11. Tousoulis D, Davies G, McFadden E, Clarke J, Kaski JC, Maseri A. Coronaryvasomotor effects of setotonin in patients with angina. Relationship to coronarystenosis morphology.Circulation 1993;88 [part 1]:1518–1526.12. Tousoulis D, Davies G, Tentolouris C, Crake T, Toutouzas P. Coronarystenosis dilatation induced by L-arginine.Lancet1997;349:1812–1813.13. Arnal JF, Munzel T, Verema RC, James NL, Bai CL, Mitch WE, HarrisonDG. Interactions between L-arginine and L-glutamine change endothelial NOproduction.J Clin Invest1995;95:2565–2572.14. Quyyumi A, Dakak N, Diodati J, Gilligan D, Panza J, Cannon RO. Effect ofL-arginine on human coronary endothelial-dependent and physiologic vasodila-tion. J Am Coll Cardiol1997;30:1220–1227.15. Tousoulis D, Tentolouris C, Crake T, Katsimaglis G, Stefanadis C, ToutouzasP, Davies G. Effects of L- and D-arginine on the basal tone of human diseasedcoronary arteries and their responses to substance P.Heart 1999;81:505–511.16. Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J,

McCarthy SN, Keech A, Celermajer DS, Deanfield JE. Oral L-arginine improvesendothelium-dependent dilation in hypercholesterolaemic young adults.J ClinInvest1996;97:1989–1994.17. Sanderson KJ, van Rij AM, Wade CR, Sutherland WHF. Lipid peroxidationof circulating low density lipoproteins with age, smoking and in peripheralvascular disease.Atherosclerosis1995;118:45–51.18. Weber C, Erl W, Weber K, Weber PC. Increased adhesiveness of isolatedmonocytes to endothelium is prevented by vitamin C intake in smokers.Circu-lation 1996;93:1488–1492.19. Heitzer T, Hanjorg J, Munzel T. Antioxidant vitamin C improves endothelialdysfunction in chronic smokers.Circulation 1996;94:6–9.20. Camprisi R, Czernin J, Schoder H, Sayre JW, Schelbert RH. L-argininenormalizes coronary vasomotion in long-term smokers.Circulation 1999;99:491–497.

Clinical and Cost Comparison of Ibutilide and Direct-Current Cardioversion for Atrial Fibrillation and Flutter

David K. Murdock, MD, Glen T. Schumock, Pharm D, Jeffrey Kaliebe, MT,Karen Olson, RN, and Amy J. Guenette, Pharm D

D irect-current cardioversion (DCC) is the mostcommon method used to convert atrial fibrillation

(AF) and atrial flutter (AFl) when the arrhythmia is.48 hours’ duration.1,2 Ibutilide fumarate (ibutilide)has recently been approved by the Food & DrugAdministration to convert AF and AFl of recent onset(0 to 90 days).3 The purpose of this study was tocompare the clinical effectiveness and costs of a con-version strategy using first-line ibutilide versus DCCfor recent-onset AF or AFl in patients undergoinganticoagulation for 3 to 4 weeks before elective car-dioversion.

• • •Patients referred for elective cardioversion with

their first episode of AF or AFl were eligible toparticipate if the duration of AF or AFl was confirmedto be.48 hours and,90 days. All patients receivedat least 3 weeks of anticoagulation therapy, had anechocardiogram within 6 months, and each patient hadnormal serum potassium and magnesium levels at thetime of attempted cardioversion. AF or AFl was de-fined as either “lone,” or associated with structuralheart disease. Structural heart disease included pri-mary myopathic, hypertensive, valvular, and isch-emic. Exclusion criteria included presence of decom-pensated congestive heart failure, unstable angina, he-modynamically instability (systolic blood pressure,90 mm Hg or diastolic pressure.105 mm Hg) oruse of class I or III antiarrhythmic agents. Beta-block-ing agents, calcium antagonists, and digoxin werepermitted. Eligible patients were randomly assigned to1 of 2 treatment algorithms defined as group A or B.The study was approved by the institutional review

committee of Wausau Hospital and each participantgave informed consent before enrollment.

