Cardioversion of atrial tachyarrhythmias: anticoagulation to reduce thromboembolic complications

Progress in

Cardiovascular Diseases

Vol. 46, No. 6 May/June 2004

Cardioversion of Atrial Tachyarrhythmias: Anticoagulation to Reduce Thromboembolic Complications Hongsheng Guo, Wassim Shaheen, Richard Kerber, and Brian Olshansky

A

trial fibrillation remains a widespread, growing, and difficult to manage clinical problem.1-3 It can cause a wide variety of serious and debilitating symptoms, lead to frequent hospitalization,4 precipitate congestive heart failure and ischemia, cause cardiomyopathy, and perhaps most important, precipitate thromboembolic events including stroke. The problem is substantial and the solutions to resolve many of the crucial issues of management remain unresolved. Clinical judgment rather than an evidence base is often the approach used to make many important management decisions. Data from several large, multicenter, prospective, randomized, controlled clinical trials indicate that ventricular rate control of atrial fibrillation has a substantial, if not preferred, role in the management of patients with atrial fibrillation,5-9 and studies are ongoing.10 When a rate-control strategy is selected to manage patients with chronic or recurrent problems with atrial fibrillation, it is not surprising that long-term risk of thromboembolic stroke exists. Lack of a favorable outcome from a rhythmcontrol approach compared to a rate-control approach,5,11 may be due to adverse effects from and inefficacy of antiarrhythmic drugs as a means to restore and maintain sinus rhythm.12 The efficacy and certainty of antiarrhythmic drugs to maintain

sinus rhythm are also questioned. The search for curative therapies remains vibrant with promising initial results.12-18 Rhythm control with drug therapy does not guarantee a lower risk for stroke and anticoagulation cannot be stopped even if drug therapy appears to reduce or eliminate risk for atrial fibrillation Consistent and persuasive data from several well-controlled clinical multicenter trials of patients with atrial fibrillation (generally elderly patients) have demonstrated that chronic anticoagulation with warfarin (not aspirin) will reduce the long-term risk of stroke in the elderly and for other select patients with identified specific highrisk factors for stroke (hypertension, diabetes, heart failure, and prior risk of stroke)19-23 no matter the specific drug treatment. Risk for stroke is not an all-or-none phenomenon but a gradation. Generally, a risk of over 5% per year or 1% to 2% acutely after cardioversion is considered a high risk. From the University of Iowa Hospital, Iowa City, IA. Address reprint requests to Brian Olshansky, MD, Professor of Medicine, Director Cardiac Electrophysiology, University of Iowa Hospital, 200 Hawkins Dr, Iowa City, IA 52242 E-mail: [email protected] 0033-0620/$ - see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2003.12.001

Progress in Cardiovascular Diseases, Vol. 46, No. 6, (May/June) 2004: pp 487-505

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Many patients benefit from warfarin, but anticoagulation is not required for all patients with atrial fibrillation.24 Whereas some question the benefit of anticoagulation in patients with atrial fibrillation,25 the data regarding the benefits of anticoagulation are indisputable in high-risk atrial fibrillation patients in study after study. What is only recently becoming clearer is that attempts to maintain sinus rhythm alone with drugs do not decrease the risk of stroke or thromboembolic events unless a long-term strategy of anticoagulation is integrated into the planned management scheme. New approaches to assess thrombi (such as transesophageal echocardiography [TEE]) and new drug therapy, including ximelagatran, may transform the approach to anticoagulation in the acute management of atrial fibrillation. At present, persuasive data demonstrate unequivocally that warfarin anticoagulation offsets the augmented risk of thromboembolism following direct current (DC) cardioversion; however, several important questions remain: (1) Is it safe to cardiovert a patient with atrial fibrillation in the first 48 hours without anticoagulation? (2) Is it safe to cardiovert atrial flutter without anticoagulation? (3) What is the level of anticoagulation needed to ensure safety during and following cardioversion? (4) Is heparin or low-molecular-weight heparin as safe and effective as warfarin anticoagulation to protect against thromboembolism? (5) What is the proper anticoagulation regimen required for those whose cardioversion attempt is guided by TEE?

Purpose of this Report The purpose of this comprehensive review is to (1) identify the need for anticoagulation with respect to cardioversion of atrial fibrillation, (2) address potential mechanisms for thrombus formation during and after atrial fibrillation, (3) delineate methods to prevent thromboembolic events related to cardioversion of atrial fibrillation, (4) provide a strategy to use anticoagulation to reduce the risk of thromboembolic events in light of cardioversion, (5) consider new therapeutic approaches to anticoagulation to prevent thromboembolic events surrounding cardioversion, (6) contrast thrombogenic risk of atrial flutter and atrial fibrillation in light of cardioversion or ablation, and (7) discuss specific clinical situa-

tions in which anticoagulation may not be preferable at time of cardioversion.

Benefits and Role of Cardioversion DC cardioversion remains a standard, common, and accepted outpatient procedure used to treat a growing number of patients with symptomatic atrial flutter and fibrillation. Antiarrhythmic drugs are another, less successful method to convert atrial fibrillation and maintain sinus rhythm. Despite renewed interest in the rate control of atrial fibrillation, based on controlled multicenter randomized trials,5,11 clinically necessary cardioversion of atrial fibrillation to return the patient to sinus rhythm is a time-honored approach26 that will likely continue despite the well-known potential for complications.27,28 Several populations of patients with atrial fibrillation can benefit from cardioversion and/or maintenance of normal sinus rhythm. Those who may benefit the most include patients who (1) have hemodynamic intolerance or development of congestive heart failure directly due to atrial fibrillation; (2) may remain in sinus rhythm after cardioversion relatively long term without requiring extended antiarrhythmic drug use; (3) have only one episode of persistent, possibly, symptomatic atrial fibrillation; (4) have developed tachycardiainduced cardiomyopathy; (5) develop severe symptoms directly from atrial fibrillation despite rate control (i.e., not due to rapid rate alone); and (6) have paroxysmal or chronic atrial fibrillation during and immediately after ablative therapy. Other select populations, as well, may benefit. It is unlikely that recent randomized controlled clinical trials will have a substantial impact on the use of cardioversion for atrial fibrillation. Cardioversion indications may become even more complex as increasing use of nonpharmacologic therapies become integrated into clinical practice. The management of anticoagulation before and after ablative therapy for atrial fibrillation poses new problems regarding management to prevent stroke. Patients who have atrial fibrillation may undergo spontaneous or forced cardioversion, even if maintenance of sinus rhythm is not the desired goal. These include those who have implantable cardioverter defibrillators and may receive a commanded shock during implantation or a therapeutic shock during a ventricular arrhythmia,29 and those who have paroxysmal atrial fibrillation who

CARDIOVERSION OF ATRIAL TACHYARRHYTHMIAS

489

Fig 1. Time course of thromboembolic events after cardioversion. (Adapted from Berger and Schweitzer.31)

convert spontaneously or in light of specific drug therapy. Concern regarding proper anticoagulation in these patients, and others, will persist.

