- Email: [email protected]
Safety and efficacy of intravenousdiltiazem in atrial fibrillation or atrial flutter
Safety and Efficacy of Intravenous DMuzem in Atwal Fibrillation or Atrial Flutter Kenneth A. Ellenbogen, MD, Virgil C. Dias, PharmD, Frank P. Cardello, MD, William E. Strauss, MD, Charles A. Simonton, MD, Scott J. Pollak, MD, Mark A. Wood, MD, and Bruce S. Stumbler, MD This study examines the efficacy of various doses of intravenous diltiazem to control the ventricular response during atrial fibrillation or atrial flutter. Control of the ventricular response of patients with atrial fibrillation and a rapid ventricular response can provide patients with relief of symptoms and improve hemod namics. Eighty-four consecutive patients with atrial fi ii rillation or atrial flutter, or both, received an intravenous bolus dose of diltiazem followed by a continuous infusion of diltiazem at 5, 10, and 15 mg/hour. The mean ventricular response and blood pressure were monitored. Overall, 94% of patients (79 of 84) responded to the bolus dose with a >20% reduction in heart rate from baseline, a conversion to sinus rhythm, or a heart rate ~100 beak/min. Seventy-eight patients received the continuous infusion. After 10 hours of infusion, 47% of patients (confidence interval [Cl]: 36%, 59%) had maintained response with the 5 mg/hour infusion, 68% (Cl: 57%, 79%) maintained response after the infusion was
titrated to 10 mg/hour, and 76% (Cl: 66%, 85%) after titration from the 5 and 10 mg/hour infusion to the 15 mg/hour dose. For the 3 diltiazem infusions studied, mean (+ SD) heart rate was reduced from a baseline value of 144 f 14 beak/min to 98 f 19, 107 + 25, 107&22,101 +22,91 ?I 17,and88+ 18beak/min at infusion times 0, 1, 2, 4, 8, and 10 hours, respectively. By the end of the infusion, 18% of patients (14 of 78) had conversion to sinus rhythm. Hypotension was the most common side effect, occurring in 13% of patients. Symptomatic hypotension was present in 3.6% of patients, and responded to normal saline solution in all cases. We conclude that a bolus dose of 20 or 25 mg followed by titration of a continuous infusion of 5, 10, and 15 mg/hour of intravenous diltiazem is a safe and effective regimen to rapidfy lower heart rate in patients with atrial fibrillation and atrial flutter. (Am J Cardiol 1995;75:45-49)
bolus of intravenous diltiazem has been reported to A be safe and effective for acutely slowing the ventricular response during atria1 fibrillation and atrial flut-
The present study assessesthe safety and efficacy of intravenous diltiazem administered in bolus doses of 20 or 2.5 mg followed by a continuous infusion starting at a rate of 5 mg/hour and increasing to 10 and 15 mg/hour as needed in patients with atrial fibrillation and atrial flutter with a rapid ventricular response.
ter, l-3 and in converting paroxysmal supraventricular tachycardia to sinus rhynnnM In a recent study, intravenous diltiazem was administered to patients with atrial fibrillation and atria1 flutter as a bolus dose (20 mg, followed by 25 mg if needed) and a continuous infusion of 10 to 15 mg/hour, with a ventricular response of >120 beats/min.3 This sustained diltiazem infusion produced slowing of the ventricular response by >20% or a heart rate ~100 beats/min in about 80% of patients with a low incidence of adverse effects. Subsequent pharmacokinetic and pharmacodynamic data suggest that the minimal effective plasma concentration of diltiazem required to achieve a 20% decrease in heart rate from baseline is 79 ng/m1.7 This plasma concentration would be approximately produced by an intravenous diltiazem infusion at a rate of 5 mg/hour. From the Medical College of Vir inia and the McGuire Veterans Administration Medical Center, Ricii mond, Virginia; Veterans Administration Medical Center, Phoenix, Arizona; Veterans Administration Medical Center, West Roxbury, Massachusetis; the Sanger Clinic, Charlotte, North Carolina; Marion Merrell Dow, Inc., Kansas City, Missouri; and the Central Florida Cardiology Group, Orlando, Florida. This study was supported in part by a grant from Marion Merrell Dow, Inc., Kansas City, Missouri. Manuscript received May 27, 1994; revised manuscript received August 1 1, 1994, and accepted Au ust 12. A c?dress for reprints: Kenneth A. Ellenbogen, MD, Medical College of Virginia, Box 980053, Richmond, Virginia 23298-0053.
ARRHYTHMIAS
AND
METHODS The protocol was approved by the investigational review board of each of the 14 participating research sites (see Appendix). Each patient gave written informed consent before entry into the study. Patients were included in this study if they had the spontaneous occurrence of acute atria1 fibrillation or atria1 flutter or chronic atial fibrillation or atria1 flutter with a ventricular response of >120 beats/min during the 15-minute period before administration of the study drug. Atria1 fibrillation or atria1 flutter was documented by a 12-lead electrocardiogram, and heart rates were measured from a l-minute electrocardiographic rhythm strip obtained at the tirst and fifteenth minute of the baseline period. Patients were excluded if they were <18 years of age, were women of childbearing potential, had a known history of sick sinus syndrome, third-degree atrioventricular block, WolffParkinson-White syndrome, were hypotensive with a systolic blood pressure of ~90 mm Hg, or were allergic to diltiazem. No patient was taking oral diltiazem or intravenous or oral verapamil for 25 elimination halflives and for 24 hours plus 5 elimination half-lives for the sustained-release preparations. Patients were not excluded because of the presence of congestive heart
CONDUCTION
DISTURBANCES/DIlTIAZEM
IN ATRIA1
FlBRlllATlON
45
r
TABLE I Patient Baseline Characieristics 201~s
Trial Over
llncrease
Increase
Infusion
20 mg IV DILla
5 mgihr d
Infusion
to 15 mg/hr
sex Men (%)/women j%) Age (years] [mean * SD] Weight (kg) [mean * SD) Cardiac surgery within 2 weeks First occurrence of AF/AFt Type of AF/AFL Atrial fibrillation 1%) Paroxysmal (%) Chronic j%) Unknown w) Atrial flutter (%I Paroxysmal 1%)
IV DILT Infusion
to 10 mghr
I
IV DILT
IV DILT
Trial Over
<1 hour (%I 21 hour, < 12 hours (%)
Hour 10
