40%, respectively.8 Pharmacokinetic simulation of dose and plasma levels (taking into account the nonlinear pharmacokinetics of diltiazem) suggests that oral diltiazem CD doses of 180 to 360 mg/day are likely to produce plasma concentrations in the range of 80 to 300 ng/ ml. The object of this study was to explore the safety and efficacy of transferring patients in AF and AFl to 1 of 3 oral doses of diltiazem CD after initial heart rate control with intravenous diltiazem.
METHODS Approval for the protocol was given by institutional review boards at each of the 6 medical centers that participated in the study (see Appendix); PaFrom the Mayo Clinic Jacksonville and St. Luke’s Hospital, Jacksonville, Florida; McGuire Veterans Administration Medical Center, Richmond, Virginia; West Roxbury Veterans Administration, Boston, Massachusetts; Montreal Heart Institute, Quebec, Canada; and Hoechst Marion Roussel, Inc., Kansas City, Missouri. This study was supported by a grant from Hoechst Marion Roussel, Inc. [formerly Marion Merrell Dow, Inc.), Kansas City, Missouri. Manuscript received March 1, 1996; revised manuscript received and accepted June 3, 1996. Address for reprints:Joseph L. Blackshear, MD, Mayo Clinicjacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224.
1246
01996 by Excerpta Medico, All rights reserved.
Inc.
0002.9149/96/S 15.00 PII SOOO2.9149(96)00604-2
TABLE I Study Schematic Baseline (15 min)
Before Study History, exam, ECG, CXR, informed consent, lab work
Heart rate 2 120 beats/min by 1 min; rhythm strips x 2, 15 min apart
B&s (20-40 min)
Infusion (2-20 h)
Transition (48 h)
After Study
0.25 mg/kg or 20 mg bolus i.v. diltiazem; if no response in 20 min, second bolus of 0.35 mg/kg or 25
10 mg/h i.v. diltiazem infusion. If response lost, 1O-mg bolus and increase infusion to 15 mg/h; if excessive slowing, decrease infusion to 5 mg/h; if additional rate control desired without loss of response, can increase to 15 mg/h.
After 2 h with stable response during infusion, oral diltiazem CD given. At final infusion rate of 5, 10, or 15 mg/h; transfer to oral diltiazem CD dose at 180, 300, or 360 mg, respectively. Infusion continued for 4 h after oral dose.
Exam, ECG, lab work
mg
CXR = chest x-ray;
ECG = electrocardiogram;
TABLE II Characteristics
i.v. = intravenous.
of the Study Group
(n = 40) 68L 10 31 (77.5) 832 18 13 (33)
Age (yd Men Weight (kg) Active pulmonary disease Angina Hypertension Congestive heart failure (NYHA class I or II) Coronary artery disease Prior coronary bypass or angioplasty Prior myocardial infarction Valvular heart disease Digoxin 548 h Any rate control medicine ~48 h Data ore presented NYHA
= New
as mean
York Heart
2 SD or number
8 (20) 27 (68) 10 (25) 11 (28) 5 If31
8 WI 6 (151 24 (60) 29 (73)
(%).
Association.
diogram strips, spaced 30 minutes apart, were considered nonresponders and exited the study. Patients who maintained a therapeutic response for at least 2 consecutive hours at a constant rate of infusion were eligible to receive long-acting oral diltiazem (Cardizem CD, Hoescht Marion Roussel, Inc., Kansas City, Missouri). The intravenous diltiazem infusion was abruptly discontinued 4 hours after oral diltiazem administration. The oral dose was determined by the final infusion rate. Patients receiving 5, 10, or 15 mg/ hour of intravenous diltiazem received 180, 300, or 360 mg of diltiazem CD per day, respectively, for the 2 days of the in-hospital study. Data collected after institution of oral therapy included: heart rate and rhythm; blood pressure; number of patients maintaining a therapeutic response at hours 4,6, 8, 12, 18, and 24 of the first 24 hours; and number of patients maintaining a therapeutic response at hours 6, 12, and 24 of the second 24 hours. Efficacy: The primary measure of efficacy was the time to loss of therapeutic response during the transition to oral therapy. Time of loss of response was designated as that time halfway between the last time in which response was maintained and the first of the 2 times of absent therapeutic response. Thus, if the patient responded at hour 6 of the transition period but lost response at hours 8 and 9, then the time to loss of response for that patient was 7 hours. The proportion of patients maintaining responseat each time in the 48hour period was plotted over time using Kaplan-Meier methods. Logistic regression methods were used to assessthe association between the odds of responding to diltiazem CD and subgroups of entrants based on age, arrhythmia type, baseline heart rate, and cumulative dose of diltiazem given. Adverse events: Adverse events were assessedby physician investigators and assigned a probability score for relation to study medication.
