2. Lind L, Lithell H. Decreased peripheral blood flow in the pathogenesis of themetabolic syndrome comprising hypertension, hyperlipidemia and hyperinsulin-emia. Am Heart J 1993;125(suppl):1494–1497.3. Krauss RM, Winston M, Fletcher BJ, Grundy SM. Obesity: impact on cardio-vascular disease. Circulation 1998;98:1472–1476.4. NHLBI Obesity Task Force. Clinical guidelines on the identification, evalua-tion, and treatment of overweight and obesity in adults—the evidence report.Obes Res 1998;6(suppl 2):51S–209S.5. 1999 World Health Organization—International Society of Hypertension.Guidelines for the management of hypertension. J Hypertens 1999;17:151–183.6. Koh KK, Cardillo C, Bui MN, Hathaway L, Csako G, Waclawiw MA, PanzaJA, Cannon RO III. Vascular effects of estrogen and cholesterol-lowering ther-apies in hypercholesterolemic postmenopausal women. Circulation 1999;99:354–360.7. Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, WaclawiwM, Cannon RO III. Effects of hormone-replacement therapy on fibrinolysis inpostmenopausal women. N Engl J Med 1997;336:683–690.8. Koh KK, Jin DK, Yang SH, Lee S-K, Hwang HY, Kang MH, Kim W, Kim DS,Choi IS, Shin EK. Vascular effects of synthetic or natural progestagen combinedwith conjugated equine estrogen in healthy postmenopausal women. Circulation2001;103:1961–1966.9. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestinregimens on heart disease risk factors in postmenopausal women: the Postmeno-pausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1995;273:199–208.10. Xu X-P, Meisel SR, Ong JM, Kaul S, Cercek B, Rajavashisth TB, Sharifi B,Shah PK. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9and its tissue inhibitor in human monocyte-derived macrophages. Circulation1999;99:993–998.11. Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa WC, Bender JR. 17�-estradiol regulation of human endothelial cell basal nitric oxide release indepen-dent of cytosolic Ca2� mobilization. Circ Res 1997;81:885–892.

12. Gurjar MV, Sharma RV, Bhalla RC. ENOS gene transfer inhibits smoothmuscle cell migration and MMP-2 and MMP-9 activity. Arterioscler ThrombVasc Biol 1999;19:2871–2877.13. Koh KK. Effects of statins on vascular wall: vasomotor function, inflamma-tion, and plaque stability [review]. Cardiovasc Res 2000;47:648–657.14. Koh KK. Effects of HMG-CoA reductase inhibitor on hemostasis [review].Int J Cardiol 2000;76:23–32.15. Frazier-Jessen MR, Kovacs EJ. Estrogen modulation of JE/monocygte che-moattractant protein-1 mRNA expression in murine macrophages. J Immunol1995;154:1838–1845.16. Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R.Estrogen decreases TNF gene expression by blocking JNK activity and theresulting production of c-Jun and JunD. J Clin Invest 1999;104:503–513.17. Hulley S, Grady D, Bush T, Furberg C, Herrington DM, Riggs B,Vittinghoff E. Randomized trial of estrogen plus progestin for secondaryprevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–613.18. Glueck CJ, Wang P, Fontaine RN, Tracy T, Sieve-Smith L, Lang JE. Effectof exogenous estrogen on atherothrombotic vascular disease risk related to thepresence or absence of the factor V Leiden mutation (resistance to activatedprotein C). Am J Cardiol 1999;84:549–554.19. Koh KK, Horne MK III, Cannon RO III. Effects of hormone replacementtherapy on coagulation and fibrinolysis in postmenopausal women. ThrombHaemost 1999;82:626–633.20. Shlipak MG, Simon JA, Vittinghoff E, Lin F, Barrett-Connor E, Knopp RH,Levy RI, Hulley SB. Estrogen and progestin, lipoprotein(a), and the risk ofrecurrent coronary heart disease events after menopause. JAMA 2000;283:1845–1852.