failure or a low ejection fraction. During the bolus evaluation and infusion periods, patients did not receive p blockers or class I, III, or IV an&rhythmic drugs. Study design: This was an open-label, dose titration study (Figure 1). Each patient with atrial fibrillation or atria1 flutter with a mean ventricular response of >120 beats/min for 21.5 minutes before study drug administration was given 1 or 2 bolus doses of intravenous diltiazem after the 15-minute baseline period. The first dose of intravenous diltiazem was 20 mg administered over 2 minutes. If a patient did not achieve a therapeutic response within 15 minutes (conversion to sinus rhythm, slowing of the ventricular response to ~100 beats/min or by >20% assessed from a l-minute electrocardiographic rhythm strip), or if a further heart rate reduction was desired, a second dose of 25 mg was adtiinistered over 2 minutes. Patients who did not achieve a therapeutic response within 15 minutes of receiving the second bolus dose were withdrawn from the study and further therapy was chosen by the investigator. A continuous infusion of 5 mg/hour of intravenous diltiazem was started immediately after satisfactory therapeutic response with the jirst or second bolus. Patients were observed for a continued therapeutic response every 30 minutes throughout the lo-hour infusion period. If a therapeutic response was lost on 2 consecutive evaluations while receiving the 5 mg/hour infusion, the rate was increased to 10 mg/hour. If a therapeutic response was lost on the infysion rate of 10 mg/hour, the rate was increased to 15 mg/hour. Additionally, intravenous diltiazem could be increased from 5 mg/hour if the patient had maintained response for 24 hours at the lower dose, but further heart THE AMERICAN
JOURNAL
OF CARDIOLOGYa
71
Chronic w] Unknown 1%) Time since onset of AF/AFL
212 224
FIGURE 1. Study design for the intravenous diltiazem trial. The infusion rate could be increased from 5 to 10 mg/hour or from 10 to 15 mg/hour if patient (PT) maintained response for 24 hours at the lower dose (5 mg/hour) or for 2 hours at the hi her dose (10 mg/hour]. Loss of response was defined as a response criteria (e.g., ~20% decrease in fa!ure to maintain heart rati? from baseline, heart rate cl00 beats/min, or reversion to sinus rhythm) during 2 consecutive evaluations spaced 30 minutes apart. AF = atrial fibrillation; AFL = atrial flutter; DILT = diltiazem; IV = intravenous.
46
Diltiazem Bolus (n = 84)
Characteristics
VOL.
75
hours, 124 hours (Xl
Unknown (%) CHF: NYHA class No CHF (%) Class I (%) Class II w) Class Class
III (%) IV (%)
hours
(%I
(85)/13 (15) 66+ 10 85.4 t 22.2
Diltiazem Infusion (n = 79)
66 (84]/13 (lb] 66i 10 85 i 22.3
26 (3 1) 42 (50)
3.5 (44) 38 (481
62 30 13 19 22 16 4 2
(74) (48) (21) (31) (26) 173) I181 191
60 29 13 18 19 13 4 2
1 29 5 26 2
11) (351 (6) (3 I] 191
1 Ill 28 (35) 23 (291 2 I31
43
(511
42
8 (101 26
5
(761 (48) (221 (30) (24) (68) I211 (31
WI
(53)
8 I101
(31)
24 (30)
5 16)
4 (5) 1 (11
2 PI
AF = atrial fibrillation; AFL = atria/ flu&r, CHF = congestive NYHA = New York Heart Association.
heart failure;
rate reduction was desired by the clinician. The infusion could be increased from 10 mg/hour if the response was maintained for 22 hours, but further heart rate reduction was desired. The maximal infusion rate was 15 mg/hour. Patients who did not maintain therapeutic response at this infusion rate could be treatid with alternate antiarrhythmic therapy or electrical cardioversion. Statistical analysis: Heart rate and blood pressure data are expressed as mean f SD. Time to response after the bolus dose and during each maintenance dose was estimated by the Kaplan-Meier method. The percentage of patients in response at hour 10 for all infusion rates combined (5, 10, and 15 mg/hour) and for each infusion rate separately was obtained from the observed response rate at hour 10 and from the Kaplan-Meier method, respectively. The 95% confidence intervals are reported for the percent response for each dose of intravenous diltiazem administered.
RESULTS The study group consisted of 84 patients (62 with atria1 fibrillation and 22 with atrial flutter) who received bolus doses of intravenous diltiazem. Baseline characteristics of the patient population are described in Table I. Twenty-five patients (30%) were enrolled within 2 weeks of coronary artery bypass surgery. Forty-three patients (51%) were taking oral digoxin before study enrollment. The last mean dose of oral digoxin was 0.26 * 0.12 mg, resulting in a digoxin plasma concentration before study entry of 1.09 i 0.88 rig/ml. Efficacy: All 84 patients received the 20 mg bolus dose and, in addition, 42 patients received the 25 mg bolus JAN.
1, 1995
dose. Eighty-one percent of patients (68 of 84) responded to the 20 mg dose, and 69% (11 of 16) who were nonresponders to the 20 mg dose responded to the 25 mg dose. There was no difference in efficacy of intravenous diltiazem between patients with atria1 fibrillation and those with atrial flutter. Overall, 94% of patients (79 of 84) responded to either the tirst or second bolus. Forty-six percent of patients responded to the bolus by minute 2, 67% by minute 7, and 94% responded by minute 17 after receiving the 25 mg dose. Median time to response after the bolus dose was 7 minutes from the beginning of the bolus infusion. The baseline mean heart rate before the bolus infusion was 147 f 16 beats/ min, and decreased to 126 + 20 beats/min 17 minutes after the 20 mg bolus and to 109 f 24 beats/min 17 minutes after the 25 mg bolus. Mean heart rate reduction at minute 17 after the 20 and 25 mg bolus doses was 14 + 11% and 25 rt 15%, respectively. Infusion: Seventy-eight of the 79 patients who responded in the bolus period received a continuous infusion of diltiazem (1 had conversion to sinus rhythm). The percentage of patients maintaining response for 10 hours on the 5, 10, and 15 mg/hour infusion rates was 47% (conlidence interval [CI]: 36%, 59%), 68% (CI: 57%, 79%), and 76% (CI: 66%, 85%), respectively (Figure 2). Figure 3 displays the mean heart rates for the 78 patients who received the intravenous infusion. The mean (& SD) baseline heart rate was 144 2 14 beats/min. During the continuous infusion, heart rate decreased to 98 Z!Z 19, 107 + 25, 107 + 22, 101 f 22,91 + 21, and 88 f 18 beats/min at infusion hours
0, 1, 2, 4, 8, and 10, respectively. The number of patients with sinus rhythm at hours 0, 1,2,4, and 8 was 2,4,5, 10, and 13, respectively. By the end of the lo-hour infusion, 14 of 78 patients (18%) had conversion to sinus rhythm. There was no relation between the dose of diltiazem or a history of coronary artery bypass grafting that predicted which patients would revert to sinus rhythm during the infusion. The presence of more severe degrees of heart failure or a history of coronary artery bypass grafting did not predict the requirement for the highest infusion dose of diltiazem. Safety: BLOOD PRESSURE: In the 84 patients who received the 20 mg bolus dose of diltiazem, systolic and diastolic blood pressure was reduced after bolus administration, and remained reduced during ARRHYTHMIAS
P 2 z:w i$ 22 5% UK B 2
100 90 80 70 60 50 40 30 20 10
-
5 mgihr
---
5-10 mg/hr
-‘*
5-1 O-15 mgihr
0
I
I
I
I
I
I
I
I
I
I
1
2
3
4
5
6
7
8
9
10
TIME
(HOURS)
FIGURE 2. A Kaplan-Meier analysis therapeutic response to each dose
160
of the percentage of patients maintaining level of the intravenous infusion of diltiazem.
