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(Circulation. 1997;95:2003-2006.)
© 1997 American Heart Association, Inc.

Articles

Activation of the Hemostatic Mechanism After Pharmacological Cardioversion of Acute Nonvalvular Atrial Fibrillation

Luigi Oltrona, MD; Marco Broccolino, MD; Piera A. Merlini, MD; Alessandra Spinola, MD; Antonio Pezzano, MD; Pier M. Mannucci, MD

From the 2nd Division of Cardiology (L.O., M.B., P.A.M., A.S., A.P.), De Gasperis Cardiology Department, Niguarda Hospital, and the Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre and Institute of Internal Medicine (P.M.M.), IRCCS Maggiore Hospital, University of Milan, Italy.

Correspondence to Luigi Oltrona, MD, 2nd Divisione Cardiologica, Ospedale Niguarda, Piazza Ospedale Maggiore, 3, 20162 Milano, Italy.

	Abstract

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Background Given that the restoration of sinus rhythm after chronic atrial fibrillation is associated with embolic events, anticoagulation is prescribed before and after pharmacological and electrical cardioversion. However, the need for anticoagulation in patients with acute atrial fibrillation (lasting <48 hours) who undergo cardioversion is less clear. In addition, it is not known whether cardioversion to sinus rhythm determines a hypercoagulable state in these patients.

Methods and Results In 21 patients with acute nonvalvular atrial fibrillation, plasma median concentrations of thrombin-antithrombin complex, a marker of thrombin generation, significantly increased from 2.8 ng/mL (interquartile range, 2.1 to 4.0 ng/mL) on hospital admission to 3.5 ng/mL (interquartile range, 2.9 to 6.0 ng/mL) after cardioversion to sinus rhythm obtained by means of infusion of antiarrhythmic drugs and decreased to 2.5 ng/mL (interquartile range, 2.0 to 3.5 ng/mL) at the 1-month follow-up visit (P=.04). Similarly, the levels of fibrinopeptide A, a marker of thrombin activity, increased from 1.1 nmol/L (interquartile range, 0.7 to 1.5 nmol/L) at baseline to 1.8 nmol/L (interquartile range, 1.1 to 3.0 nmol/L) after cardioversion and returned to 0.8 nmol/L (interquartile range, 0.6 to 1.1 nmol/L) at the 1-month follow-up visit (P=.02).

Conclusions A significant increase in plasma levels of the markers of thrombin generation and activity was observed in patients with acute atrial fibrillation early after pharmacological cardioversion to sinus rhythm. This is the first biochemical evidence that cardioversion of recent-onset atrial fibrillation determines a hypercoagulable state.

Key Words: fibrillation • coagulation • cardioversion

	Introduction

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Chronic atrial fibrillation predisposes to thromboembolism,^{1 2} and cardioversion itself is also associated with cerebral, systemic, and pulmonary embolic events.^{3 4} The mechanism of the occurrence of embolic episodes after the restoration of sinus rhythm in these patients is poorly understood. The reduction of the incidence of cardioversion-related embolic events induced by the administration of warfarin³ has led to the widespread recommendation that anticoagulation should be prescribed for several weeks before and after cardioversion in patients with chronic atrial fibrillation.^{5 6} On the contrary, the use of anticoagulants is not recommended in patients with acute atrial fibrillation (lasting <48 hours) who undergo cardioversion, although definitive data concerning the risk of postcardioversion embolism in these patients are scanty.^{5 6} The recent finding of atrial thrombosis in 14% of patients with recent-onset atrial fibrillation suggests that these patients are also at risk of embolic events,⁷ but whether or not the use of cardioversion determines a state of hypercoagulability in such patients has not been investigated, even though the presence of a prothrombotic condition may have implications relating to the best anticoagulant strategy to adopt.

To detect whether cardioversion is associated with activation of the hemostatic mechanism, we measured plasma concentrations of the markers of thrombin generation and activity (thrombin-antithrombin complex [TAT] and fibrinopeptide A [FPA]) in a series of patients with acute nonvalvular atrial fibrillation who underwent pharmacological cardioversion.

	Methods

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Study Population
Thirty-three patients with acute atrial fibrillation who visited the emergency department of Niguarda Hospital, Milan, were considered eligible to enter the study. Acute atrial fibrillation was defined as atrial fibrillation lasting <48 hours, as determined by (1) ECG documentation and (2) patient reports of the abrupt onset of new or worsening cardiovascular symptoms (palpitations, dyspnea, or dizziness) in the previous 48 hours. Twelve of the eligible patients were excluded because they had severely limited venous access (n=4), valvular heart disease (n=4), or neoplastic or inflammatory disorders (n=2) or were receiving anticoagulant medication (n=2). The remaining 21 patients were included in the study.