Biphasic Waveform Cardioversion as an Alternative toInternal Cardioversion for Atrial Fibrillation

Refractory to Conventional Monophasic WaveformTransthoracic Shock

David G. Benditt, MD, Nemer Samniah, MD, Demosthenes Iskos, MD,Keith G. Lurie, MD, Benzy J. Padanilam, MD, and Scott Sakaguchi, MD

External transthoracic electrical cardioversion fortermination of atrial fibrillation (AF) is among the

most frequently performed and effective cardiovascu-lar procedures.1–4 It has been estimated that overallsuccess is about 90%.1,2 However, 2 types of treat-ment failures are observed. The first is transient ter-mination of AF with subsequent early recurrence (so-called “immediate” or early recurrence of AF). Thesecond is complete inability to cardiovert AF despiteusing both the highest available energy and a presum-ably optimum cardioversion vector. This latter failuremay be overcome in some cases by modifying elec-trode position, by use of pharmacologic reduction ofdefibrillation threshold, or by undertaking an internalcardioversion procedure.5 Recently, however, basedon experience with implantable biphasic waveform

cardioverter-defibrillators, the greater effectiveness ofbiphasic transthoracic waveform shocks (comparedwith previously conventional monophasic cardiover-sion waveforms) has been established in the setting oflife-threatening ventricular tachyarrhythmias.6–8 Fur-ther, by extension of these observations, the applica-tion of biphasic waveforms in the setting of electivetransthoracic AF cardioversion has become increas-ingly accepted in clinical practice. In this study, weexamined whether biphasic waveform shock offeredsufficient additional benefit as to obviate the need forinternal transcatheter cardioversion in patients whowere being considered for this procedure because offailure of conventional monophasic waveform cardio-version.

• • •Outcomes were examined in patients referred to

the Cardiac Arrhythmia Service for elective transtho-racic cardioversion of AF over a 12-month periodending March 2001. In all cases, the protocol forcardioversion used an anterior-posterior vector. Ad-herent pad electrodes were used initially, but in almostall cases standard metal plate electrodes (anterior-posterior vector) were also used before the cardiover-sion attempt was considered a failure.

From the Cardiac Arrhythmia Center, Cardiovascular Division, Depart-ment of Medicine, Minneapolis, Minnesota. Dr. Samniah was sup-ported by educational grants from Medtronic Inc. and the MidwestArrhythmia Research Foundation, Minneapolis, Minnesota. Dr. Pada-nilam was supported in part by a grant from the American HeartAssociation, Minnesota Affiliate, Minneapolis, Minnesota. Dr. Ben-ditt’s address is: Cardiac Arrhythmia Center, MMC 508, 420 Dela-ware Street, Minneapolis, Minnesota 55455. E-mail: bendi001@tc.umn.edu. Manuscript received May 29, 2001; revised manuscriptreceived and accepted August 17, 2001.

1426 ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 December 15, 2001 PII S0002-9149(01)02127-0

Patients in whom �2 transthoracic cardioversion at-tempts using conventional monophasic waveforms hadfailed to terminate AF, even transiently, were identified.These patients were considered candidates for internaltranscatheter cardioversion,5 but were offered the optionof an additional transthoracic cardioversion attempt,which was conventional apart from the use of a Food andDrug Administration–approved biphasic waveform defi-brillator (M3500B Heartstream XLT, Agilent Technol-ogies Inc., Andover, Massachusetts). Written informedconsent for transthoracic atrial electrical cardioversionwas obtained. QRS-synchronized cardioversion was per-formed during a brief period of general anesthesia. Pa-tients had been in the fasting state for 8 to 10 hours, andhad an international normalized ratio �2.5 but �3.5 fora minimum of 3 weeks. After the procedure, patientswere monitored for at least 2 hours before being dis-charged home.