Anticoagulation During and Following Cardioversion One of the most serious consequences of atrial fibrillation is a catastrophic stroke or clinically apparent thromboembolism. Stroke and other thromboembolic events following cardioversion, although rare, even without anticoagulation, can almost always be prevented with a proper anticoagulation prescription. The use of anticoagulants to protect patients with atrial fibrillation from thromboembolism after cardioversion is not new.30 Thromboembolism is a known complication of chronic atrial fibrillation. Acute reversion of atrial fibrillation to sinus rhythm (spontaneously, by a drug, or by an electric shock) can increase the risk 10-fold. An analysis of 32 published studies with 4,621 patients who underwent electric cardioversion for atrial fibrillation or atrial flutter shows that 90 of 92 (98%) embolic episodes occurred within 10 days of cardioversion31 (Fig 1). It appears that the risk of thromboembolic events immediately and several weeks after cardioversion remains even more elevated than for the patient who has long-standing atrial fibrillation not undergoing cardioversion (Table 1). The incidence

of clinically apparent thromboembolism is only the tip of the iceberg; many thromboemboli may go undetected.28 Perhaps following cardioversion the level of attention to the presence of thromboembolism is elevated and thus thromboembolism that occurs following cardioversion is more likely to be detected. Strokes or thromboembolism caused by the purposeful return to sinus rhythm by drug, ablation, or electrical shock are generally preventable with proper attention to anticoagulation.

Mechanisms of Thrombus Formation in Atrial Fibrillation and Flutter The cause for the increased thromboembolic risk related to cardioversion is not clear, but it is multifactorial and complex. Electrical, contractile, and structural remodeling occur during atrial fibrillation.32 Hemostasis resulting from decreased atrial emptying related to mechanical asystole despite the return of atrial electrical function could promote intracardiac thrombi formation. Preformed senescent atrial thrombi may become dislodged after cardioversion and travel. Left atrial echo contrast representative of slow atrial transport has been associated with greater risk.33 The risk increases even further if thrombus is seen in the left atrium (usually in the appendage) by TEE just before cardioversion. Return of atrial function

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Table 1. Postcardioversion Thromboembolic Events and Effect of Anticoagulation Therapeutic Anticoagulation (INR ⱖ 2.0)

Authors

Patient Population

Follow-up Duration

N (Procedures/ Patients)

Overall (%)

Yes

No or Unknown

Arnold et al98

AF and flutter, 68% postsurgery

2w

454/428

6/454 (1.3)

0/185 (0) AF: 0/153 (0) Flutter: 0/32 (0)

6/269 (2.2) AF: 6/179 (3.3) Flutter: 0/90 (0)

Gentile et al101

AF

30 d

834/717

7/834 (0.8)

1/334 (0.3)*

6/471 (1.3)

Botkin et al72

AF and flutter, and atrial tachycardia Flutter

532/370

3/532 (0.6)

0/301 (0)

3/231 (4.2)

30 d

615/493

3/615 (0.5)

0/187 (0)

3/428 (0.7)

Flutter

30 mo

NA/41

3/41 (7.3)

0/3 (0)

3/38 (7.9)

NA/100

6/100 (6.0)

0/54 (0)

6/46 (13.0)**

26 mo

NA/191

13/191 (6.8)

3/67 (4.5) Ablation: 1/28 (3.6)

10/124 (8.1) DC: 3/138 (2.2)

30 d

128/104

1/128 (0.8)

0/67 (0)

1/61 (1.6)

1 mo

NA/134

2/134 (1.5)

1/NA

1/NA

14/2639 (0.5)

⬍48 hours 0/ 91 (0) ⱖ48 h 9/1841 (0.5)

⬍48 h 1/352 (0.3) ⱖ48 h 4/355 (1.1)

Elhendy et al100 Mehta et al103 Lanzarotti et al102 Seidl et al104

Elhendy et al99 Corrado et al117

Gallagher et al73

Flutter, 6% with history of AF Flutter, 34% with history of AF

AF and flutter, with history of stroke Flutter

All 3–4 w cardioversion for atrial tachyarrhythmias

2639/1950

Notes PT ⬎ 15 sec (1.5 times lower control) and PTT ⬎ 50 sec (2 times lower control) are considered therapeutic. *Patient received therapeutic heparin. Outpatients only.

Rates are events per patient. **Flutter-related events only Rates are events per patient. Means used for cardioversion: electrical (72%), chemical (10%), pacing (3%), ablation (15%).

One patient was on subcutaneous unfractionated heparin, the other was on heparin and warfarin (spontaneous conversion). There were no thromboembolic events in 779 patients who had an INR ⱖ 2.5, 4 events in 530 patients who had an INR 2.0–2.4.