Patients randomized to group A received intrave-nous ibutilide (Covert, Pharmacia & Upjohn, Kalama-zoo, Michigan) under at least 4 hours of continuouselectrocardiographic monitoring.3 A 10-minute infu-sion containing 1 mg of ibutilide was administered. Ifthe patient was unable to achieve conversion to sinusrhythm within 10 minutes of completion of the firstdose, a second 10-minute infusion containing 1 mg ofibutilide was begun. If at any time the patient con-verted to sinus rhythm the infusion was immediatelystopped. The infusion was also stopped if new repet-itive (.3) ventricular premature complexes or hemo-dynamic instability occurred. If the patient did notconvert within 30 minutes of completion of the seconddose of ibutilide (1 hour after start of the first dose),the patient underwent DCC.

Patients randomized to group B underwent DCCwithout antecedent ibutilide. An anesthesiologist ornurse anesthetist using intravenous sodium metho-hexital anesthetized each patient undergoing DCC.DCC was performed using a 100 to 360 J impulsesapplied to the chest in an anterior-posterior paddleconfiguration.

The primary end point of the study was the termi-nation of AF or AFl. Success was defined as conver-sion to sinus rhythm for any length of time.4 Adverseeffects were noted such as profound bradycardia(heart rate,40 beats/min), polymorphic ventriculartachycardia (.3 beats of a continuously varying QRScomplex morphology at.100 beats/min),4 or hemo-dynamic instability. Each patient had an electrocar-diogram recorded 3 to 4 weeks after conversion andrelapse to AF or AFl was noted at that time.

Resource use and cost data were obtained from 3categories: physicians (anesthesiology and cardiolo-gy), hospital, and pharmaceutical. We obtained thecost of the physician component by summing theMedicare charges submitted by cardiology and anes-

From the Cardiovascular Associates of Northern Wisconsin, Wausau;The CARE Foundation, Wausau; and Wausau Hospital, Wausau,Wisconsin. This study was supported in part by The CARE Foundation,Inc., Wausau, Wisconsin, the Wausau Hospital, Wausau Wisconsin.Dr. Murdock’s address is: 520 North 28th Avenue, Wausau, Wis-consin 54401. Manuscript received May 20, 1999; revised manu-script received September 13, 1999, and accepted September 14.

503©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matterThe American Journal of Cardiology Vol. 85 February 15, 2000 PII S0002-9149(99)00782-1

thesiology departments according to standard Medi-care current procedural terminology codes. We ob-tained the cost of the hospital component of treatmentfrom charge data adjusted by cost-to-charge ratiosappropriate for each cost center at Wausau Hospital.Pharmaceutical costs were determined by obtainingthe average wholesale costs for each drug used. TableI lists general resources and costs for patients in eacharm of the study. Hospital resources, including admis-sion to the cardiovascular intervention unit and intra-venous access and associated supplies, were the samefor both groups. An hourly charge was also includedand varied by patient. All patients who received DCCincurred a hospital cost for the procedure as well ascosts for the anesthesiologist and cardiologist. If thepatient had conversion with ibutilide, no anesthesiafee was rendered. The cardiologist fee was determinedby the need to perform DCC. If DCC was performed,charges were submitted for that Medicare code only(92960). If the patient converted with ibutilide, anobservation level 1 Medicare code (99218) was usedto generate the charge. Medication costs were foributilide (ibutilide arm only, all patients required 2doses) and/or sodium methohexital (if the patient re-ceived DCC).

Continuous variable data are presented as mean6SD. Categorical data are reported as the frequency ofoccurrence of the variable. For continuous variables,group A was compared with group B using an F test.A chi-square test was used for categorical data. A pvalue#0.05 was considered significant.

Enrollment in the study was discontinued after 30patients, when interim analysis demonstrated signifi-cant differences in cost outcome were already presentbecause of a low conversion rate with ibutilide. Sev-enteen patients were randomized to treatment group Aand 13 patients were randomized to group B. Table IIsummarizes the clinical characteristics of the patientsin each group. Although comparable in most respects,there was a nonsignificant trend for group B to besomewhat older than group A. All but 2 patients hadsome form of structural heart disease. AF was thepredominant rhythm in both groups.

