and Manage Cerebrovascular Accidents
A. ROSSILLO, A. BONSO, S. THEMISTOCLAKIS, A. CORRADO, B. DEPICCOLI, A. RAVIELE
Introduction
Atrial fibrillation is a common arrhythmia associated with significant mor- bidity and mortality. This arrhythmia increases the risk of ischaemic stroke, probably due to an atrioembolic mechanism. Without anti-thrombotic thera- py, the incidence of this complication varies from fewer than 2 to more than 10 strokes per 100 patient-years [1, 2].
Warfarin substantially decreases the risk of stroke in patients with non- valvular atrial fibrillation (AF) by about 60% but increases the risk of major bleeding to about 1% per year [3–8]. Recently, many authors have had a high success rate in treating AF by means of radiofrequency catheter ablation and electrical isolation of the pulmonary veins [9–11]. However, the role of anti- coagulation therapy in preventing atrioembolic stroke after such a proce- dure is still unclear. Thus, quantifying the efficacy of AF ablation in prevent- ing cerebrovascular accident is crucial to determining whether oral anticoag- ulation therapy may be safely stopped or not after radiofrequency catheter ablation of AF, and perhaps which patients should continue it.
In the present study we evaluate the incidence of ischaemic stroke after the interruption of oral anticoagulation therapy after 3 months in patients in whom an intracardiac echocardiography-guided pulmonary vein antrum isolation procedure had been performed.
Division of Cardiology, Cardiovascular Department, Umberto I Hospital, Mestre- Venice, Italy
Methods
Patients
Between September 2002 and May 2004, 109 consecutive patients were referred to our institution for ablation of symptomatic drug-refractory AF.
All patients gave their written informed consent for the procedure. Patients’
characteristics are shown in Table 1. Amiodarone treatment was discontin- ued at least 3 months before the procedure. The other anti-arrhythmic drugs were discontinued at least five half-lives before ablation.
Oral anticoagulation therapy was started 1 month before the procedure in all patients.
Paroxysmal AF was defined as self-terminating episodes lasting less than 7 days. Persistent AF was defined as when AF episodes lasted longer than 7 days and when pharmacological or electrical cardioversion were necessary to restore sinus rhythm. AF episodes failing to respond to cardioversion or for which no cardioversion attempt was made were classified as permanent AF.
Procedure Description
Patients came to the electrophysiology laboratory fasting. Immediately prior to the procedure, trans-oesophageal echocardiography was performed in all cases to exclude the presence of left atrial thrombi. A 20-polar catheter (St.
Jude Medical DAIG Division, Minnetonka, Minn., USA) was inserted into the coronary sinus from the right internal jugular vein. The proximal electrodes Table 1.Demographic characteristics of study population
All patients (n = 109)
Age, years (mean ± SD) 58.0 ± 10.0
Male sex, n (%) 84 (77)
AF duration, years (mean, range) 8, 1–24
Left atrial size, cm (mean ± SD) 4.4 ± 0.6
Left ventricular ejection fraction (%) 58 ± 6
Structural heart disease, n (%) 73 (67)
Paroxysmal AF, n (%) 40 (36.7)
Persistent AF, n (%) 48 (44.0)
Permanent AF, n (%) 21 (19.3)
were positioned between the superior vena cava and the high crista termi- nalis, while the distal electrodes were placed laterally in the coronary sinus.
A trans-oesophageal recording lead was used to record activation of the left atrial posterior wall and to define the position of the oesophagus. A 10-Fr phase array intracardiac echocardiography (ICE) catheter (Acunav Division, Acuson Inc., USA) was introduced into the right atrium from the left femoral vein.
Mapping of the left atrium and pulmonary veins was carried out after approaching the left atrium via the trans-septal puncture. The trans-septal sheaths were connected to continuous infusion of heparinised solution throughout the procedure.