Numbers are events/procedures (%), unless otherwise noted. Abbreviations: AF, atrial fibrillation; INR, International Normalized Ratio; NA, data not available.

may flush these clots out of the atria causing early thromboembolic complications after cardioversion.34 Delayed return of atrial function postcardioversion (so-called atrial stunning), even after brief atrial fibrillation, has been suggested as a cause.35-40 A hypercoagulable state after cardioversion of acute atrial fibrillation has been reported.41 The presence of atrial fibrillation alone may create this condition.42-44 The risk of hypercoagulability may

be related to elevation in blood pressure.45 Elevation in tissue factor (an initiator of coagulation), vascular endothelial growth factor (a marker of angiogenesis), and its receptor (sFlt-1) has been reported.46 D-dimer, ␤-thromboglobulin and soluble glycoprotein V levels can also be elevated.47,48 It appears that this reported hypercoagulable state is not due to an increase in factor V Leiden mutation.49 Atrial fibrillation can alter fibrinolytic function.50

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Compared to controls, higher plasma fibrinopeptide A and lower plasma antithrombin III levels have been reported.51,52 D-dimer levels and plasma fibrinogen levels are elevated in nonvalvular atrial fibrillation.44 In patients with atrial fibrillation, left atrial blood contains an excessive amount of platelet activity, thrombin generation, and fibrinolysis compared with the blood from the right atrium, and the femoral veins and arteries.52 Left atrial pressure overload resulting from atrial fibrillation might be partly responsible for thromboembolism. The abnormalities of these markers associated with a prothrombotic state may indicate a coagulation cascade gone awry. Endothelial/endocardial dysfunction may contribute to the elevated thromboembolic risk associated with atrial fibrillation, as suggested by studies in both experimental animals and humans.53-56 In pigs, it has been noted that atrial fibrillation is associated with a marked decrease in endocardial nitric oxide synthase expression, nitric oxide bioavailability, and an increase in plasminogen activator inhibitor 1 (a prothrombotic protein) expression in the left atrium.53,56 In patients with atrial fibrillation, decreased plasma levels of nitrite and nitrate as well as lower levels of platelet cyclic guanosine monophosphate (cGMP), when compared with sex- and agematched controls, have been observed, suggesting that there may be decreased levels of bioavailable nitric oxide in this setting.54 The precise mechanism for the decreased nitric oxide levels associated with atrial fibrillation is not clear. Turbulent flow conditions, however, have been associated with decreased nitric oxide synthase activity, perhaps owing to endothelial/endocardial injury.55

Does the Risk Vary by Type of Cardioversion? Spontaneous versus Drug versus DC Shock Conversion to sinus rhythm can be spontaneous, by a drug, by ablation, or by an electrical shock. Atrial fibrillation with no associated heart disease, acute onset, and related to an acute precipitant, such as open heart surgery, often converts spontaneously.57 The thromboembolic risk associated with these self-terminating episodes of atrial fibrillation, that is, paroxysmal or intermittent episodes, should not be underestimated. A study of 460 patients with intermittent atrial fibrillation from Stroke Prevention in Atrial Fibrillation

491 (SPAF) I, II, and III, who were assigned to aspirin or to a combined aspirin and ineffective (International Normalized Ratio [INR] ⱕ1.4) fixed-dose warfarin, reported a 3.2% per year ischemic stroke rate, which was not different from the rate among those with sustained atrial fibrillation (3.3% per year).58 Similar observation was made in other studies,59,60 although others reported a lower risk with intermittent atrial fibrillation.61-63 In long-term follow-up, a population that develops atrial fibrillation is at increasing risk of stroke over time. A peak in strokes occurs early, though, suggesting the intermittent or self-terminating episodes may increase risk before more sustained and permanent forms of atrial fibrillation intervene. Pharmacologic cardioversion has become less popular due to worries about adverse effects from antiarrhythmic drugs and its less predictable outcome, although several class III drugs have recently been developed.64-71 Drug therapy helps to maintain sinus rhythm after the cardioversion. Drug therapy may be used in conjunction with electrical cardioversion. There appears to be risk of thromboembolic events with drug conversion and this risk seems similar to that which is present with electrical conversion. No randomized trial has been completed to compare risk of thromboembolism by method of cardioversion. External electrical cardioversion is a well-accepted, effective, economical, outpatient, and low-risk (if performed properly) procedure that treats a growing number of patients with symptomatic atrial arrhythmias.72,73 Thromboemboli, when they occur related to cardioversion, tend to occur several days after rather than immediately during electrical cardioversion. It is possible, especially with high-energy shock delivery, that electrical cardioversion may cause transient or even long-lasting atrial damage. If this were to occur, electrical atrial stunning may effect atrial function and create greater risk of thromboembolic events. Cardioversion with biphasic, triphasic, or even quadraphasic74,75 shocks compared to monophasic waveform shocks is more effective and significantly reduces energy requirements to convert atrial fibrillation or atrial flutter to sinus rhythm.76-86 It is not clear that biphasic waveform shock advantages translate into lower thromboembolic risk. Sinus rhythm can be effectively restored by in-

492 tracardiac DC shock, or by rapid pacing, through temporary catheterization or an implantable device.87,88 The risks are likely equal to transthoracic DC cardioversion. Data regarding safety of internal cardioversion are scarce, and observations from transthoracic cardioversion should not be extrapolated. However, evidence available suggests it is probably safe to cardiovert internally as long as the patient is fully anticoagulated for 3 weeks or longer prior to and after cardioversion.89,90 A retrospective study90 analyzed the thromboembolic events and bleeding complications in 114 patients who underwent internal cardioversion for persistent atrial fibrillation after 3 weeks of warfarin anticoagulation. Warfarin was replaced by intravenous periprocedure heparin. There was no thromboembolic event in the 4-week period after cardioversion, although major bleeding (pericardial effusion) occurred in 2 patients and minor bleeding was observed in 8 patients. There are data to demonstrate a greater chance of thromboembolism directly owing to electrical cardioversion compared to other means of cardioversion or to spontaneous reversion to sinus rhythm. There are data to suggest that amiodarone, though, may not affect atrial mechanical function (“stunning”) to the extent that a DC shock does.91 It is not clear that using lower energies for cardioversion lowers the risk of thromboembolism. Cardioversion can always pose a risk. All undergoing cardioversion by whatever means should be considered to have risk of thromboembolism. These risks depend on age of the patient, underlying heart disease, heart failure, diabetes, prior thromboembolism, and length of episodes of atrial fibrillation.