‘t
ok,,,,,,,,,,,,,,,,,,,,,, Base-End
0
1 lI.78
line Ekllus“=,6 Il.78 n.70
TIME
2
3
4
5
6
7
8
9
10
n=75
n=76
n.71
II=69
n=6a
n-65
n-64
n.64
lxx?
START
OF
(HOURS
FROM
INFUSION)
FIGURE 3. Heart rate during intravenous TO-hour infusion. The number of tients is shown below the time. The number of patients who received the r olus and the number who finished the study are different because those who did not respond to infusion or had reversion to sinus rhythm were withdrawn. Four patients had reversion to sinus rhythm by hour 1, 10 patients by hour 4, and 15 patients by hour 10. 1
T
0
SYSTOLIC
m
DIASTOLIC
T
T
T
BASELINE n=79
END BOLUS n=79
HOUR 1 INFUSION n=79
HOUR 5 INFUSION t-i=71
HOUR 10 INFUSION n=65
FIGURE 4. Systolic and diastolic blood pressures for all infusion doses shown. patient numbers decrease across time as infusion nonresponders those with conversion to sinus rhythm are withdrawn from the study.
AND
CONDUCTION
DISTURBANCES/DItTIAZEM
are
IN ATRIA1 FlBRlttATlON
and
47
infusion of diltiazem. Mean baseline systolic and diastolic blood pressure before infusion was 129 f 21/X0 f 16 mm Hg. Two minutes after the 20 mg bolus, blood pressure was 117 + 20/70 + 13 mm Hg (p = 0.0001). In 79 patients who received the diltiazem infusion, mean blood pressure at baseline was 129 + 22/80 f 16 mm Hg. At hours 0, 1, 2, 4, 8, and 10 of the infusion period, blood pressure was 118 + 29/69 f 13, 119 + 20/70 + 11, 120 + 19/71 f 12, 118 + B/70 + 12, 119 f 19/68 f 11, and 118 f B/67 + 12 mm Hg, respectively; p = NS (Figevents: Twenty-one percent of patients (18 of 84) had treatment-related adverse events. Hypotension was the most common adverse event, occurring in 13% of patients (11 of 84), 3.6% (3 of 84) of whom were symptomatic. Of the 11 patients with treatment-related hypotension, only 4 had hypotension lasting >35 minutes. No patient had an increase in heart rate accompanying the hypotensive episode. All 3 symptomatic patients were treated with normal saline solution, and recovered. Patient age, previous cardiac bypass surgery, weight, New York Heart Association class of congestive heart failure, sex, or presence of atrial fibrillation versus atria1 flutter did not predict the occurrence of hypotension. The only variables that predicted development of hypotension after the intravenous diltiazem bolus were the concomitant use of digoxin or a baseline diastolic blood pressure ~75 mm Hg. Other adverse events included headache in 2 patients, pruritus in 2, nausea in 1, dizziness and confusion in 1, and bradycardia in 1. No patient experienced an exacerbation of congestive heart failure while receiving the infusion.
The calcium antagonist agents verapamil and diltiazem may be used for the treatment of supraventricular arrhythmias. They act by slowing atrioventricular conduction and prolonging refractoriness in the atrioventricular node in a use-dependent fashion.8 Intravenous verapamil has limited usefulness in patients with atria1 arrhythmias and congestive heart failure because of its negative inotropic effect. 9~10In addition, when verapamil is used in conjunction with digoxin, a significant increase in plasma digoxin levels has been noted.ll In contrast, short-term administration of intravenous diltiazem is well tolerated in patients with severe congestive heart failure.12J3 Diltiazem does not produce a clinically significant interaction with digoxin. l4 This study conlirms several earlier studies that showed a high rate of response to bolus doses of diltiazem in patients with atrial fibrillation and atrial flutter.‘+J3 It also conlirms our previous report of a high rate of efficacy for a maintenance infusion.3 In our previous infusion study, 94% of patients responded to the bolus and 83% responded to a 24-hour infusion. The present study extends these observations by including patients after coronary artery bypass graft surgery and patients with New York Heart Association class III and IV congestive heart failure. Our previous study did not include postcoronary bypass surgery patients or patients with more severe degrees of heart failure. These patient populations have a high prevalence of atria1 fibrillation. This study includes these groups of patients and documents that the efficacy of intravenous diltiazem in these patient populations is similar to that seen in our previously reported study.
DISCUSSION
Role of iptrwenous diltiazem in the treatment of atrial fibrillation/atrial flutter: Intravenous diltiazem has valu-
This study provides safety and efficacy information during continuous titration of an intravenous infusion of diltiazem in a large group of patients. In addition, our study extends the experience of the use of a continuous infusion of diltiazem in patients with more severe degrees of heart failure and in those recovering from cardiac surgery. In this study, bolus doses of 20 mg followed by 25 mg of intravenous diltiazem produced a high response rate and a rapid response. The infusion titration of 5, 10, and 15 mg/hour of intravenous diltiazem was successful in maintaining response for 210 hours in 80% of patients. The 5 mg/hour infusion rate was successful in maintaining response in 47% of patients who had responded to the bolus dose of diltiazem. Acute management of atria1 fibrillation or atria1 flutter often involves control of the ventricular response with digoxin, l3 blockers, or calcium antagonists before establishing whether pharmacologic or electrical cardioversion can be safely performed. In some patients, the duration of atrial fibrillation may be longer than 48 to 72 hours, or the risk of embolic events is sufficiently great to warrant postponing conversion to sinus rhythm until sometime in the future. The primary goal of all drugs that slow atrioventricular conduction is to rapidly and safely control the ventricular rate without adding to the hemodynamic deterioration that occurs with a rapid ventricular rate.