Eight patients with multiple (�2 attempts at 360 J)unsuccessful conventional monophasic waveform car-dioversion procedures were identified during the studyperiod (Table 1). Clinical factors that may have contrib-uted to cardioversion resistance in these 8 patients in-cluded overall history of AF for �1 year in 6 of 8, leftatrial enlargement (�40 mm) in 5 of 8, and obesity in 2of 8. Significant systolic left ventricular dysfunction wasdocumented by echocardiography (estimated ejectionfraction �45%) in 2 patients (Table 1). Diverse antiar-rhythmic drug regimens had been used in these patientsduring the year before the attempted biphasic cardiover-sion. At the time of the procedure, 6 patients had beentaking amiodarone for �3 months (range 3 to 36), and 2patients were being treated with sotalol.

All 8 patients had failed cardioversion by conven-tional monophasic waveform technique on �2 occa-sions with energies of 360 J. Apart from lower energyshocks, each patient received a mean of 2.4 (range 2 to4) 360-J shocks within 2 months of the biphasic wave-form cardioversion procedure. The duration of themost recent sustained AF episode before the biphasiccardioversion procedure ranged from 1 month to ap-proximately 6 to 8 months (Table 1). Biphasic wave-form energy was initially set to 150 J. If the cardio-version attempt failed to terminate AF, even tran-siently, the attempt was considered a failure and theenergy was increased to 200 J. In 3 of 8 cases, a 150-Jshock was effective in terminating AF (see later). In 4

other cases, 200-J shocks were effec-tive after the initial 150-J shock hadfailed. In 1 patient (no. 8), neither150-J nor 200-J shocks were capableof terminating AF.

In 1 patient (no. 4), biphasic car-dioversion was only successful in re-storing sinus rhythm for a few min-utes, after which AF resumed andfurther cardioversion attempts wereabandoned. In 1 other patient (no. 1),AF recurred at 2 months despite ami-odarone therapy. Internal cardiover-sion was recommended to this pa-tient but she declined. These latter 2

patients are now considered to be in permanent AF.The remaining 6 patients are either in sinus rhythm (5cases) or atrial paced rhythm (1 case) at follow-uptimes ranging from 4 to 15 months. All are beingtreated with either amiodarone (4 patients) or sotalol(2 patients). There were no complications associatedwith the biphasic cardioversion procedure.

• • •In this study, a biphasic shock waveform appeared to

enhance the likelihood of transthoracic atrial cardiover-sion success in patients in whom AF had initially ap-peared to be refractory to conventional monophasictransthoracic cardioversion. Furthermore, availability ofthe biphasic waveform cardioversion largely obviatedthe need for internal transcatheter cardioversion proce-dures. Prolonged termination (�6 months) of AF wasachieved in 6 of 8 cases (75%). In the remaining 2patients, biphasic shock was transiently effective in 1(early recurrence of AF occurred), whereas in the otherpatient sinus rhythm was maintained for approximately 2months before AF recurrence.

Conventional electrical shock waveforms for defi-brillation are generated by discharging an electricallycharged capacitor through a largely resistive-capaci-tive impedance made up of the internal connections ofthe defibrillator, the patient wires or leads, the elec-trode-tissue interface, and ultimately the patient. Byvirtue of the capacitor and the electrical characteristicsof the external impedance, the waveform typically hasa single electrical polarity (monophasic) and an expo-nential decay. However, the long tail of the waveformdecay is thought to be ineffective in the defibrillationprocess, and may in fact be detrimental by reinitiatingcellular electrical activity and restarting fibrillation.Consequently, traditionally the monophasic defibrilla-tion waveform has been electronically foreshortened(i.e., so-called truncated exponential waveform). Inthe case of the biphasic waveform, the electrical out-put of the device is not only truncated, but at approx-imately its midpoint, the polarity is reversed electron-ically (i.e., biphasic). The effect of this modificationhas been a substantial reduction (approximately onethird) in defibrillation threshold. The basis for thereduction is not clear, but it may in part relate todiminution of the duration of the nonhomogeneous(and thereby conceivably arrhythmogenic) electrical

TABLE 1 Echocardiographic Findings

PatientAge (yrs)

& SexLA Size(mm)

MR(0–3�) LVEF

AF Duration BeforeBiphasic Cardioversion (mo)

AF Duration(yrs)

1 68 F 35 1� 55–60% 1 �42 51 M 35 1� 60% 12 13 55 F 44 0 60% 3 104 48 M 40 1� 55% 7 55 54 M 48 1� 55% 5 86 49 M 44 1� 35% 3 0.257 56 F 35 0 65% 3 �18 46 F 46 0 45% 2 �1

CV � cardioversion; LA � left atrial; LVEF � left ventricular ejection fraction; MR � mitral valveregurgitation.