Study Protocol
A baseline venous blood sample was collected for biochemical analyses before any medical therapy was administered and before the insertion of intravenous lines. Intravenous antiarrhythmic treatment was then started, and the patients were hospitalized. During hospitalization, an ECG was performed every 12 hours, as well as transthoracic two-dimensional and Doppler echocardiography. Additional venous blood samples for biochemical analyses were drawn 24 and 72 hours after the start of antiarrhythmic therapy. In a subset of 11 patients, an additional blood sample was drawn and an ECG performed 6 hours after the beginning of antiarrhythmic drug administration. The postcardioversion sample was considered that which was first obtained after ECG documentation of stable sinus rhythm. The patients were discharged between 6 and 12 hours after the restoration of sinus rhythm. An additional blood sample was collected at the 1-month follow-up visit. Informed consent was obtained from all participants, and the study protocol was approved by the Institutional Review Board of Niguarda Hospital.

Biochemical Measurements
The venipunctures were performed atraumatically by specially trained investigators using 19-gauge butterfly infusion sets and a two-syringe technique. After the first 4 mL of blood was discarded, the samples were placed directly into refrigerated evacuated tubes containing an anticoagulant mixture composed of a thrombin inhibitor, EDTA, and aprotinin (purchased from Byk-Sangtec). The ratio of anticoagulant to blood was 1:9 (vol/vol). The blood samples were immediately centrifuged at 2500g for 25 minutes at 4°C; the plasma was frozen on dry ice and stored at -80°C until used. Plasma levels of TAT were measured with the use of a commercially available kit (Enzygnost TAT kit; Beringwerke AG). The coefficient of variation of this method is 5%. Plasma concentrations of FPA were determined in duplicate by means of enzyme-linked immunosorbent assay in plasma extracted twice with bentonite to remove fibrinogen (Diagnostica Stago). This technique has an interassay coefficient of variation of 5%.

Statistical Analysis
Given that the plasma levels of the markers of coagulation system activation were not normally distributed, repeated measures were compared by means of the Friedman test, and subsequent pairwise comparisons with baseline were made by use of the Wilcoxon signed rank test with a downward adjustment of the -level to compensate for multiple comparisons. The number of patients with plasma TAT and FPA concentrations above the upper normal limits was calculated by determining the 90th percentile of the distribution in a control group of 22 age- and sex-matched healthy individuals selected from the blood donors of Maggiore Hospital, Milan. The blood samples from these subjects were collected during routine visits to the blood bank by use of the same method as that described for the patients. The upper normal limits were set at 4.0 ng/mL and 2.2 nmol/L for TAT and FPA, respectively. Prevalences were compared using the ² test. Descriptive statistics include means and SDs or medians and interquartile ranges as appropriate. The tests presented are two-tailed, and values of P<.05 were regarded as statistically significant.

	Results

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Clinical Characteristics
Demographic and clinical characteristics of the patients with acute nonvalvular atrial fibrillation are shown in the Table. The mean duration of atrial fibrillation before hospital admission was 8 hours. The patients received an intravenous infusion of amiodarone (5 mg/kg for 30 minutes followed by 0.5 mg/h) (n=10), propafenone (2 mg/kg for 10 minutes followed by 24 mg/h) (n=10), or flecainide (2 mg/kg bolus followed by 0.25 mg·kg^-1·h^-1) (n=1). The intravenous administration of these antiarrhythmic agents obtained restoration of sinus rhythm within 24 hours in 18 patients and between 24 and 72 hours in 3. The echocardiographic variables are shown in the Table. Transthoracic echocardiography did not reveal any atrial or left appendage thrombi. At the 1-month follow-up, all of the patients were in sinus rhythm, and no embolic episodes had occurred.

View this table: [in this window] [in a new window]   Table 1. Clinical and Echocardiographic Variables in Patients With Acute Atrial Fibrillation

Plasma TAT and FPA Levels
The plasma concentrations of TAT and FPA in the patients with acute atrial fibrillation at the different time points are shown in Fig 1.

View larger version (34K): [in this window] [in a new window]   Figure 1. Individual plasma levels of thrombin-antithrombin complex (top) and fibrinopeptide A (bottom) in patients with acute atrial fibrillation at baseline, after pharmacological cardioversion, and at 1-month follow-up visit.

Plasma TAT levels increased from median baseline values of 2.8 ng/mL (interquartile range, 2.1 to 4.0 ng/mL) to 3.5 ng/mL (interquartile range, 2.9 to 6.0 ng/mL) after cardioversion and decreased to 2.5 ng/mL (interquartile range, 2.0 to 3.2 ng/mL) after 1 month (P=.04). The TAT levels were abnormal in five patients (24%) at baseline, in nine (43%) after cardioversion, and in two (10%) after 1 month (P=.05).