Does Risk Vary by Underlying Disease or is it Related to Atrial Fibrillation Alone? The tendency to form thrombi is dependent upon underlying risk factors in patients with atrial fibrillation. This risk likely continues with cardioversion as well. Patients at highest risk should be more aggressively anticoagulated. Alternatively, low risk does not imply complacence as a stroke in a young patient with a normal heart is disastrous. Any risk short of a zero risk may not be acceptable. Although anticoagulation regimens are generally not recommended for low-risk, young, and other-

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wise healthy patients, these recommendations are not binding in the acute conversion of atrial fibrillation. Compared to age- and sex-matched controls, patients with nonrheumatic and rheumatic atrial fibrillation have 5- and 17-fold increase in risk of stroke, respectively.92 Data from the pre-anticoagulation era shows acute reversion to sinus rhythm carries a 5% to 7% risk for clinical thromboembolism in patients with atrial fibrillation lasting 2 days or more.26,27,30,93,94 This represents a 10-fold cardioversion-associated risk increase from the already elevated baseline risk in these patients. Despite this, many elderly patients in particular are not anticoagulated for cardioversion and may suffer the consequence.95 Table 1 summarizes cardioversion-related thromboembolic complications.

Risk Reduction by Anticoagulation Data from placebo-controlled randomized trials demonstrate clear benefit of long-term anticoagulation in high-risk patients with atrial fibrillation. A compilation of data from 6 major multicenter trials show a 45% relative risk reduction for any stroke, 52% for ischemic stroke, and 29% relative risk reduction for cardiovascular events with warfarin given chronically based on an intention-totreat analysis,96 but the benefits may really be greater than that. A recently published large retrospective study of 13,559 patients with nonvalvular atrial fibrillation reports that anticoagulation with warfarin with an INR ⱖ2.0 reduces not only the frequency of ischemic stroke but also its severity and the risk of death from stroke, when compared with aspirin or warfarin with an INR ⱕ2.0.97 There are no prospective, randomized, placebocontrolled studies regarding anticoagulation for cardioversion-related thromboembolic risk. However, several retrospective case-control series72,73,98-104 have repeatedly shown that adequate periprocedure anticoagulation effectively minimizes, if not completely abolishes, this risk related to reversion of atrial tachyarrhythmias to normal sinus rhythm (Table 1). Based on these observational data, the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) Guidelines for the Management of Patients with Atrial Fibrillation recommend that anticoagulation be used for 3 to 4 weeks before and after cardiover-

CARDIOVERSION OF ATRIAL TACHYARRHYTHMIAS

sion for patients with atrial fibrillation of unknown duration or with atrial fibrillation for more than 48 hours (Class I, Level of Evidence B).1 Although the risk of thromboembolism following cardioversion is much greater than it is otherwise in patients with atrial fibrillation, it remains unclear how long atrial fibrillation can exist before thrombi actually begin to form. The guideline recommendation of 48 hours is relatively soft, as is the 3- to 4-week recommendation following cardioversion. In fact, many patients who are cardioverted will require a lifetime of anticoagulation to prevent risk for stroke. Data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial suggests that it may never be safe to stop anticoagulation despite apparently effective antiarrhythmic drug therapy.104a For many patients, initial and recurrent atrial fibrillation events are silent. In a recent study,105,106 a total of 848 patients with chronic atrial fibrillation were randomized to receive sotalol, quinidine, and verapamil, or placebo after cardioversion. The patients were followed with daily transtelephonic electrocardiogram (ECG) recording. Within 1 year, about two thirds of the patients had recurrence. Of these patients, 70% had at least 1 asymptomatic event, and the incidence of stroke was the same with or without symptoms. Therefore, unless there is a sound reason to stop, anticoagulation should continue indefinitely.

Outpatient Versus Inpatient Cardioversion Much of the data that describe the use of cardioversion are based on information related to the inpatient cardioversion of atrial fibrillation. Several recent reports72,73 have demonstrated the feasibility, efficacy, and safety of outpatient cardioversion of atrial fibrillation. As long as the patient is well-anticoagulated based on standards described and is not at risk for bradycardia or other serious arrhythmias, it is safe to cardiovert. Generally, the patient is kept from eating for 4 to 6 hours and then is sedated or anesthetized. We advocate general anesthesia because many heavily sedated patients may never forget the event. After cardioversion, the patient is observed for at least 1 hour and is discharged if hemodynamically stable. This approach can save costs, and is effective and safe.

493 Is It Safe to Cardiovert Atrial Fibrillation Onset of <48 Hours If No Anticoagulation? Although this appears safe, occult thromboemboli can occur and left atrial clots may be present that do not embolize.107 Several trials demonstrated a low risk for thromboembolism even if a patient with short-term atrial fibrillation is not anticoagulated at the time of cardioversion or soon thereafter. Weigner et al showed that, of 1822 patients with atrial fibrillation, 375 episodes lasted ⬍48 hours and, of these, only 3 (0.8%), converting spontaneously to sinus rhythm, had thromboembolic events.108 Arguably, this represents a moderate risk for an elective procedure. Gallagher et al even more strongly support the concept that cardioversion of short-term atrial fibrillation is associated with a low risk of thromboembolism.73 Only 1 event occurred in 443 patients (0.22% or 0.28% for those not receiving prolonged anticoagulation) who had an atrial arrhythmia lasting ⱕ2 days. Unfortunately, the data in this ⱕ48-hour group are difficult to assess in Gallagher’s report, because the use of anticoagulation and the number with atrial flutter is unclear.73 ACC/AHA guidelines recommend that it is acceptable to withhold anticoagulation in patients undergoing cardioversion for atrial arrhythmias lasting ⱕ2 days.1 However, atrial fibrillation may be asymptomatic, silent, and longer lasting than suspected. Further, a patient with recurrent bursts of atrial fibrillation, closely spaced, is likely at higher risk. The concern remains: How certain is the arrhythmia onset? Risks increase if there are sputtering, multiple, self-terminating atrial fibrillation episodes before cardioversion. Atrial fibrillation occurring in multiple, self-terminating paroxysms cannot be considered similar to a single episode of atrial fibrillation. If a patient has multiple recurrences in a short time period, but the last episode occurred within 48 hours, the risk of thromboembolism may be unacceptably high.