by the investigator, a second dose of 25 mg of intravenous diltiazem was administered. Patients who did not achieve a therapeutic response within 17 minutes of a second intravenous diltiazem bolus were deemed not to have responded and were treated outside the study protocol. An open-label infusion period began immediately on documentation of a therapeutic response to the bolus injection. Diltiazem infusion was administered at 10 mg /hour through an infusion pump. Heart rate and rhythm were monitored every 30 minutes by l-minute rhythm strips. Manual or automated blood pressure was assessedevery 15 minutes for the first hour and every 30 minutes thereafter while the patient was awake and receiving the intravenous infusion of diltiazem. During the intravenous infusion, if the therapeutic effect was lost (heart rate 2 100 beatsknin or <20% decrease in heart rate from baseline) or if additional heart rate reduction was desired, an additional lo-mg bolus of intravenous diltiazem was given over 2 minutes, and the infusion was increased to 15 mg/ hour. If excessive slowing of heart rate was noted, a decreaseto 5 mg/hour was allowed. During the infu- RESULTS sion period, patients who had absence of heart rate Table II describes the characteristics of the study responsecriteria on 2 consecutive l-minute electrocar- population. Seventy-three percent of the patients had ARRHYTHMIAS
AND
CONDUCTION
DISTURBANCES/RATE
CONTROL
WITH
ORAL
DllTlAZEM
1247
40! 0
-
1-I.‘.‘*‘-‘.‘*““‘.“’ 4
2
6
8
10
12
14
16
18
20
22
24
Time from start of dlltiazem (hours) L
J
FIGURE1. Ventricular rate in a single patient with atrial fibrillation to long-acting
and the response to intravenous
oral diltiazem (diltiazem CD).
TABLE III Patients Who Maintained
Heart Rate Control
During
Each Phase [n = 40)* Phase
Number
Baseline
40 (100%) 37(92.5%) 35 (88%) 28 (70%) 27 (67.5%)
Bolus
Infusion Transition Transition * Twelve (marked during
day 1 day 2 had loss of response;
liver function infusion
1 had adverse
abnormalities);
and 5 during
transition
7 patients day
event during converted
transition
day
to sinus rhythm:
1 2
1.
received rate control medicines >6 but ~48 hours before study entry. Figure 1 describes the heart rate response of a single patient. Efficacy: Table III lists the numbers and percentages of patients who maintained heart rate control during each period of the study. BOLUS PERIOD: Of the 40 patients, 37 (92.5%, 95% confidence interval [CI] 84% to 100%) had a therapeutic response to bolus injectable diltiazem. Eight patients received a second bolus, and 5 of these 8 responded. No patient converted to sinus rhythm. INFUSION PERIOD: Two of 37 patients who entered the infusion phase of the study failed to maintain a therapeutic heart rate response. Two of 37 patients converted to normal sinus rhythm. Entry into the transition phase required a constant therapeutic response for 2 consecutive hours. Thirty-two of the 35 patients who achieved stable heart rate control during diltiazem intravenous infusion did so within the first 6 hours. During the infusion period, 6 patients received an additional lo-mg intravenous bolus of diltiazem injectable, 12 patients had their infusion rate increased from 10 to 15 mg/hour, and 3 patients 1248
(IV) bolus, infusion, and transition
THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 78
had their infusion rate decreased from 10 to 5 mg/ hour. The duration of the infusion period ranged from 2 to 19 hours (mean 3.5, median 2). ~a~.smoN PERIOD: Thirty-five patients (88%, 95% CI 77% to 98%) achieved heart rate control with bolus and infusion of diltiazem injectable and entered the transition period. Based on their final infusion rates, 1 patient received 180 mg/day, 23 patients received 300 mg/day, and 11 patients received 360 mg/day of oral diltiazem CD. Twenty-seven of the original 40 patients (67.5%, 95% CI 53% to 82%) maintained a therapeutic heart rate response through the 48-hour transition period. Figure 2 illustrates the timing of the loss of response for the 35 patients who entered the transition phase. For the 35 patients who responded to intravenous bolus and infusion diltiazem and entered the transition period, this represents a 77% (95% CI 63% to 91%) response rate to oral long-acting diltiazem. Five patients converted to normal sinus rhythm during the transition period, all during the first 24 hours. Figure 3 shows the values of heart rate and blood pressure of responders at the end of each study period, with the number of patients who responded. By logistic regression analysis, patient age, arrhythmia type (AF vs AFl), and baseline heart rate did not predict treatment failure. Adverse events: Only 1 patient was discontinued from study medication prematurely. This patient, a 68-year-old man, was found to have markedly abnormal liver function tests. The event abated spontaneously but did result in prolonged hospitalization. Other events not requiring discontinuation of study medication included hypotension (2 patients) and new chest rales on examination after the study (1 patient). DECEMBER 1, 1996
5 '5
60-
*0 I 6
50 0
1 12
I 18
, 24
I 30
1 36
I 42
I 46
Time after oral diltiazem CID (hr) FIGURE 2. Kaplan-Meier survival curve of maintenance of thempeutic heart rare response after oral diltiazem CD in 35 patients initially controlled with intravenous diltiazem infusion. QD = daily.