BRIEF REPORTS 1427

shock field generated over the heart by conventionalmonophasic waveforms.9

In terms of transthoracic defibrillation, biphasicwaveforms became important as the reduced size re-quirements for portable automatic external defibrilla-tors demanded development of more efficient systems.In this regard, Schneider et al10 demonstrated thatbiphasic defibrillator shocks of 150 J were more ef-fective than 200- to 360-J shocks in resuscitatingout-of-hospital cardiac arrest victims. In brief, 98%were defibrillated with 3 biphasic waveform shockscompared with 67% with 3 conventional shocks. Withrespect to AF, biphasic shocks have been evaluated asa means of facilitating low-energy cardioversion byimplantable devices,11–17 and it appears that this ap-proach offers important advantages over monophasicwaveforms. However, less is known regarding themerits of biphasic transthoracic shock for atrial car-dioversion. Mittal et al17 reported findings of a ran-domized study comparing the efficacy of rectilinearbiphasic to conventional damped sine wave monopha-sic cardioversion in patients undergoing elective AFcardioversion. First-shock efficacy with 70-J biphasicwaveforms (68%) was significantly greater than with100-J monophasic waveforms (21%), as was the cu-mulative efficacy after completion of the protocol(94% vs 79%, p �0.005).

In summary, our findings suggest that biphasicwaveforms offer improved transthoracic cardio-version effectiveness in the patients with AF whoare hardest to treat (i.e., those in whom prior con-ventional transthoracic shocks have failed to inter-rupt AF, even transiently). In such patients, thebiphasic waveform technique may diminish theneed for undertaking transcatheter internal car-dioversion procedures.