Table III summarizes the results of treatment ingroups A and B. Successful conversion was achieved

with both algorithms in most cases. Note the low rateof conversion with ibutilide alone. On only 4 occa-sions (24%) did ibutilide successfully convert the pa-tient to sinus rhythm. Three of the 4 ibutilide suc-cesses were for AF and 1 was for AFl. Patients whohad no success with initial ibutilide responded suc-cessfully to DCC. Patients tolerated each algorithmwell. Only 1 adverse outcome was observed. Thisconsisted of an 8-beat run of polymorphic ventriculartachycardia occurring in group A a few minutes aftercompleting the second, 1-mg infusion of ibutilide. Noadverse sequelae occurred. Relapse to AF or AFl by 3to 4 weeks was frequent and similar for both groups.

Table III also summarizes the cost of administeringeach algorithm. Because most group A patients re-ceived ibutilide and DCC, the cost of administratingalgorithm A was significantly higher than proceedingdirectly to DCC. The reason for the increased cost wasprimarily related to higher pharmaceutical costs (ibuti-lide cost $197/mg, and all group A patients received 2doses), and longer time at the hospital. Because only asmall percentage of patients receiving ibutilide re-sponded, the reduction in DCC costs (cardiology andanesthesiology charges) in these few patients wasmore than offset by the higher costs incurred in theother patients receiving ibutilide and DCC.

• • •Patients with AF or AFl usually present in 1 of 2

ways. They present most often with an acute, highlysymptomatic arrhythmia that frequently prompts themto seek immediate attention. Acute AF and AFl pre-senting as such are usually,48 hours in duration.Conversion to sinus rhythm may occur spontaneously.If not, successful conversion is usually achieved withDCC or a variety of antiarrhythmic agents.5

Nonacute AF and AFl usually present with moresubtlety. Frequently it is detected incidentally as partof a routine physical examination or during evaluationfor nonspecific complaints. In this setting, AF or AFlis usually.48 hours in duration. Because there is asmall risk of embolism after cardioversion, it is theusual practice to first treat these patients with 3 to 4

TABLE II Patient Characteristics

Group A(n 5 17)

Group B(n 5 13) p Value

Age (yrs) 69 6 5 73 6 9 0.08Sex (M/F) 10/7 8/4 0.65Rhythm (AF/AFI) 15/2 12/1 0.65Congestive heart failure 6 (35%) 3 (23%) 0.45Left atrial size (mm) 49 6 9 49 6 9 0.8Ejection fraction 49 6 13 54 6 13 0.8Associated heart disease

Hypertensive 7 (41%) 9 (69%) 0.15Ischemic 4 (24%) 2 (15%) 0.55Valvular 3 (18%) 1 (8%) 0.35Myopathic 2 (12%) 0 (0%) 0.15None 1 (6%) 1 (8%) 0.75

Cardiac medicationsDigoxin 9 (53%) 7 (54%) 0.98b blockers 9 (53%) 8 (62%) 0.65Calcium antagonist 1 (6%) 1 (8%) 0.75

TABLE I Resource Use and Costs

Resources Group A Group B

HospitalAdmit charge $204 $204Hourly charge $7 $7IV supplies $51 $51DCC $45 (if ibutilide failed) $45

PhysicianCardiology level 1 $57 (if ibutilide successful) NACardiology DCC $144 (if ibutilide failed) $144Anesthesiology $139 (if ibutilide failed) $139

PharmaceuticalIbutilide 1-mg dose $197 (2 doses used) NASodium methohexital $22 (if ibutilide failed) $22

IV 5 intravenous; NA 5 not applicable.

504 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 85 FEBRUARY 15, 2000

weeks of anticoagulation.6 Nonacute AF and AFl ofrecent onset are the most common arrhythmias re-ferred to us for elective cardioversion. We were spe-cifically interested in whether ibutilide could prove tobe a clinically useful and less costly alternative toDCC in patients with recent-onset AF or AFl whowere scheduled for elective cardioversion after 3 to 4weeks of anticoagulation.