able properties that make it a first-line agent when rapid slowing of the heart rate in atria1 fibrillation or atria1 flutter is a goal. It has a rapid onset of action, high response rate, and relatively little negative inotropic effect. In addition, a continuous infusion of intravenous diltiazem is easily and safely titratable to a desired reduction in heart rate.4,7 Thus, therapy can be altered as required by the patient’s clinical condition. Digoxin may be administered either intravenously or orally, but its onset of action is slower, generally taking hours until maximal heart slowing is observed. Digoxin is less easily and rapidly titrated to slowing of the ventricular response. The digoxin level should be checked before initiation of chemical cardioversion (with quinidine or procainamide) or electric cardioversion. Intravenous diltiazem can be administered during or before pharmacologic or electrical cardioversion15 without concern for toxicity or interaction with type Ia antiarrhythmic agents. It can be thought of as a “therapeutic bridge” in patients with atrial fibrillation or atria1 flutter while awaiting the onset of action of antiarrhythmic drugs with a long half-life, such as amiodarone. Intravenous diltiazem (like intravenous digoxin and verapamil) has been reported to accelerate the ventricular rate in a patient with an accessory atrioventricular bypass tract during an episode of atrial flutters; therefore, it should not be given to patients’with preexcited atrial fibrillation or flutter.
ure 4). @verse
48
THE AMERICAN
JOURNAL
OF CARDIOLOGY@
VOL.
75
JAN.
1, 1995
APPENDIX VA Medical Center. Phoenix, AZ: Frank P. Cardello, MD, Herschel Richter. MD, Cynthia L. Krome, RN. CVNS, ANP; VA Medical Cmter, Rlckmond, VA: Kenneth A. Ellenbogen, MD, Mark A. Wood. MD, Bruce S. Stambler, MD, Alan Cyan, RN, Donna Sargeant. RN; VA Medical Center-, West Rnwbury, MA: William E. Strauss. MD, William D&y. MD, David T. Martin, MD, Diane Lap&y, RN, MS, CS; Sanger Clmrc, Charlotte, NC; Charles A. Simonton, MD, Susan Lingelbach, RN; The Good Sanxzntan Hospital, B&imuw. MD: David A. Goldsher, MD, Jeral Insell, MD, Linda Fleiner, RN; Bosror~ City Hospital. Boston, MA: Rodney H. Falk, .MD, Sunder R. Rae, MD, Nancy Battinelli, RN; Mt. Sinai Medical Center, New Ymk, NY: Stephen Winters, MD, Elena Pe, RN; United Hospitals, Inc., St. Paul, MN: Victor Tschida, MD, David Fuhs, PharmD, Roseann Pitzen, RN; University of Texas at Ausfiiz, Austin, TX: Robert L. Talbert, PharmD, Eun Mee Lee; St. Paul Ramsey Medical Center, Sf. Paul, MN: Robert J. St&a, PharmD, John W. McBride, MD, Susan Gilliland, RN, BS: Gewge Was/zing&m University Medical Center, Washington, DC: Alan G. Wasserman, MD, Richard Katz, MD, Leslie Buff. BSN, MSN; Central Florida Cardiology Group, Orlando, FL: Scott J. Pollak, MD, Susie Bethel, RN, BS; Henrzepin County Medical Center, Minneapolis, MN: David Salerno. MD, PhD, David Dunbar, MD, Cheryl Fanner, RN; Marion Mewell Dow, /nc., Kansas City, MO: Virgil C. Dias, PharmD, Robert D. Reynolds, PhD, Susan Hamke, MS, Sheri Daniels, BS.
1. Salerno DM, Dns VC, Kleiger RE. Efficacy and safety of IV diltiazem for treatment of atria1 fibrillation and ahial flutter. Am J Cardinl 1989;63:1046-1051. 2. Dias VC, Plumb VJ. Intravenous diltiarem in patients with atrial fibrillation/ahial flutter. Dixg invest 1991;3:8-13. 3. Ellenbcgen KA, Dias VC, Plumb VJ, Heywood JT, Mirvis DM. A placebo-controlled trial of continuous intravenous diltiazem infusion for twenty-four hour rate control during atria1 fibrillation and atria1 flutter. J Am Co/l Cardiol 1991;18: 891-897. 4. Betriu A, Chaitman BR, Bourassa MC, Brevers G. Scholl JM, Bruneau P, Gag-
ARRHYTHMIAS
AND
gne P, Chabot M. Beneficial effect of intravenous diltiazem in the acute management of paroxysmal supraventricular tachyarrhythmias. Circulation 1983;67:88-94. 5. Huycke EC, Sung RJ. Dias VC, Milstein S, Harriman RJ, Platia EV. Intravenous diltiazem for termination of reentrant supraventicular tachycardia: a placebo-controlled, randomized, double-blind multicenter study. J Am Coil Car-dial 1989,13: 538-544 6. Dougherty
AM, Jackman WM, Naccarelli GV, Ftiday KM, Dias VC, and the IV Diltiazem Study Group. Acute conversion of paroxysmal supraventicula~ tachycardia with intravenous diltiazem. Am J Cardiol 1992;70:587-592. 7. Dias VC, Weir SJ, Ellenbogen KA. Phannacokinetics and phwmacodynamics of intravenous diltiazem in patients with atrial fibrillation or atrial flutter. Cimdadon 1992;86:1421-1428, 8. Mitchell LB, Schroeder JS, Mason JW. Comparative clinical electrophysiologic effects of diltiazem, verapamil, and nifedipine: a review. Am J Cardiol 1982;49: 629435. 9. Bohm M, Schwinger
RHG, Erdmann E. Cardiodepressant potency of various calcium channel antagonists in human myocardium. Am J Cardiol 1990;66: 1039-1041. 10. Chew CYC, Hect HS, Collett JT, McAllister RG, Singh BN. Influence of severity of ventricular dysfunction on hemodynamic response to intravenously administered verapamil in ischemic heart disease. Am J Cardiol 1981;4’7:917-922. 11. Hedman A, Angelin B, Arvidson A, Beck 0, Schenck GA. Digoxin-verapamil interaction. Clin Pharmacol Tker 1991;49:25&262. 12. Heywood TJ, Graham B, Marais GE, Jutzy KR. Effect of intravenous diltiazem on rapid atrial fibrillation accompanied by congestive heart failure. Am J Cardiol 1987;59:1150-1152. 13. Goldenberg IF, Longhurst JC, Dias VC, Heywood JT, Pedersen WR. lntravenous diltiazem in atria1 fibrillation/flutter patients with moderate to severe congestive heart failure: a placebo-controlled study (abstr). Chest 1992;102:102S. 14. Rameis H, Magometschnig D, Ganzinger U. The diltiazem-digoxin interaction. Clin Pkarmacol Tker 1984;36:183-189. 15. Fellows CL, Weaver WD, Swenson RD, Reichenbach DD, Emery M, Niskanen RA. Hemodynamic, electrocardiographic, and cellular effects of diltiarem treatment after cardiac arrest and resuscitation. J Crif Care 1989:4:166-175.