Cardioversion of Atrial Flutter: Is It Safe Without Anticoagulation? Arnold et al98 reported in a retrospective case series that whether anticoagulation was given or not, there were no embolic complications with cardioversion in 122 patients with atrial flutter,

494 although most (68%) were post cardiac surgery (Table 1). Concern was raised several years ago in longterm follow-up of patients with atrial flutter and from observations after atrial flutter ablation.102,109,110 Data from our laboratory102,110 and others109 have shown that chronic atrial flutter is associated with long-term risk of thromboembolism, similar to atrial fibrillation, and that the risk is reduced by maintaining effective warfarin anticoagulation (Table 1). Biblo et al reviewed 8 years of retrospective Medicare population data and showed that the risks of stroke are substantial in patients with atrial flutter (relative risk of 1.41, compared to control), but perhaps lower than that with atrial fibrillation (relative risk of 1.64, compared to control).111 Thromboembolism can occur from cardioversion of atrial flutter.100,102-104,112 Thrombi and spontaneous echo contrast have been observed by TEE in atrial flutter.113,114 Left atrial stunning can occur after ablation or cardioversion of atrial flutter with return to sinus rhythm.37,115 In our laboratory,116 TEE before cardioversion of atrial flutter revealed abnormal left atrial transport. The mechanisms responsible for thromboembolism in atrial flutter, and its conversion to sinus rhythm, may differ from that for atrial fibrillation; regardless, the risks are noteworthy. Gallagher et al73 confirm that thromboembolism can occur with cardioversion of atrial flutter. The actual risk is difficult to determine because policies regarding anticoagulation, the time to enrollment in the study, the length of episode, the underlying cardiac diagnoses, and other undetermined factors were not controlled. Only 21.6% with atrial flutter lasting ⱖ2 days had an INR ⱖ2.5 at time of cardioversion. Those with INR values ⱖ2.5 had no embolic complications compared to those not receiving anticoagulation (0.9% risk) or those taking ineffective anticoagulation (0.5% risk; P ⫽ ns). The FLutter Atriale Societa Italiana di Ecografia Cardiovascolare (FLASIEC) multicenter study117 suggested that the risk for cardioversion of atrial flutter might be lower than for atrial fibrillation and that the risk of an atrial thrombus was “small” (left atrial appendage thrombus in 1.6% and right atrial thrombus in 1.0%). An embolic event occurred after cardioversion in 2 of 93 (2.2%) patients (1-month follow-up in 78 and restoration of

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sinus rhythm in 62 patients). Thirty-four percent were anticoagulated with warfarin or heparin. Elhendy et al100 reported 615 cardioversions of 493 patients with atrial flutter, and concluded that without therapeutic anticoagulation, the 30-day risk of thromboembolism after cardioversion may be “acceptable”—3 embolic events after 428 cardioversion (0.7%). There were no events, however, after 187 cardioversions with therapeutic anticoagulation (0.0%). Based on these data, it is clearly desirable to anticoagulate patients with atrial flutter, as with atrial fibrillation, before cardioversion.

What Is the Best Approach to Anticoagulation After Ablation Attempts? Elevated risk for thromboembolism has been reported in patients after catheter ablation,37,118 similar to those after cardioversion. Significantly depressed left atrial function (stunning) after catheter ablation of atrial flutter has been observed in studies using TEE.37,118,119 The left atrial appendage emptying velocity markedly decreased immediately after ablation and conversion to sinus rhythm, although it recovered completely in 2 to 3 weeks. Spontaneous echo contrast developed in 29% to 80% patients after flutter ablation and resolved also in 2 to 3 weeks.37,118,119 Complete atrial standstill and new left atrial appendage thrombus have also been observed after ablation.118 We recommend continuing anticoagulation with warfarin after atrial fibrillation and flutter ablation. It can be stopped 1 month after flutter ablation and 3 months after atrial fibrillation ablation if treatment effectively eliminated the arrhythmia.

What Level of Anticoagulation Is Needed During and After Cardioversion? INR values that ensure safety from thromboembolism in patients with chronic atrial fibrillation may not apply to those being cardioverted. An INR between 2.0 and 3.0 has been considered generally safe and effective.1 Based on available data and reasonable evidence, clinical guidelines now state: “Administer anticoagulation therapy regardless of the method (electrical or pharmacological) used to restore sinus rhythm in patients with atrial fi-

495

CARDIOVERSION OF ATRIAL TACHYARRHYTHMIAS

brillation lasting ⬎48 hours or of unknown duration for at least 3 to 4 weeks before and after cardioversion (INR: 2-3).”1 There is a rapid fall-off in efficacy as the INR drops below 2.0 and there is increased risk of bleeding as the INR exceeds 3.0. Data from 1 study call into question an INR of 2.0 as an acceptable lower limit to prevent stoke from cardioversion of atrial fibrillation.73 This group now advocates attempting to achieve an INR floor of 2.5. An INR of 2.5 at time of cardioversion may ensure that recent INR values before cardioversion have remained over 2.0, considering daily fluctuations. Although this approach makes sense, there are few data substantiating the need for this higher INR value, which could be harder to achieve and at greater risk. Data from our laboratory on 532 consecutive patients undergoing outpatient DC cardioversion of atrial flutter and fibrillation confirm these recommendations are effective as long as there is scrupulous attention to the INR value (measured at least weekly for 3 weeks with INR values ⱖ2.0 at each measurement).72 No embolic events occurred in those so anticoagulated. Some risk of stroke may always be present with elective DC cardioversion of atrial fibrillation but that risk, far less than 1%, is now achievable. Our study supports the concept that it is safe to cardiovert a patient with an INR measured at over 2.0 for 4 consecutive weeks.

tion cause about 17,000 major hemorrhagic complications in the United States per year, of which about 4000 are fatal.121 In 5 randomized trials with follow-up periods of 1.3 to 2.3 years, 10% to 38% of patients permanently discontinued anticoagulants. Perhaps this is one of the reasons that many physicians turn away from the use of warfarin in atrial fibrillation patients, particularly the elderly who are at highest risk for stroke due to atrial fibrillation. Scrupulous attention to detail may be required for safe warfarin use long term.122 In contrast to the concept that warfarin is inappropriately underutilized in atrial fibrillation patients, perhaps it is underutilized for good reason123 and better alternatives are needed. Other means of anticoagulation are often considered for patients at risk of thromboemboli in atrial fibrillation. Unfractionated Heparin Historically, heparin has been considered a surrogate for warfarin for atrial fibrillation. In fact, anticoagulants are often used in an inconsistent pattern from patient to patient.124 This appears to be similar worldwide,125 but heparin and warfarin have marked differences and the risk/benefit ratio of heparin has not been explored carefully. Despite recent guidelines that advocate its use,1 the efficacy and safety of heparin anticoagulation is not well established for atrial fibrillation. Fractionated Heparin