Numerous studies confirm the use of ibutilide tocardiovert AF and AFl.4,7–12Conversion rates of 31%to 51% have been reported for AF, and 63% to 76%for AFl.4,12 Ibutilide appears more successful than anyother agent in accomplishing this task.10–12 The highsuccess rate of converting AF and AFl has led to thesuggestion that ibutilide be considered the first-lineapproach to treat these arrhythmias. With use of amodeling technique using published ibutilide andDCC conversion rates and assumed resource utiliza-tion, Zarkin et al13 suggested that a stepped conversionregimen of first-line ibutilide, followed by DCC forpatients who fail to convert, is more cost-effectivethan proceeding directly to DCC. Our study usedactual conversion rates and resource utilization ratherthan assumed values. Not only did we fail to confirmtheir prediction, but DCC was so much more cost-effective than first-line ibutilide that it was evidentwith our first interim analysis and resulted in prema-ture termination of our study. This discrepancy isexplainable because our observed ibutilide conversionrate was lower (only 24%), our conversion rate withfirst-line DCC was higher (93%), and the cost ofibutilide was considerably more than they assumed.

Our low ibutilide conversion rate shows that welimited our study to patients with AF and AFl inwhom the arrhythmia persisted although the 3- to4-week period of antecedent anticoagulant therapy.The importance of the duration of the arrhythmia onability of ibutilide to successfully convert AF and AFlhas been shown by Stambler et al.4 These investiga-tors noted a conversion rate of 46% when the arrhyth-mias were treated within 7 days of onset, decreasing toonly 18% after 7 days. In this respect, ibutilide be-haves similarly to other antiarrhythmic agents. Nu-

merous studies have confimed thatlonger-duration AF and AFl aremore difficult to convert with antiar-rhythmic agents.5,14–18 Althoughibutilide is approved for AF and AFlof recent onset (0 to 90 days), ourresults and those of Stambler et al4

demonstrate it has limited efficacy inpatients selected for cardioversionwhen the arrhythmia is still presentafter 3 to 4 weeks of antecedent an-ticoagulation.

The small size of our study is alimitation. This is particularly truewith respect to AFl. This arrhythmiaaccounted for only 10% of our pa-tients. Our study is similar to all pub-lished data to date on ibutilide inthat it includes far more patients with

AF than AFl.4,7–9,11,12Ibutilide may be more effectivein converting AFl than AF.4

In summary, we found that ibutilide produced alow rate of converting recent-onset AF and AFl inpatients scheduled for cardioversion after 3 to 4weeks of anticoagulation. Treating nonacute AFand AFl of recent onset with first-line ibutilide,followed by DCC for patients who fail to convert,was more costly than preceding directly to DCC.

1. Kerber RE. Transthoracic cardioversion of atrial fibrillation and flutter: Stan-dard techniques and new advances.Am J Cardiol1996;78(suppl 8A):22–26. 12.2. Goldman MJ. The management of chronic atrial fibrillation: indications andmethod of cardioversion to sinus rhythm.Prog Cardiovasc Dis1959;2:465–479.3. Corvert injection (ibutilide fumarate). Package insert, The Upjohn Company,Kalamazoo, MI: 1/96.4. Stambler BS, Wood MA, Ellenbogen KA, Perry KT, Wakefield LK,Vanderlugt JT. Efficacy and safety of repeated intravenous doses of ibutilide forrapid conversion of atrial flutter or fibrillation.Circulation 1996;94:1613–1612.5. Anderson JL. Acute treatment of atrial fibrillation and flutter.Am J Cardiol1996;78(suppl 8A):17–21.6. Laupacis A, Albers GW, Dalen JE, Dunn MI, Feinberg W, Jacobson AK.Antithrombotic therapy in atrial fibrillation.Chest 1995;108(suppl):352S-359S.7. Ellenbogen KA, Stambler BS, Wood MA, Sager PT, Wesley RC, MeissnerMD, Zoble RG, Wakefield LK, Perry KT, Vanderlugt JT. Efficacy of intravenousibutilide for rapid termination of atrial fibrillation and atrial flutter: a doseresponse study.J Am Coll Cardiol1996;28:130–136.8. Ellenbogen KA, Clemo HF, Stambler BS, Wood MA, Vanderlugt JT. Efficacyof ibutilide for termination of atrial fibrillation and flutter.Am J Cardiol1996(suppl 8A):42–45.9. Abi-Mansour P, Carberry PA, McCowan RJ, Henthorn RW, Dunn GH, PerryKT. Conversion efficacy and safety of repeated doses of ibutilide in patients withatrial flutter and atrial fibrillation.Am Heart J1998;136(4 Pt 1):632–642.10. Buchanan LV, Kabell G, Gibson JK Acute intravenous conversion of canineatrial flutter: comparison of antiarrhythmic agents.J Cardiovasc Pharmacol1995;4:539–544.11. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intra-venous ibutilide compared with procainamide during human atrial flutter andfibrillation: electrophysiological determinants of enhanced conversion efficacy.Circulation 1997;96:4298–4306.12. Volgman AS, Carberry PA, Stambler B, Lewis WR, Dunn GH, Perry KT,Vanderlugt JT, Kowey PR. Conversion efficacy and safety of intravenous ibuti-lide compared with intravenous procainamide in patients with atrial flutter orfibrillation. J Am Coll Cardiol1998;31:1414–1419.13. Zarkin GA, Bala MV, Calingaert B, Vanderlugt JT. The cost-effectiveness ofibutilide verses electrical cardioversion in the conversion of atrial fibrillation andflutter to normal rhythm.Am J Managed Care1997;3:1387–1394.14. Fenster P, Comess KA. Marsh R, Katzenberg C, Hager WD. Conversion ofatrial fibrillation to sinus rhythm by acute intravenous procainamide.Am Heart J1983;106:501–504.15. Galve E, Rius T, Ballester R, Artaza MA, Arnau JM, Garcia-Dorado D,