CONDUCTION
DISTURBANCES/DItTIAZEM
IN ATRIAL FlBRlttATlON
49
titrated to 10 mg/hour, and 76% (Cl: 66%, 85%) after titration from the 5 and 10 mg/hour infusion to the 15 mg/hour dose. For the 3 diltiazem infusions studied, mean (+ SD) heart rate was reduced from a baseline value of 144 f 14 beak/min to 98 f 19, 107 + 25, 107&22,101 +22,91 ?I 17,and88+ 18beak/min at infusion times 0, 1, 2, 4, 8, and 10 hours, respectively. By the end of the infusion, 18% of patients (14 of 78) had conversion to sinus rhythm. Hypotension was the most common side effect, occurring in 13% of patients. Symptomatic hypotension was present in 3.6% of patients, and responded to normal saline solution in all cases. We conclude that a bolus dose of 20 or 25 mg followed by titration of a continuous infusion of 5, 10, and 15 mg/hour of intravenous diltiazem is a safe and effective regimen to rapidfy lower heart rate in patients with atrial fibrillation and atrial flutter. (Am J Cardiol 1995;75:45-49)
bolus of intravenous diltiazem has been reported to A be safe and effective for acutely slowing the ventricular response during atria1 fibrillation and atrial flut-
The present study assessesthe safety and efficacy of intravenous diltiazem administered in bolus doses of 20 or 2.5 mg followed by a continuous infusion starting at a rate of 5 mg/hour and increasing to 10 and 15 mg/hour as needed in patients with atrial fibrillation and atrial flutter with a rapid ventricular response.
ter, l-3 and in converting paroxysmal supraventricular tachycardia to sinus rhynnnM In a recent study, intravenous diltiazem was administered to patients with atrial fibrillation and atria1 flutter as a bolus dose (20 mg, followed by 25 mg if needed) and a continuous infusion of 10 to 15 mg/hour, with a ventricular response of >120 beats/min.3 This sustained diltiazem infusion produced slowing of the ventricular response by >20% or a heart rate ~100 beats/min in about 80% of patients with a low incidence of adverse effects. Subsequent pharmacokinetic and pharmacodynamic data suggest that the minimal effective plasma concentration of diltiazem required to achieve a 20% decrease in heart rate from baseline is 79 ng/m1.7 This plasma concentration would be approximately produced by an intravenous diltiazem infusion at a rate of 5 mg/hour. From the Medical College of Vir inia and the McGuire Veterans Administration Medical Center, Ricii mond, Virginia; Veterans Administration Medical Center, Phoenix, Arizona; Veterans Administration Medical Center, West Roxbury, Massachusetis; the Sanger Clinic, Charlotte, North Carolina; Marion Merrell Dow, Inc., Kansas City, Missouri; and the Central Florida Cardiology Group, Orlando, Florida. This study was supported in part by a grant from Marion Merrell Dow, Inc., Kansas City, Missouri. Manuscript received May 27, 1994; revised manuscript received August 1 1, 1994, and accepted Au ust 12. A c?dress for reprints: Kenneth A. Ellenbogen, MD, Medical College of Virginia, Box 980053, Richmond, Virginia 23298-0053.
ARRHYTHMIAS
AND
METHODS The protocol was approved by the investigational review board of each of the 14 participating research sites (see Appendix). Each patient gave written informed consent before entry into the study. Patients were included in this study if they had the spontaneous occurrence of acute atria1 fibrillation or atria1 flutter or chronic atial fibrillation or atria1 flutter with a ventricular response of >120 beats/min during the 15-minute period before administration of the study drug. Atria1 fibrillation or atria1 flutter was documented by a 12-lead electrocardiogram, and heart rates were measured from a l-minute electrocardiographic rhythm strip obtained at the tirst and fifteenth minute of the baseline period. Patients were excluded if they were <18 years of age, were women of childbearing potential, had a known history of sick sinus syndrome, third-degree atrioventricular block, WolffParkinson-White syndrome, were hypotensive with a systolic blood pressure of ~90 mm Hg, or were allergic to diltiazem. No patient was taking oral diltiazem or intravenous or oral verapamil for 25 elimination halflives and for 24 hours plus 5 elimination half-lives for the sustained-release preparations. Patients were not excluded because of the presence of congestive heart
CONDUCTION
DISTURBANCES/DIlTIAZEM
IN ATRIA1
FlBRlllATlON
45
r
TABLE I Patient Baseline Characieristics 201~s
Trial Over
llncrease
Increase
Infusion
20 mg IV DILla
5 mgihr d
Infusion
to 15 mg/hr
sex Men (%)/women j%) Age (years] [mean * SD] Weight (kg) [mean * SD) Cardiac surgery within 2 weeks First occurrence of AF/AFt Type of AF/AFL Atrial fibrillation 1%) Paroxysmal (%) Chronic j%) Unknown w) Atrial flutter (%I Paroxysmal 1%)
IV DILT Infusion
to 10 mghr
I
IV DILT
IV DILT
Trial Over
<1 hour (%I 21 hour, < 12 hours (%)
Hour 10
failure or a low ejection fraction. During the bolus evaluation and infusion periods, patients did not receive p blockers or class I, III, or IV an&rhythmic drugs. Study design: This was an open-label, dose titration study (Figure 1). Each patient with atrial fibrillation or atria1 flutter with a mean ventricular response of >120 beats/min for 21.5 minutes before study drug administration was given 1 or 2 bolus doses of intravenous diltiazem after the 15-minute baseline period. The first dose of intravenous diltiazem was 20 mg administered over 2 minutes. If a patient did not achieve a therapeutic response within 15 minutes (conversion to sinus rhythm, slowing of the ventricular response to ~100 beats/min or by >20% assessed from a l-minute electrocardiographic rhythm strip), or if a further heart rate reduction was desired, a second dose of 25 mg was adtiinistered over 2 minutes. Patients who did not achieve a therapeutic response within 15 minutes of receiving the second bolus dose were withdrawn from the study and further therapy was chosen by the investigator. A continuous infusion of 5 mg/hour of intravenous diltiazem was started immediately after satisfactory therapeutic response with the jirst or second bolus. Patients were observed for a continued therapeutic response every 30 minutes throughout the lo-hour infusion period. If a therapeutic response was lost on 2 consecutive evaluations while receiving the 5 mg/hour infusion, the rate was increased to 10 mg/hour. If a therapeutic response was lost on the infysion rate of 10 mg/hour, the rate was increased to 15 mg/hour. Additionally, intravenous diltiazem could be increased from 5 mg/hour if the patient had maintained response for 24 hours at the lower dose, but further heart THE AMERICAN
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OF CARDIOLOGYa
71
Chronic w] Unknown 1%) Time since onset of AF/AFL
212 224
FIGURE 1. Study design for the intravenous diltiazem trial. The infusion rate could be increased from 5 to 10 mg/hour or from 10 to 15 mg/hour if patient (PT) maintained response for 24 hours at the lower dose (5 mg/hour) or for 2 hours at the hi her dose (10 mg/hour]. Loss of response was defined as a response criteria (e.g., ~20% decrease in fa!ure to maintain heart rati? from baseline, heart rate cl00 beats/min, or reversion to sinus rhythm) during 2 consecutive evaluations spaced 30 minutes apart. AF = atrial fibrillation; AFL = atrial flutter; DILT = diltiazem; IV = intravenous.