Alternative Therapies to Reduce Thromboembolic Risk After Cardioversion Warfarin is presently the drug of choice for anticoagulation patients with atrial fibrillation. Due to its inherent pharmacokinetic and pharmacodynamic disadvantages, there are problems using this drug. Several caveats apply: (1) INR values fluctuate. (2) The INR value, even if elevated at the time of initial anticoagulation may not reflect full anticoagulant. Efficacy is not always assured despite an INR ⬎2.0. It can take time to achieve therapeutic anticoagulation. (3) Termination of warfarin can induce a prothrombotic state (although this is not completely clear and is disputed120). (4) Proper management requires frequent INR measurements. It can take time to reverse its effect, when necessary. Anticoagulants for nonvalvular atrial fibrilla-

Interest in the use of low molecular weight heparin is growing.126-128 A multicenter, randomized trial (ACUTE II) is enrolling 200 patients with atrial fibrillation ⬎48 hours requiring cardioversion. TEE-guided intravenous unfractionated heparin bridge therapy to warfarin is being compared to TEE-guided subcutaneous enoxaparin bridge therapy to warfarin.128 While awaiting the results from the ongoing ACUTE II trial,128 findings from several observational clinical series are encouraging. De Luca et al129 studied the use of enoxaparin in TEE-guided cardioversion of 48 patients with atrial fibrillation lasting ⬎48 hours. Enoxaparin was started and cardioversion was performed after a TEE showing no intracardiac thrombi or spontaneous echo contrast. TEE was then repeated 7 days after cardioversion. Enoxaparin was discontinued in 24 patients after a repeated TEE showing no

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intracardiac thrombi. There was no thromboembolic event during 2-month follow-up.129 Dalteparin, another low-molecular-weight heparin, has been tested in 125 patients with TEEguided cardioversion.130 The authors suggest that simple, well-tolerated, and effective anticoagulation was possible.130 In another study of 172 patients,131 the feasibility and safety of TEE-guided early cardioversion with short-term dalteparin (2 ⫻ 5,000U) (90 patients) was compared to 82 patients receiving heparin (5,000U bolus and infusion). All received warfarin for 1 month after cardioversion. No patient had a thromboembolic event noted in 4 weeks.131 Although low-molecular-weight heparin may be as effective as warfarin, more information is needed before it can be recommended without restraint. Two ongoing prospective randomized multicenter trials128,132 will provide more insights into this issue. Ximelagatran An ideal anticoagulant would fulfill these criteria: easy administration (oral or topical); predictable absorption; rapid onset and offset of action; no or rare interaction with other drugs; favorable side effect profile; no monitoring and frequent dose adjustment required. Although warfarin effectively reduces stroke risk in patients with atrial fibrillation, it causes bleeding and is difficult to manage, requiring regular blood monitoring and frequent dose adjustments. Furthermore, warfarin interacts with a host of foods and other medications. As a result, warfarin is underutilized. There have been continuous efforts searching for a replacement.133 Ximelagatran, the first oral compound from a novel class of anticoagulants, direct thrombin inhibitors, might solve many of these current difficulties.133-136 Several parenteral direct thrombin inhibitors, namely, argatroban, hirudin, and bivalirudin, have been successfully developed and are commercially available. However, these agents are less suitable for long-term anticoagulation. Ximelagatran, 1 of the 2 oral direct thrombin inhibitors (BIBR 1048, the other) currently in clinical development, is a prodrug that, after absorption, is biotransformed into melagatran, a potent competitive inhibitor of human ␣-thrombin. Melagatran inhibits both free and clot-bound thrombin. It ef-

Fig 2. Mechanisms of how the direct thrombin inhibitor ximelagatran works on the coagulation cascade in relationship to heparin and warfarin.

fectively reduces thrombin generation and thrombin activity.137,138 Figure 2 shows the mechanisms of how ximelagatran works on the coagulation cascade in relationship to heparin and warfarin. In addition, melagatran potently inhibits thrombininduced platelet activation and aggregation.139-141 The results of the second Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF-II) trial suggested an acceptable safety profile of the drug.142 In this 12-week randomized double-blind study (ximelagatran versus warfarin), of 254 patients with at least 1 risk factor for stroke in addition to atrial fibrillation, ximelagatran given in fixed doses up to 60 mg twice daily was well tolerated without the need for coagulation monitoring or dose adjustment. In the ximelagatran-treated group, there were only 2 thromboembolic events: 1 patient with hypertension, left ventricular dysfunction, and diabetes, and a previous history of transient ischemic attacks, experienced a nonfatal ischemic stroke; another patient had a transient ischemic attack. Two transient ischemic attacks

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occurred in the warfarin group. No major hemorrhages were observed in the ximelagatran group, whereas one occurred in the warfarin group. Elevated liver enzymes while taking ximelagatran were observed in 8 patients, but normalized with continuous treatment in 5 patients and after discontinuation of the drug in 3.142 The preliminary results from the Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF-III) trial, recently presented at the American College of Cardiology 52nd Annual Scientific Session, are very promising. This open-label trial enrolled 3,407 patients with atrial fibrillation in 23 nations. The design has been reported elsewhere.143 All patients had nonvalvular atrial fibrillation and some additional risk factor for stroke, such as hypertension, congestive heart failure, previous stroke, thromboembolism, or various combinations involving diabetes or coronary artery disease. The trial compares adjusted-dose warfarin regulated by monthly measurements of the prothrombin time (INR: 2 to 3) against ximelagatran of a fixed oral dose (36 mg twice daily) without coagulation monitoring or dose adjustment. Ximelagatran did prove as effective as well-controlled warfarin in preventing both ischemic and hemorrhagic strokes, and systemic embolic events. In addition, ximelagatran caused less bleeding than warfarin. This trial is complemented by the results from the double-blind North American SPORTIF V trial, the largest clinical trial conducted to date to address the issue. The efficacy of ximelagatran is equivalent to warfarin but it has not been tested for efficacy in light of cardioversion. These data, however, address the long-term use of anticoagulation of atrial fibrillation but do not directly focus on the short-term benefits in those patient who have acute-onset atrial fibrillation or require cardioversion. There is also some concern about liver toxicity. This issue has not been completely resolved at this time. Nonpharmacologic approaches These are being tested to reduce the risk of thrombus formation in the left atrium. One, Percutaneous Left Atrial Appendage Occlusion (PLAATO), involved placement of an occlusive device in the left atrial appendage to eliminate it from the circulation.144 These approaches are not well tested nor are they widely available. Although they may