TABLE III Results of Therapy

Group A(n 5 17)

Group B(n 5 13) p Value

Clinical outcomeSuccessfully converted 17 (100%) 12 (92%) 0.25Converted with ibutilide 4 (24%) NATime in hospital (hrs 6 SD) 5.9 6 1.3 3.9 6 0.5 0.004Adverse reactions 1 (6%) 0 (0%) 0.45Relapse at 3–4 weeks 11 (65%) 7 (54%) 0.55

Cost of treatmentHospital $338 6 35 $317 6 4 ,0.0001Physician $248 6 72 $283 6 0 ,0.0001Pharmaceutical $411 6 9 $22 6 0 ,0.0001

Total $978 6 121 $622 6 4 ,0.0001

NA 5 no applicable.

BRIEF REPORTS 505

Soler-Soler J. Intravenous amiodarone in the treatment of recent-onset atrialfibrillation: results of a randomized, controlled study.J Am Coll Cardiol1996;27:1079–1082.16. Reisinger J, Gatterer E, Heinze G, Wiesinger K, Zeindlhofer E, GattermeierM, Poelzl G, Kratzer H, Ebner A, Hohenwallner W, Lenz K, Slany J, Kuhn P.Prospective comparison of flecainide versus sotalol for immediate cardioversionof atrial fibrillation. Am J Cardiol1998;81:1450–1454.

17. Suttorp MJ, Kingma JH, Lie-A-Huen L, Mast EG. Intravenous flecainideversus verapamil for acute conversion of paroxysmal atrial fibrillation or flutter tosinus rhythm.Am J Cardiol1989;63:693–696.18. Suttorp MJ, Kingma JH, Jessurun ER, Lie-A-Huen L, van Hemel NM, LieKI. The value of class IC antiarrhythmic drugs for acute conversion of paroxys-mal atrial fibrillation or flutter to sinus rhythm.J Am Coll Cardiol1990;7:1722–1727.

Vasopressin in the Treatment of Milrinone-InducedHypotension in Severe Heart Failure

Jeffrey Gold, MD, Suzanne Cullinane, BA, Jonathan Chen, MD, Susan Seo, BA,Mehmet C. Oz, MD, Juan A. Oliver, MD, and Donald W. Landry, MD, PhD

Management of patients with severe heart failureand hemodynamic instability remains a difficult

challenge. Phosphodiesterase (PDE) III inhibitors in-crease myocardial contractility and potentiate the in-otropy of b agonists, and can be very useful in thissetting.1–3 However, PDE III inhibitors also act invascular smooth muscle to increase cyclic adenosinemonophosphate and, via PDE IV inhibition, cyclicguanosine monophosphate.3,4 Although there is littleresponse to these changes in normal subjects,5 inpatients with severe heart failure and neurohumoralactivation of adenylate and guanylate cyclases,6 PDEIII inhibitors induce vasodilation and hypotension.7,8

A specific antagonist for the vascular action of PDEinhibitors could be clinically useful, and exogenousarginine vasopressin was of interest because this hor-mone inhibits activation of both adenylate cyclase andguanylate cyclase in vascular smooth muscle.9,10 Ac-cordingly, we examined whether vasopressin at lowdoses, having no pressor effect in normal subjects,could maintain arterial pressure in patients with severecongestive heart failure receiving PDE III inhibitors.