46
Diltiazem Bolus (n = 84)
Characteristics
VOL.
75
hours, 124 hours (Xl
Unknown (%) CHF: NYHA class No CHF (%) Class I (%) Class II w) Class Class
III (%) IV (%)
hours
(%I
(85)/13 (15) 66+ 10 85.4 t 22.2
Diltiazem Infusion (n = 79)
66 (84]/13 (lb] 66i 10 85 i 22.3
26 (3 1) 42 (50)
3.5 (44) 38 (481
62 30 13 19 22 16 4 2
(74) (48) (21) (31) (26) 173) I181 191
60 29 13 18 19 13 4 2
1 29 5 26 2
11) (351 (6) (3 I] 191
1 Ill 28 (35) 23 (291 2 I31
43
(511
42
8 (101 26
5
(761 (48) (221 (30) (24) (68) I211 (31
WI
(53)
8 I101
(31)
24 (30)
5 16)
4 (5) 1 (11
2 PI
AF = atrial fibrillation; AFL = atria/ flu&r, CHF = congestive NYHA = New York Heart Association.
heart failure;
rate reduction was desired by the clinician. The infusion could be increased from 10 mg/hour if the response was maintained for 22 hours, but further heart rate reduction was desired. The maximal infusion rate was 15 mg/hour. Patients who did not maintain therapeutic response at this infusion rate could be treatid with alternate antiarrhythmic therapy or electrical cardioversion. Statistical analysis: Heart rate and blood pressure data are expressed as mean f SD. Time to response after the bolus dose and during each maintenance dose was estimated by the Kaplan-Meier method. The percentage of patients in response at hour 10 for all infusion rates combined (5, 10, and 15 mg/hour) and for each infusion rate separately was obtained from the observed response rate at hour 10 and from the Kaplan-Meier method, respectively. The 95% confidence intervals are reported for the percent response for each dose of intravenous diltiazem administered.
RESULTS The study group consisted of 84 patients (62 with atria1 fibrillation and 22 with atrial flutter) who received bolus doses of intravenous diltiazem. Baseline characteristics of the patient population are described in Table I. Twenty-five patients (30%) were enrolled within 2 weeks of coronary artery bypass surgery. Forty-three patients (51%) were taking oral digoxin before study enrollment. The last mean dose of oral digoxin was 0.26 * 0.12 mg, resulting in a digoxin plasma concentration before study entry of 1.09 i 0.88 rig/ml. Efficacy: All 84 patients received the 20 mg bolus dose and, in addition, 42 patients received the 25 mg bolus JAN.
1, 1995
dose. Eighty-one percent of patients (68 of 84) responded to the 20 mg dose, and 69% (11 of 16) who were nonresponders to the 20 mg dose responded to the 25 mg dose. There was no difference in efficacy of intravenous diltiazem between patients with atria1 fibrillation and those with atrial flutter. Overall, 94% of patients (79 of 84) responded to either the tirst or second bolus. Forty-six percent of patients responded to the bolus by minute 2, 67% by minute 7, and 94% responded by minute 17 after receiving the 25 mg dose. Median time to response after the bolus dose was 7 minutes from the beginning of the bolus infusion. The baseline mean heart rate before the bolus infusion was 147 f 16 beats/ min, and decreased to 126 + 20 beats/min 17 minutes after the 20 mg bolus and to 109 f 24 beats/min 17 minutes after the 25 mg bolus. Mean heart rate reduction at minute 17 after the 20 and 25 mg bolus doses was 14 + 11% and 25 rt 15%, respectively. Infusion: Seventy-eight of the 79 patients who responded in the bolus period received a continuous infusion of diltiazem (1 had conversion to sinus rhythm). The percentage of patients maintaining response for 10 hours on the 5, 10, and 15 mg/hour infusion rates was 47% (conlidence interval [CI]: 36%, 59%), 68% (CI: 57%, 79%), and 76% (CI: 66%, 85%), respectively (Figure 2). Figure 3 displays the mean heart rates for the 78 patients who received the intravenous infusion. The mean (& SD) baseline heart rate was 144 2 14 beats/min. During the continuous infusion, heart rate decreased to 98 Z!Z 19, 107 + 25, 107 + 22, 101 f 22,91 + 21, and 88 f 18 beats/min at infusion hours
0, 1, 2, 4, 8, and 10, respectively. The number of patients with sinus rhythm at hours 0, 1,2,4, and 8 was 2,4,5, 10, and 13, respectively. By the end of the lo-hour infusion, 14 of 78 patients (18%) had conversion to sinus rhythm. There was no relation between the dose of diltiazem or a history of coronary artery bypass grafting that predicted which patients would revert to sinus rhythm during the infusion. The presence of more severe degrees of heart failure or a history of coronary artery bypass grafting did not predict the requirement for the highest infusion dose of diltiazem. Safety: BLOOD PRESSURE: In the 84 patients who received the 20 mg bolus dose of diltiazem, systolic and diastolic blood pressure was reduced after bolus administration, and remained reduced during ARRHYTHMIAS
P 2 z:w i$ 22 5% UK B 2
100 90 80 70 60 50 40 30 20 10
-
5 mgihr
---
5-10 mg/hr
-‘*
5-1 O-15 mgihr
0
I
I
I
I
I
I
I
I
I
I
1
2
3
4
5
6
7
8
9
10
TIME
(HOURS)
FIGURE 2. A Kaplan-Meier analysis therapeutic response to each dose
160
of the percentage of patients maintaining level of the intravenous infusion of diltiazem.