160
F E
% k r^
140
120 100
%l $30 60
1
Baseline n=40
Bolus n=37
Infusion n=35
Transition n=27
FIGURE 3. Heart rate (HR) (solid line) and systolic (dashed line) and diastolic (doffed and dashed line) blood pressure (BP) response to intravenous followed by oral diltiazem in mpid atrial fibrillation or flutter. Values depicted are from the end of each study period. The dumtion of each period was bolus (20 to 40 minutes), infusion (2 to 20 hours), and transition (48 hours).
DISCUSSION The objectives of rate control therapy in AF and AFl include control of the resting heart rate and control of the exercise heart rate individualized to patient activity level and co-morbidities.’ In this study, intravenous diltiazem was 88% effective in rapidly controlling heart rates in AF and AFl, as shown previously.2*5-7 This study extends prior experience by demonstrating that, among patients with heart rate initially controlled using intravenous diltiazem, an oral dose of diltiazem determined by the effective infusion rate was 77% effective in maintaining resting heart rate control over 48 hours. For asymptomatic patients, those in whom rapid control of heart rate is not urgently required on a clinical basis, and perhaps for those with left ventricular systolic dysfunction, digoxin is either the drug of choice or, at least, is acceptable first-line ARRHYTHMIAS AND CONDUCTION
therapy.’ Its effect is complementary when used in combination with other rate control medications, such as p blockers, diltiazem, or verapamil. lo-l5 However, the obligatory use of digoxin for all patients with AF or AFI is being reassessed.16,17Its disadvantages include a slow onset of response in the acute setting with frequent loss of heart rate control, inadequate exercise rate control during chronic therapy, and failure to provide adequate rate control during episodes in patients with paroxysmal AF.9*16,18 Potential advantages of the strategy tested in this study over digoxin-based monotherapy are quicker attainment of control of rapid heart rates, shortened hospital stay or even avoidance of hospitalization, as well as the use of an agent that is indicated therapy for comorbid conditions. More than half of patients with AF require antihypertensive therapy, and approximately one quarter have angina.‘+23 Medications such as diltiazem may serve a dual purpose in such patients. This study evaluated the control of resting heart rates over 48 hours in hospitalized patients. Many patients may require additional therapy to reduce heart rate increases during activity. Edema, which has been associated with high doses of oral diltiazem, was not noted in this study, but is a potential adverse effect of long-term therapy. These limitations aside, a strategy of intravenous and oral diltiazem monotherapy was safe and effective over 48 hours in two thirds of patients with rapid AF or AFl.
APPENDIX Sites (number of patients enrolled), Principal and Associate Investigators, and Study Coordinators: Mayo Clinic Jacksonville, Jacksonville, FL (15): Joseph L. Blackshear, Randall C. Thompson, Robert E. Safford, and M. Kathleen Ebener; VA Medical Center, Richmond, VA (11): Bruce S. Stambler, Kenneth A. Ellenbogen, Mark Wood, Alan Cyan, and Donna Sergeant; VA Medical Center, West Roxbury, MA (8): William E. Strauss, William D&y, David Martin, and Diane Lapsley; Montreal Heart Institute, Montreal, Quebec, Canada (4): Denis Roy, Mario Talajic, and David Radzik; Hennepin County Medical Center, Minneapolis, MN (1): David M. Salerno, David Dunbar, and Adrienne Ettinger; St. Joseph’s Heart Institute, Tampa, FL (1): Peter Alagona, Dennis Cassidy, and Carol Riggio; and Hoechst Marion Rowe1 (formerly Marion Merrell Dow, Inc.), Kansas City, MO: Virgil C. Dias, C. L. Beach, Robert Reynolds, Lisa Vaughan, Diane LaFontaine, and Christine Bugos.