1. Kastor JA. Atrial Fibrillation. In: Kastor JA, ed. Arrhythmias. Philadelphia:WB Saunders, 1994:25–104.2. Falk RH, Podrid PJ. Electrical cardioversion of atrial fibrillation. In: Falk RH,Podrid PJ, eds. Atrial Fibrillation: Mechanisms and Management. Philadelphia,PA: Raven Press, 1992:181–195.3. Bjork U, Karesoja M, Hirvonen P. Elective cardioversion in the elderly. In:Olsson SG, Allessie MA, Campbell RWF, eds. Atrial Fibrillation: Mechanismsand Therapeutic Strategies. Armonk NY: Futura Publishing, 1994:343–347.4. Pritchett ELC. Management of atrial fibrillation. N Engl J Med 1992;326:1264–1271.5. Levy S, Lacombe P, Cointe R, Bru P. High energy transcatheter cardioversionof chronic atrial fibrillation. J Am Coll Cardiol 1988;12:514–518.6. Bardy GH, Ivey TD, Allen MD, Johnson G, Mehra R, Greene HL. Aprospective randomized evaluation of biphasic versus monophasic waveformpulses on defibrillation efficacy in humans. J Am Coll Cardiol 1989;14:728–733.7. Saksena S, An H, Mehra R, DeGroot P, Krol RB, Burkhardt E, Mehta D, John T.Prospective comparison of biphasic and monophasic shocks for implantable cardio-verter-defibrillators using endocardial leads. Am J Cardiol 1992;70:304–310.8. Wyse DG, Kavanaugh KM, Gillis AM, Mitchell LB, Duff HJ, Sheldon RS,Kieser TM, Maitland A, Flanagan P, Rothschild J, Mehra R. Comparison ofbiphasic and monophasic shocks for defibrillation using a nonthoracotomy sys-tem. Am J Cardiol 1993;71:197–202.9. Blanchard SM, Ideker RE. Mechanisms of electrical defibrillation: impact ofnew experimental defibrillator waveforms. Am Heart J 1994;127:970–977.10. Schneider T, Martens PR, Paschen H, Kuisma M, Wolcke B, Gliner BE,Russell JK, Weaver WD, Bossaert I, Chamberlain D, for the Optimized Responseto Cardiac Arrest (ORCA) Investigators. Multicenter randomized controlled trialof 150–J biphasic compared with 200–to 360–J monophasic shocks in theresuscitation of out–of–hospital cardiac arrest victims. Circulation 2000;102:1780–1787.11. Cooper RAS, Alferness CA, Smith WM, Ideker RE. Internal cardioversion ofatrial fibrillation in sheep. Circulation 1993;87:1673–1686.12. Keane D, Boyd E, Anderson D, Robles A, Deverall P, Morris R, Jackson G,Sowton E. Comparison of biphasic and monophasic waveforms in epicardialatrial defibrillation. J Am Coll Cardiol 1994;24:171–176.13. Tomassoni G, Newby KH, Kearney MM, Brandon MJ, Barold H, Natale A.Testing different biphasic waveforms and capacitances: effect on atrial defibril-lation threshold and pain perception. J Am Coll Cardiol 1996;28:695–699.14. Harbinson MT, Allen JD, Imam Z, Dempsey G, Anderson JM, Ayers GM,Adgey AA. Rounded biphasic waveform reduces energy requirements for trans-venous catheter cardioversion of atrial fibrillation and flutter. PACE 1997;20:226–229.15. Sra J, Bremner S, Krum D, Dhala A, Blanck Z, Deshpande S, Biehl M, Li H,Jazayeri MR, Akhtar M. The effect of biphasic waveform tilt in transvenous atrialdefibrillation. PACE 1997;20:1613–1618.16. Tse HF, Lau CP, Camm AJ. Transvenous atrial defibrillation—techniquesand clinical applications. Clin Cardiol 1999;22:614–622.17. Mittal S, Ayati S, Stein KM, Schwartzmann D, Cavlovich D, Tchou PJ,Markowitz SM, Slotweiner D, Scheiner MA, Lerman BB. Transthoracic cardio-version of atrial fibrillation: comparison of rectilinear biphasic versus dampedsine wave monophasic shocks. Circulation 2000;101:1282–1287.

Time Course and Frequency of SubtherapeuticAnticoagulation for Newly Prescribed Warfarin

Anticoagulation Before Elective Cardioversion ofAtrial Fibrillation or Flutter

Michael H. Kim, MD, Kousik Krishnan, MD, Sandeep Jain, MD, andBenigno F. Decena, MD

The traditional approach to anticoagulation beforeelective cardioversion of atrial fibrillation (AF) of

�2 days duration, as recommended by the American

College of Chest Physicians, requires 3 weeks oftherapeutic warfarin as defined by an internationalnormalized ratio (INR) �2.0 (target INR 2.0 to 3.0)before cardioversion followed by 4 weeks of therapeuticwarfarin anticoagulation.1 Despite these frequently ac-cepted guidelines for cardioversion of AF, data on thetime course required to achieve 3 weeks of therapeuticanticoagulation and the impact of subtherapeutic INRvalues on the timing of cardioversion in the clinicalpractice setting are lacking. This investigation sought to

From the Cardiovascular Division, Washington University, St. Louis,Missouri. This report was supported, in part, by a research grant toMichael H. Kim, MD, from St. Jude Medical, Sylmar, California. Dr.Kim’s address is: Cardiac Electrophysiology, Burch 300, EvanstonHospital, 2650 Ridge Avenue, Evanston, Illinois 60201. Manuscriptreceived May 25, 2001; revised manuscript received and acceptedAugust 9, 2001.

1428 ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 December 15, 2001 PII S0002-9149(01)02128-2