‘t
ok,,,,,,,,,,,,,,,,,,,,,, Base-End
0
1 lI.78
line Ekllus“=,6 Il.78 n.70
TIME
2
3
4
5
6
7
8
9
10
n=75
n=76
n.71
II=69
n=6a
n-65
n-64
n.64
lxx?
START
OF
(HOURS
FROM
INFUSION)
FIGURE 3. Heart rate during intravenous TO-hour infusion. The number of tients is shown below the time. The number of patients who received the r olus and the number who finished the study are different because those who did not respond to infusion or had reversion to sinus rhythm were withdrawn. Four patients had reversion to sinus rhythm by hour 1, 10 patients by hour 4, and 15 patients by hour 10. 1
T
0
SYSTOLIC
m
DIASTOLIC
T
T
T
BASELINE n=79
END BOLUS n=79
HOUR 1 INFUSION n=79
HOUR 5 INFUSION t-i=71
HOUR 10 INFUSION n=65
FIGURE 4. Systolic and diastolic blood pressures for all infusion doses shown. patient numbers decrease across time as infusion nonresponders those with conversion to sinus rhythm are withdrawn from the study.
AND
CONDUCTION
DISTURBANCES/DItTIAZEM
are
IN ATRIA1 FlBRlttATlON
and
47
infusion of diltiazem. Mean baseline systolic and diastolic blood pressure before infusion was 129 f 21/X0 f 16 mm Hg. Two minutes after the 20 mg bolus, blood pressure was 117 + 20/70 + 13 mm Hg (p = 0.0001). In 79 patients who received the diltiazem infusion, mean blood pressure at baseline was 129 + 22/80 f 16 mm Hg. At hours 0, 1, 2, 4, 8, and 10 of the infusion period, blood pressure was 118 + 29/69 f 13, 119 + 20/70 + 11, 120 + 19/71 f 12, 118 + B/70 + 12, 119 f 19/68 f 11, and 118 f B/67 + 12 mm Hg, respectively; p = NS (Figevents: Twenty-one percent of patients (18 of 84) had treatment-related adverse events. Hypotension was the most common adverse event, occurring in 13% of patients (11 of 84), 3.6% (3 of 84) of whom were symptomatic. Of the 11 patients with treatment-related hypotension, only 4 had hypotension lasting >35 minutes. No patient had an increase in heart rate accompanying the hypotensive episode. All 3 symptomatic patients were treated with normal saline solution, and recovered. Patient age, previous cardiac bypass surgery, weight, New York Heart Association class of congestive heart failure, sex, or presence of atrial fibrillation versus atria1 flutter did not predict the occurrence of hypotension. The only variables that predicted development of hypotension after the intravenous diltiazem bolus were the concomitant use of digoxin or a baseline diastolic blood pressure ~75 mm Hg. Other adverse events included headache in 2 patients, pruritus in 2, nausea in 1, dizziness and confusion in 1, and bradycardia in 1. No patient experienced an exacerbation of congestive heart failure while receiving the infusion.
The calcium antagonist agents verapamil and diltiazem may be used for the treatment of supraventricular arrhythmias. They act by slowing atrioventricular conduction and prolonging refractoriness in the atrioventricular node in a use-dependent fashion.8 Intravenous verapamil has limited usefulness in patients with atria1 arrhythmias and congestive heart failure because of its negative inotropic effect. 9~10In addition, when verapamil is used in conjunction with digoxin, a significant increase in plasma digoxin levels has been noted.ll In contrast, short-term administration of intravenous diltiazem is well tolerated in patients with severe congestive heart failure.12J3 Diltiazem does not produce a clinically significant interaction with digoxin. l4 This study conlirms several earlier studies that showed a high rate of response to bolus doses of diltiazem in patients with atrial fibrillation and atrial flutter.‘+J3 It also conlirms our previous report of a high rate of efficacy for a maintenance infusion.3 In our previous infusion study, 94% of patients responded to the bolus and 83% responded to a 24-hour infusion. The present study extends these observations by including patients after coronary artery bypass graft surgery and patients with New York Heart Association class III and IV congestive heart failure. Our previous study did not include postcoronary bypass surgery patients or patients with more severe degrees of heart failure. These patient populations have a high prevalence of atria1 fibrillation. This study includes these groups of patients and documents that the efficacy of intravenous diltiazem in these patient populations is similar to that seen in our previously reported study.
DISCUSSION
Role of iptrwenous diltiazem in the treatment of atrial fibrillation/atrial flutter: Intravenous diltiazem has valu-
This study provides safety and efficacy information during continuous titration of an intravenous infusion of diltiazem in a large group of patients. In addition, our study extends the experience of the use of a continuous infusion of diltiazem in patients with more severe degrees of heart failure and in those recovering from cardiac surgery. In this study, bolus doses of 20 mg followed by 25 mg of intravenous diltiazem produced a high response rate and a rapid response. The infusion titration of 5, 10, and 15 mg/hour of intravenous diltiazem was successful in maintaining response for 210 hours in 80% of patients. The 5 mg/hour infusion rate was successful in maintaining response in 47% of patients who had responded to the bolus dose of diltiazem. Acute management of atria1 fibrillation or atria1 flutter often involves control of the ventricular response with digoxin, l3 blockers, or calcium antagonists before establishing whether pharmacologic or electrical cardioversion can be safely performed. In some patients, the duration of atrial fibrillation may be longer than 48 to 72 hours, or the risk of embolic events is sufficiently great to warrant postponing conversion to sinus rhythm until sometime in the future. The primary goal of all drugs that slow atrioventricular conduction is to rapidly and safely control the ventricular rate without adding to the hemodynamic deterioration that occurs with a rapid ventricular rate.
able properties that make it a first-line agent when rapid slowing of the heart rate in atria1 fibrillation or atria1 flutter is a goal. It has a rapid onset of action, high response rate, and relatively little negative inotropic effect. In addition, a continuous infusion of intravenous diltiazem is easily and safely titratable to a desired reduction in heart rate.4,7 Thus, therapy can be altered as required by the patient’s clinical condition. Digoxin may be administered either intravenously or orally, but its onset of action is slower, generally taking hours until maximal heart slowing is observed. Digoxin is less easily and rapidly titrated to slowing of the ventricular response. The digoxin level should be checked before initiation of chemical cardioversion (with quinidine or procainamide) or electric cardioversion. Intravenous diltiazem can be administered during or before pharmacologic or electrical cardioversion15 without concern for toxicity or interaction with type Ia antiarrhythmic agents. It can be thought of as a “therapeutic bridge” in patients with atrial fibrillation or atria1 flutter while awaiting the onset of action of antiarrhythmic drugs with a long half-life, such as amiodarone. Intravenous diltiazem (like intravenous digoxin and verapamil) has been reported to accelerate the ventricular rate in a patient with an accessory atrioventricular bypass tract during an episode of atrial flutters; therefore, it should not be given to patients’with preexcited atrial fibrillation or flutter.
ure 4). @verse
48
THE AMERICAN
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OF CARDIOLOGY@
VOL.