Plasma FPA levels increased from median baseline values of 1.1 nmol/L (interquartile range, 0.7 to 1.5 nmol/L) to 1.8 nmol/L (interquartile range, 1.1 to 3.0 nmol/L) after cardioversion and decreased to 0.8 nmol/L (interquartile range, 0.6 to 1.1 nmol/L) after 1 month (P=.02). The FPA levels were above the upper normal limits in 2 patients (10%) at baseline, in 10 (48%) after cardioversion, and in 1 (5%) after 1 month (P=.01).

Plasma concentrations of TAT and FPA measured 6 and 24 hours after beginning antiarrhythmic therapy and divided according to the achievement of sinus rhythm in the period before the 6- and 24-hour blood collections are shown in Fig 2. A trend toward higher TAT and FPA concentrations was observed in the patients with cardioversion compared with those still in atrial fibrillation.

View larger version (14K): [in this window] [in a new window]   Figure 2. Plasma levels of thrombin-antithrombin complex (top) and fibrinopeptide A (bottom) in patients with acute atrial fibrillation at 6 and 24 hours after start of antiarrhythmic therapy in relation to the restoration of sinus rhythm (yes and no). The box plot shows the range associated with 50% of the values (25th to 75th percentile); the median concentration is indicated by the line in each box. The concentrations for the 10th and 90th percentiles are indicated by the bars.

	Discussion

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The major finding of this study is the significant increase in plasma concentrations of the markers of thrombin generation and activity in patients with acute atrial fibrillation early after pharmacological cardioversion. The levels decreased toward baseline values 1 month after the restoration of sinus rhythm.

Plasma TAT and FPA levels are abnormally high in patients with acute coronary syndromes and provide a highly sensitive indication of activation of the coagulation mechanism.^{8 9 10} Similarly, in the present study, increased plasma levels of TAT and FPA reflected activation of the mechanisms of coagulation after cardioversion in patients with atrial fibrillation lasting <48 hours, who may therefore be at risk of thromboembolic events. The current recommendation with regard to the management of anticoagulation in patients undergoing cardioversion for chronic atrial fibrillation states that these patients should receive warfarin for 4 weeks after cardioversion.^{5 6} The rationale for antithrombotic prophylaxis is based on the demonstration that a higher incidence of embolic events occurs soon after cardioversion³ and the hypothesis that preexisting thrombi may enter the systemic circulation as a result of the return of mechanical atrial contraction.^{1 4} However, transthoracic and transesophageal echocardiographic observations suggest that a thrombogenic milieu may develop and that new thrombi occur as a result of cardioversion in patients without a preexisting thrombus.^{11 12}

In patients with recent-onset atrial fibrillation undergoing cardioversion, antithrombotic therapy is not recommended; however, there are reports of embolic episodes in such patients.^{7 12} The recent finding of the presence of thrombi in the left atrial appendage before cardioversion in patients with recent-onset atrial fibrillation confirms that this condition carries a potential embolic risk.⁷ Moreover, the demonstration of new postcardioversion left atrial thrombi in these patients¹² supports the view that the acute atrial stunning induced by cardioversion may predispose to blood stasis and thrombus formation. Our results provide the first biochemical evidence of the generation of a hypercoagulable state after the cardioversion of acute atrial fibrillation.

One of the limitations of this study is the relatively small sample size that may have limited the identification of different changes in marker levels after cardioversion in relation to the different clinical conditions underlying the acute atrial fibrillation. However, the exclusion of patients with valvular disease eliminated the confounding factor of the known baseline activation of the homeostatic mechanism in this condition.¹³ The activation of the hemostatic mechanism observed in the studied population may be due to atrial fibrillation itself; however, the higher plasma TAT and FPA concentrations in the patients who returned to sinus rhythm compared with those still in atrial fibrillation is consistent with a procoagulant effect determined by cardioversion. Atrial thrombosis cannot be excluded in this population because of the low sensitivity of transthoracic echocardiography in detecting the presence of atrial thrombus.¹⁴

This study demonstrates the presence of a hypercoagulable state early after pharmacological cardioversion, but considerations concerning the embolic risk of this condition may be extended to electrical cardioversion, which, as suggested by previous reports, carries the same risk of embolism.¹⁵ In addition, the impairment of atrial mechanical function that determines blood stasis has been demonstrated to be similar in patients undergoing pharmacological or electrical cardioversion.¹⁶ Prospective large-scale studies aimed at assessing the risk of thromboembolism after successful cardioversion in patients with atrial fibrillation lasting <48 hours are necessary to determine whether anticoagulation before and after the restoration of sinus rhythm should be recommended in these patients.

Received November 19, 1996; revision received March 6, 1997; accepted March 7, 1997.

	References

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