Isolation of the pulmonary veins was performed using ICE to define the pulmonary vein ostium and to titrate the power. A decapolar circular catheter (Lasso-Biosense Webster, Diamond Bar, Calif., USA) was placed at the pulmonary vein–left atrium antrum as determined by ICE, where abla- tion was performed with an 8-mm tip catheter (Biosense-Webster, Diamond Bar) w ith power titration guided by the formation of microbubbles.
According to Marrouche et al. [11], the delivery of radiofrequency energy is controlled by progressively increasing the power (watts) until scattered microbubbles are observed by ICE. When type I bubbles were seen, energy was immediately titrated downward by 5- W decrements until the microbub- bles subsided. Energy delivery was also discontinued if microbubble genera- tion did not settle, as this was considered to be an early manifestation of tis- sue overheating. Energy delivery was immediately interrupted if a brisk shower of microbubbles was observed in the left atrium cavity, although an effort was made to avoid this phenomenon. The decapolar circular catheter was placed at the superior vena cava–right atrium junction as defined by ICE, and ablation was performed in a temperature-controlled mode.
Anticoagulation Protocols
Anticoagulation therapy with intravenous heparin infusion was restarted after the first trans-septal puncture with a 10 000 IU intravenous bolus plus continuous infusion at a rate of 1000 IU/h. A second bolus of 5000 IU was repeated after the second puncture.
Activated clotting time was maintained at about 350–400 s throughout the entire procedure.
Follow-Up
At the end of the procedure a single dose of aspirin 325 mg was adminis- tered orally. All patients were discharged on oral anticoagulation therapy
with warfarin, with the dose adjusted to reach a INR value between 2 and 3.
Follow-up and Holter monitoring was scheduled at 1, 3, 6, and 12 months after ablation.
A trans-oesophageal echocardiographic evaluation was performed in all patients at 3 months’ follow-up. A spiral computed tomogram (CT) of the pul- monary veins was obtained within 3 months after the procedure. If any pul- monary vein narrowing was detected at the first examination, CT was repeat- ed at 6 and 12 months to evaluate progression of the lesion. CT was also per- formed as a diagnostic test whenever symptoms compatible with pulmonary vein stenosis developed. Pulmonary vein stenosis was defined as mild if less than 50% luminal narrowing was evident, moderate if it was between 50%
and 69%, and severe if it was 70% or more. Patients with severe stenosis were referred for pulmonary vein angiography and angioplasty.
After 3 months, anticoagulation treatment was stopped in all patients except in cases where one of the following conditions was observed: (1) patients experienced recurrence of AF between 6 and 12 weeks after the pro- cedure; (2) more than 60% narrowing of the treated pulmonary vein was demonstrated by spiral CT performed 3 months after ablation; (3) non-opti- mal atrial contractility was shown by echocardiography, or (4) other indica- tions for oral anticoagulation therapy were present. In the case of recurrence of symptoms, event recorder monitoring was performed. The occurrence of AF during the first 6 weeks after ablation was not considered predictive of late recurrence and did not necessarily indicate continuation of oral antico- agulation therapy after 3 months follow-up.
Control Group
As control, we evaluated all the published data on patients with AF treated with oral anticoagulation therapy to prevent cerebrovascular accidents.
Statistical Analysis
Continuous variables were expressed as mean ± SD. Continuous variables were compared by Student’s t test. Differences among groups of continuous variables were determined by analysis of variance (ANOVA). Categorical variables were compared by χ2analysis or using Fisher’s exact test. A P value below < 0.05 was taken to indicate statistical significance.
Results
All four pulmonary veins were disconnected in all patients. In addition, com- plete electrical isolation of the superior vena cava was achieved in 95
patients (87%). In the other 14 patients this was not possible because of stimulation of the phrenic nerve or the presence of the sinus node on the ablation site. During the procedure a stroke occurred in a 74-year-old woman with a history of transient ischaemic attack and permanent AF after electrical cardioversion at the end of the ablation (0.9%).
After 15 ± 7 months’ follow-up, 90 of 109 patients (82.5%) were in stable sinus rhythm. A previously ineffective anti-arrhythmic drug was necessary to maintain sinus rhythm in 16 of 109 patients (14.5%). Trans-oesophageal echocardiography showed good atrial contractility in all patients with stable sinus rhythm.