75
JAN.
1, 1995
APPENDIX VA Medical Center. Phoenix, AZ: Frank P. Cardello, MD, Herschel Richter. MD, Cynthia L. Krome, RN. CVNS, ANP; VA Medical Cmter, Rlckmond, VA: Kenneth A. Ellenbogen, MD, Mark A. Wood. MD, Bruce S. Stambler, MD, Alan Cyan, RN, Donna Sargeant. RN; VA Medical Center-, West Rnwbury, MA: William E. Strauss. MD, William D&y. MD, David T. Martin, MD, Diane Lap&y, RN, MS, CS; Sanger Clmrc, Charlotte, NC; Charles A. Simonton, MD, Susan Lingelbach, RN; The Good Sanxzntan Hospital, B&imuw. MD: David A. Goldsher, MD, Jeral Insell, MD, Linda Fleiner, RN; Bosror~ City Hospital. Boston, MA: Rodney H. Falk, .MD, Sunder R. Rae, MD, Nancy Battinelli, RN; Mt. Sinai Medical Center, New Ymk, NY: Stephen Winters, MD, Elena Pe, RN; United Hospitals, Inc., St. Paul, MN: Victor Tschida, MD, David Fuhs, PharmD, Roseann Pitzen, RN; University of Texas at Ausfiiz, Austin, TX: Robert L. Talbert, PharmD, Eun Mee Lee; St. Paul Ramsey Medical Center, Sf. Paul, MN: Robert J. St&a, PharmD, John W. McBride, MD, Susan Gilliland, RN, BS: Gewge Was/zing&m University Medical Center, Washington, DC: Alan G. Wasserman, MD, Richard Katz, MD, Leslie Buff. BSN, MSN; Central Florida Cardiology Group, Orlando, FL: Scott J. Pollak, MD, Susie Bethel, RN, BS; Henrzepin County Medical Center, Minneapolis, MN: David Salerno. MD, PhD, David Dunbar, MD, Cheryl Fanner, RN; Marion Mewell Dow, /nc., Kansas City, MO: Virgil C. Dias, PharmD, Robert D. Reynolds, PhD, Susan Hamke, MS, Sheri Daniels, BS.
1. Salerno DM, Dns VC, Kleiger RE. Efficacy and safety of IV diltiazem for treatment of atria1 fibrillation and ahial flutter. Am J Cardinl 1989;63:1046-1051. 2. Dias VC, Plumb VJ. Intravenous diltiarem in patients with atrial fibrillation/ahial flutter. Dixg invest 1991;3:8-13. 3. Ellenbcgen KA, Dias VC, Plumb VJ, Heywood JT, Mirvis DM. A placebo-controlled trial of continuous intravenous diltiazem infusion for twenty-four hour rate control during atria1 fibrillation and atria1 flutter. J Am Co/l Cardiol 1991;18: 891-897. 4. Betriu A, Chaitman BR, Bourassa MC, Brevers G. Scholl JM, Bruneau P, Gag-
ARRHYTHMIAS
AND
gne P, Chabot M. Beneficial effect of intravenous diltiazem in the acute management of paroxysmal supraventricular tachyarrhythmias. Circulation 1983;67:88-94. 5. Huycke EC, Sung RJ. Dias VC, Milstein S, Harriman RJ, Platia EV. Intravenous diltiazem for termination of reentrant supraventicular tachycardia: a placebo-controlled, randomized, double-blind multicenter study. J Am Coil Car-dial 1989,13: 538-544 6. Dougherty
AM, Jackman WM, Naccarelli GV, Ftiday KM, Dias VC, and the IV Diltiazem Study Group. Acute conversion of paroxysmal supraventicula~ tachycardia with intravenous diltiazem. Am J Cardiol 1992;70:587-592. 7. Dias VC, Weir SJ, Ellenbogen KA. Phannacokinetics and phwmacodynamics of intravenous diltiazem in patients with atrial fibrillation or atrial flutter. Cimdadon 1992;86:1421-1428, 8. Mitchell LB, Schroeder JS, Mason JW. Comparative clinical electrophysiologic effects of diltiazem, verapamil, and nifedipine: a review. Am J Cardiol 1982;49: 629435. 9. Bohm M, Schwinger
RHG, Erdmann E. Cardiodepressant potency of various calcium channel antagonists in human myocardium. Am J Cardiol 1990;66: 1039-1041. 10. Chew CYC, Hect HS, Collett JT, McAllister RG, Singh BN. Influence of severity of ventricular dysfunction on hemodynamic response to intravenously administered verapamil in ischemic heart disease. Am J Cardiol 1981;4’7:917-922. 11. Hedman A, Angelin B, Arvidson A, Beck 0, Schenck GA. Digoxin-verapamil interaction. Clin Pharmacol Tker 1991;49:25&262. 12. Heywood TJ, Graham B, Marais GE, Jutzy KR. Effect of intravenous diltiazem on rapid atrial fibrillation accompanied by congestive heart failure. Am J Cardiol 1987;59:1150-1152. 13. Goldenberg IF, Longhurst JC, Dias VC, Heywood JT, Pedersen WR. lntravenous diltiazem in atria1 fibrillation/flutter patients with moderate to severe congestive heart failure: a placebo-controlled study (abstr). Chest 1992;102:102S. 14. Rameis H, Magometschnig D, Ganzinger U. The diltiazem-digoxin interaction. Clin Pkarmacol Tker 1984;36:183-189. 15. Fellows CL, Weaver WD, Swenson RD, Reichenbach DD, Emery M, Niskanen RA. Hemodynamic, electrocardiographic, and cellular effects of diltiarem treatment after cardiac arrest and resuscitation. J Crif Care 1989:4:166-175.
CONDUCTION
DISTURBANCES/DItTIAZEM
IN ATRIAL FlBRlttATlON
49