reduce the risk of thromboembolism long term, there is no indication that they would be effective for short-term management of the patient requiring cardioversion. During acute episodes of atrial fibrillation requiring cardioversion, even if these devices are used, anticoagulation should be considered as it is for other patients with similar conditions and episode lengths of atrial fibrillation.144-146

TEE-Guided Cardioversion TEE can determine accurately the presence of a left atrial thrombus provided that the entire left atrium, including left atrial appendage, is visualized and that it is interpreted properly. The issue of left atrial clot is complicated by presence of smoke—spontaneous ultrasound contrast—which is common in atrial fibrillation. Although smoke does not necessarily indicate clot, it indicates slow atrial flow, a potential predisposing factor for atrial thrombus. Slow atrial flow is seen frequently in atrial flutter and fibrillation.33,114 Experience and controlled trials support the use of TEE-guided cardioversion.147 It appears safe to cardiovert a patient with atrial fibrillation who has no left atrial thrombi on TEE as long as acute anticoagulation with heparin for 24 to 48 hours is undertaken at the time of cardioversion and maintained therapeutically with warfarin thereafter or if the patient has been adequately anticoagulated with warfarin at the time of cardioversion. Left atrial appendage thrombi can form rapidly early after cardioversion even if not present on a TEE immediately before cardioversion.148 The ACUTE trial was a randomized prospective multicenter trial that evaluated 2 cardioversion strategies for atrial fibrillation of ⬎2 days’ duration: TEE-guided cardioversion (with proper anticoagulation at time of cardioversion) versus a conventional approach (3 weeks of adequate warfarin anticoagulation followed by electrical cardioversion).149 The composite primary end point was cerebrovascular accident, transient ischemic attack, and peripheral embolism within 8 weeks. Secondary end points were functional status, successful restoration and maintenance of sinus rhythm, hemorrhage, and death. Normal sinus rhythm restoration was greater initially with TEE guidance than with conventional therapy, but this immediate advantage faded at 8 weeks. Interest-

498 ingly, although embolic events in both groups were similar (⬍5/619 in the TEE group and 3/603 in the conventional arm, ⬍1% in each), hemorrhagic events in the conventional group significantly exceeded that of TEE-guided therapy (18 events [2.9%] versus 33 events [5.5%], P ⫽ .03). This was due presumably to the longer duration of warfarin therapy in the conventional group. Patients in the transesophageal-echocardiography group also had a shorter time to cardioversion (mean [⫾ SD], 3.0 ⫾ 5.6 versus 30.6 ⫾ 10.6 days, P ⬍ .001) and a greater rate of successful restoration of sinus rhythm (440 patients [71.1%] versus 393 patients [65.2%], P ⫽ .03). At 8 weeks, there were no significant differences between the 2 groups in the rates of death or maintenance of sinus rhythm or in functional status.149 Ultimately, risks, benefits and costs were similar for both groups. In a substudy of the ACUTE trial, patients in the conventional group did convert to sinus rhythm on an antiarrhythmic drug at a higher rate due to the 3- to 4-week waiting period compared to the TEE group, so that some did not require electrical cardioversion. One hundred sixty-seven of 1,041 patients were identified in the TEE-guided and conventional groups who converted spontaneously with twice as many in the conventional compared with the TEE-guided group (110/523 [21%] versus 57/518 [11%]; P ⬍ .001). Those who had converted spontaneously had a higher rate of maintaining sinus rhythm at 8 weeks (87.2% versus 48.9%, P ⬍ .001). The conventional treatment strategy allowed greater opportunity for spontaneous conversion. In the absence of favorable predictors of spontaneous conversion (short duration of atrial fibrillation, lower New York Heart Association (NYHA) class, and smaller left atrial size), the TEE-guided approach should be considered first.150 The reasons to use TEE are actually more complex. TEE guidance should be considered for patients who are unlikely to tolerate atrial fibrillation well for a protracted period, for patients in whom effective anticoagulation cannot be maintained easily with large fluctuations in INR values for the 3- to 6-week periods, and patient preference. Otherwise, it is not unreasonable to anticoagulate for 3 to 4 weeks and then cardiovert as long as the INR values are consistently ⬎2.0. Retrospective data are also persuasive.73 Such data do not exclude patients undergoing cardio-

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version who do not fit into a prospective trial and dose conform to present clinical management strategies of patients with atrial fibrillation. The absence of a left atrial appendage thrombus on TEE does not guarantee absence of thromboembolism after cardioversion. There are multiple reports of thromboembolism in patients who had a negative TEE followed by cardioversion when anticoagulation is not performed.151-154 If a left atrial appendage thrombus is seen on TEE, cardioversion should not be performed. Therapeutic anticoagulation for at least 3 weeks should be achieved and then the TEE should be repeated. If a thrombus is still present, the risk of cardioversion resulting in thromboembolism may be excessive. The risk of cardioverting an anticoagulated patient with a longstanding atrial clot seen on TEE, however, is not completely clear. There may be specific TEE markers that may help stratify which patient is at higher and which is at lower risk.