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1249
safety of intravenous diltiazem for treatment of atria1 fibrillation and atria1 Autter. Am J Cardiol 1989;63: 1046- 105 1. 3. Huycke EC, Sung RJ, Dias VC, Milstein S, Hariman RJ, Platia EV, and the Multicenter Diltiazem PSVT Study Group. Intravenous diltiazem for termination of reentrant suptwenticular tachycardia: a placebo-controlled, randomized, double-blind multicenter study. JAm Coil Cardiol 1989; 13538-544. 4. Lundstrom T, Ryden L. Ventricular rate control and exercise performance in chronic atrial fibrillation: effects of diltiazem and verapamil. JAm Coil Cardiol 1990;16:86-90. 5. Ellenbogen KA, Dias VC, Plumb VJ, Heywood JT, Mirvis DM. A placebocontrolled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atria1 fibrillation and atria1 flutter: a multicenter study. JAm Coil Cardiol 1991;18:891-897. 6. Goldenberg IF, Lewis WR, Dias VC, Heywood JT, Pedersen WR. Intravenous diltiazem for the treatment of patients with atria1 fibrillation or flutter and moderate to severe congestive heart failure. Am J Cardiol 1994;74:884-889. 7. Ellenbogen KA, Dias VC, Card&o FP, Strauss WE, Simonton CA, Pollak SJ, Wood MA, Stambler BS. Safety and efficacy of intravenous diltiazem in atria1 fibrillation or atrial flutter. Am J Cardiol 1995;75:45-49. 8. Dias VC, Weir SJ, Ellenbogen KA. Pharmacokinetics and pharmacodynamits of intravenous diltiazem in patients with atria1 fibrillation or atrial flutter. Circulation 1992;86:1421-1428. 9. Falk RH. Control of the ventricular rate in atrial fibrillation. In: Falk RH, Podrid PJ, eds. Atrial Fibrillation: Mechanisms and Management. New York: Raven Press, 1992:255-282. 10. David D, Segni ED, Klein HO, Kaplinsky E. Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta adrenergic blocking agent. Am .I Cmdiol 1979;44:1378-1382. 1 I. Schwartz JB, Keefe D, Kates RE, Kirsten E, Harrison DC. Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atria1 fibrillation. Circulation 1982;65:1163- 1170. 12. Mitchell LB, Jutzy KR, Lewis SJ, Schroeder JS, Mason JW. Intracardiac electrophysiologic study of intravenous diltiazem and combined diltiazem-digoxin in patients. Am Heart J 1982;103:57-66.
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13. DiBianco R, Morganroth J, Freitag JA, Ronan JA, Lindgren KM, Donahue DJ, Larca LJ, Chadda KD, Olukotun AY. Effects of nadolol on the spontaneous and exercise-provoked heart rate of patients with chronic atrial fibrillation receiving stable dosages of digoxin. Am Heart J 1984; 108: 112 1- 1127. 14. Atwood JE, Myers JN, Sullivan MJ, Forbes SM, Pewen WF, Froelicher VF. Diltiazem and exercise performance in patients with chronic atrial fibrillation. Chest 1988;93:20-25. 15. Shettigar UR, Toole JG, Appunn DO. Combined use of esmolol and digoxin in the acute treatment of atria1 fibrillation or flutter. Am Heart J 1993;126:368374. 16. Falk RH, Leavitt JI. Digoxin for atrial fibrillation: a dmg whose time has gone? Ann Intern Med 1991;114:573-575. 17. Sarter BH, Marchlinski FE Redefining the role of digoxin in the treatment of atrial fibrillation. Am J Cardiol 1992;69:716-81G. 18. Galun E, Flugelman MY, Glickson M, Eliakim M. Failure of long-term digitalization to prevent rapid ventricular response in patients with paroxysmal atria1 fibrillation. Chest 1991;99:1038-1040. 19. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebocontrolled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atria1 fibrillation. Lmcet 1989;1(8631): 175-179. 20. Stroke Prevention in Atria1 Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study: final results. Circulation 1991;84:527-539. 21. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505- 1511. 22. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C, for the CAFA Study Coinvestigators. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. JAm Coil Cardiol 1991;18:349-355. 23. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Coiling CL, Gomick CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992;327:1406- 1412.
DECEMBER 1, 1996