• • •Subjects were patients admitted to the intensive

care units of Columbia-Presbyterian Medical Center.Attending physicians prescribed vasopressin for pa-tients with congestive heart failure and milrinone-induced hypotension, and consecutive subjects meet-ing the criteria stated below were evaluated. The studywas approved by the Columbia institutional reviewboard as a retrospective review of data.

Congestive heart failure was diagnosed by cardiacindex of #2 L/min and pulmonary capillary wedgepressure of$15 mm Hg before milrinone administra-tion. Milrinone-induced hypotension was defined assystolic arterial pressure,90 mm Hg or systolic ar-terial pressure maintained at$90 mm Hg with cate-cholamine pressors. Patients with fever, hypothermia,or an obvious source of infection were excluded. All

eligible patients had an indwelling arterial catheterand a Swan-Ganz catheter for hemodynamic measure-ments.

Vasopressin (injection USP, 8-arginine vasopres-sin) was administered into a central vein at 0.03 to0.07 U/min. Intravenous fluids and medications werenot changed for the 1 hour before or the first hour ofvasopressin administration, except that pressor cat-echolamines were decreased if systolic arterial pres-sure exceeded 130 mm Hg. In Table I, values areaverages of the hour preceding milrinone, the hourbefore vasopressin, and the first hour with vasopres-sin. All values in the tables are expressed as mean6SEM. Data were analyzed by pairedt test. Differenceswere termed significant at a p level,0.05.

Seven patients with severe heart failure were stud-ied. Before administration of milrinone, all patientshad a low cardiac index (1.636 0.09 L/min), elevatedsystemic vascular resistance (2,0396 298 dyneszs/cm5), and marginal systolic arterial pressure (11565 mm Hg) (Table I). Administration of milrinoneincreased cardiac index by 50%, from 1.636 0.09 to2.45 6 0.18 L/min (p,0.01). However, systolic ar-terial pressure declined in each patient from a meanvalue of 1156 5 to 906 3 mm Hg (p,0.001). Thisled to an increase in the number of patients requiringcatecholamines to maintain an adequate arterial pres-sure (from 1 of 7 to 5 of 7) (Table II). Cardiac indexincreased during milrinone, and thus the decrease inarterial pressure reflected a near 50% decline in sys-temic vascular resistance, from 2,0396 298 to1,1126 106 dynesz s/cm5 (p ,0.01).

The subsequent administration of vasopressin atlow doses increased systolic arterial pressure signifi-cantly, from 906 3 to 1276 2 mm Hg (p,0.01;Table I). This pressor response allowed a decrease inthe dose and the incidence of administration of nor-epinephrine (Table II). The pressor effect of vasopres-sin was due to peripheral vasoconstriction, with sys-temic vascular resistance increasing from 1,1126 106to 1,4606 119 dynesz s/cm5 (p ,0.005) and withouta significant change in cardiac index, 2.456 0.18 to2.406 0.17 L/min. Vasopressin did not significantlychange pulmonary artery diastolic pressure (from20 6 1 to 216 2 mm Hg) or central venous pressure(from 14.4 to 15.6 mm Hg, p5 NS; data not shown).

From the Departments of Medicine and Surgery, Columbia University,College of Physicians & Surgeons, New York, New York. Dr. Landry’saddress is: Columbia University, Physicians & Surgeons Building, 10thFloor, Room 445, 630 West 168th Street, New York, New York.E-mail: DWL1@Columbia.edu. Manuscript received May 5, 1999;revised manuscript received September 15, 1999, and acceptedSeptember 16.

506 ©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matterThe American Journal of Cardiology Vol. 85 February 15, 2000 PII S0002-9149(99)00783-3