Is Anticoagulation Required Before Starting all Antiarrhythmic Drugs? There are potential advantages of initiating an antiarrhythmic drug before cardioversion in an attempt to maintain sinus rhythm after conversion. Some patients have an early recurrence of atrial fibrillation. Use of antiarrhythmic drugs can prevent such episodes. However, initiation of an antiarrhythmic drug may return the patient to sinus rhythm before full anticoagulation has been achieved leading to risk of stroke. Thus, therapeutic anticoagulation should be achieved before an antiarrhythmic drug is begun for atrial fibrillation. However, this may be less of a concern for amiodarone. Low-dose amiodarone rarely converts atrial fibrillation by itself, but substantially reduces atrial fibrillation recurrences after cardioversion. Therefore, low-dose amiodarone may be initiated in select patients prior to full anticoagulation.

Cardioversion in Special Situations Pregnancy Atrial fibrillation in pregnancy is difficult to manage. The use of warfarin during pregnancy is contraindicated due to teratogenicity. Heparin is acceptable. Most pregnant patients have normal

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hearts and are at otherwise low risk for thromboembolism. However, it can be difficult to control the ventricular rate in atrial fibrillation pharmacologically during pregnancy. If a pregnant patient is in atrial fibrillation for more than a few days, there is risk of stroke. Long-term anticoagulation is not recommended and even the short-term use of anticoagulation can be problematic. In such a patient, it is best to be aggressive and try to maintain sinus rhythm with early, ideally within 48 hours, cardioversion. Available data suggest that DC cardioversion is safe in all phases of pregnancy and can be used when necessary.155-164 However, the recommendation for type of anesthesia should be discussed with the anesthesiologist prior to initiating the procedure. In addition, close fetal monitoring and readiness for emergency caesarean section should be discussed carefully with the obstetrician because rare but severe fetal distress due to sustained uterine contraction has been reported.165 Implantable Cardioverter Defibrillators Patients with chronic atrial fibrillation and an implantable cardioverter defibrillators (ICD) indication for ventricular tachyarrhythmias may inadvertently convert to sinus rhythm from an electrical shock by the device, or they may convert to sinus rhythm temporarily simply by testing the ICD during and after device implantation.29,166 Such a clinical situation may lead to a devastating stroke or death. Long-standing anticoagulation should be considered for a patient with an ICD and chronic atrial fibrillation. If this cannot be achieved or if the INR value is not high enough during the time of attempted conversion or at the time of implantation of a new device, one option would be the immediate refibrillation of the atria by the ICD. If the patient has an atrial lead, this can be achieved by rapid atrial pacing. In some cases, when an atrial lead is not present, a lowenergy shock during anesthesia synchronized to the QRS complex can be used to reinitiate atrial fibrillation. A patient who has transient sinus rhythm return but in whom atrial fibrillation is quickly reinitiated has a low risk of thromboembolism. Post-Cardiac Surgery It is not completely known if the risks of thromboembolism associated with cardioversion following coronary artery bypass graft surgery are

identical to those risks that occur in patients who are not in the acute phase of the surgical procedure. It is likely that the risks are similar and may even be higher after surgical intervention because surgery itself can lead to platelet abnormalities creating a hypercoagulable state. Also, frequent and multiple recurrences may exacerbate the risk. Compromised Hemodynamics There will always be some risk of cardioversion of atrial fibrillation in an attempt to maintain sinus rhythm. The purpose of performing this procedure is to improve outcomes for a patient. In some cases, the risk of cardioversion may exceed its benefit. However, if a patient is not tolerating atrial fibrillation hemodynamically despite reasonable attempts at rate control and there is no expectation that sinus rhythm will maintain itself after cardioversion, it is reasonable to consider cardioversion. In select patients, though, it is not possible to anticoagulate due to high risk for bleeding. In such a case, if possible, TEE should be performed to rule out the possibility of a large thrombus in the left atrial appendix. If present even if there is a good chance of maintaining sinus rhythm and benefit from sinus rhythm, it would be unwise to cardiovert the patient.

When Is It Safe to Stop Anticoagulation Following Cardioversion? The length of time required to anticoagulate the patient following cardioversion of atrial fibrillation is uncertain. Atrial function improves gradually after cardioversion. This improvement is dependent upon the chronicity of the atrial fibrillation and the underlying disease entity. On the other hand, it appears that within 4 to 6 weeks the atria have usually returned to the baseline state. It appears reasonable to anticoagulate after conversion of atrial fibrillation for at least 4 weeks with warfarin. After this time, the need for longterm anticoagulation depends on the potential risk for atrial fibrillation recurrence and other risk factors associated with thromboembolism.

General Recommendations ● Cardiovert without anticoagulation 䡩 Atrial fibrillation, single episode, or those with no recent frequent recurrences, ⬍48-

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hour duration (only when there is certainty of the time of onset). 䡩 Hemodynamically compromising atrial tachycardias with shock, ischemia, or heart failure that cannot be controlled by other means. Cardiovert with anticoagulation 䡩 Atrial fibrillation ⬎48 hours or unknown duration or associated with frequent recurrences. 䡩 Anticoagulation y heparin/warfarin, or warfarin alone for 3 to 4 weeks with weekly confirmation of INR ⬎2.0. y heparin (PTT ⬎50) followed by warfarin in lieu of a negative TEE (absence of intracardiac thrombi). Cardiovert if no clot whether or not there is smoke or spontaneous echo contrast but anticoagulate acutely for 24 to 48 hours with heparin and convert to chronic anticoagulation with warfarin for 4 weeks after cardioversion. Cardioversion in acute settings (postoperatively) is likely of a similar magnitude of risk as it is for other patients. Stop anticoagulation 1 to 3 months after cardioversion or ablation if the patient is at low longterm risk for stroke (young patients with normal hearts) and as long as risk for recurrence of atrial fibrillation is low. Anticoagulate for at least 1 month after an atrial flutter or fibrillation ablation. Ximelagatran has not been shown to be effective to reduce risk of stroke during cardioversion of an acute episode of atrial fibrillation, but available data otherwise are very promising. Treat atrial flutter like atrial fibrillation.

Conclusions Rate control, rather than rhythm control, with chronic anticoagulation results in better outcomes in the management of atrial fibrillation. Nevertheless, DC or pharmacologic cardioversion remain desirable, effective, economical, and lowrisk approaches. They can be associated with measurable increased risk of thromboembolic complications, unless meticulous attention is directed toward pericardioversion anticoagulation when indicated.

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