During the follow-up period, no pulmonary vein narrowing greater than 60% was detected by CT, and in only two patients was a pulmonary vein stenosis between 50% and 60% present(1.8%). No perfusion defects were documented by quantitative pulmonary V/Q scans. All patients with mild or moderate pulmonary vein stenosis were asymptomatic.
An iatrogenic post-AF-ablation left atrial flutter/tachycardia was docu- mented in 7 patients (6.4%).
The risk factors for stroke are shown in Table 2. Oral anticoagulation therapy was stopped after 3 months in 73 patients (68%) and no cerebrovas- cular accidents occurred during the remaining follow up.
Table 2.Stroke risk factors
All patients (n = 109)
n %
Low risk
(age < 65 years old, no hypertension, no diabetes,
no CHF or previous cerebrovascular accidents) 41 37.6 Medium risk
(age > 65 years old, no hypertension, no diabetes,
no CHF or previous cerebrovascular accidents) 13 11.9 High risk
(age > 65 years old, hypertension, diabetes,
CHF or previous cerebrovascular accidents) 55 50.5
CHF congestive heart failure
Discussion
The main finding of the present study is that ICE-guided pulmonary vein antrum isolation seems to prevent cerebrovascular accidents in patients with symptomatic drug-refractory AF who are not receiving anticoagula- tion therapy.
Anticoagulant Prophylaxis Against Stroke After Pulmonary Vein Antrum Isolation In the published literature the rate of cerebrovascular accident in patients with AF who are on warfarin therapy ranges between 1.6% and 4.8% [12]. The consumption of warfarin is associated with an increased risk of major bleed- ing, especially in subjects older than 85 years old [13, 14]. In the last 10 years various authors have tried to identify the clinical characteristics of patients who derive greater benefit from anticoagulant therapy [15–20]. Age greater than 65 years old and/or a history of hypertension, diabetes, congestive heart failure, or previous cerebrovascular event have been identified as increasing the risk of transient ischaemic attack or stroke in patients with AF.
Our data show a very low incidence of cerebrovascular accident in the medium-term follow-up after pulmonary vein antrum isolation. The cere- brovascular accident risk in our study population, according to the Stroke Prevention in Atrial Fibrillation (SPAF) trial criteria was high in 31 of 73 (43%), medium in 10 of 73 (13%), and low 32 of 73 (44%) of cases. These data are slightly different from the thromboembolic risk pattern shown in the SPAF trial. Our patients were younger and had a lower incidence of pre- vious thromboembolic events. However, this was compensated by a higher percentage of permanent AF and a longer duration of the arrhythmia in our patients.
The lower risk profile of our patient population is clearly due to the policy on indication policy for pulmonary vein antrum isolation in our electrophysi- ology laboratory. We try to perform ablation in very high risk patients only if they are highly symptomatic. Moreover, it is well known that these classifica- tion schemes are variably effective in predicting stroke risk [21].
Even if we consider only the published data on patients with low risk of cerebrovascular accident, our data showed a reduction of stroke incidence (0% vs 1.1–2%) [17].
It is well known that restoring sinus rhythm with electrical cardioversion causes stunning of the left atrial appendage, and some authors have identi- fied left atrial appendage stunning as a marker of future embolic events. As previously reported, we consider the presence of a higher peak velocity and prolonged duration of early diastolic (E+E1) and end-diastolic (A+A1) left appendage flow at trans-oesophageal echocardiography as a sign of better contractility and a mark of lower risk of stroke during the follow-up [22]. On
the basis of these parameters we interrupted anticoagulation therapy at 3 months’ follow-up in all patients in sinus rhythm with good contractility and no severe stenosis detected by spiral CT.
We also observed in our series a significant reduction of acute major bleeding and the absence of haematoma, pericardial effusion, or the need for transfusion during follow-up. It is known that in clinical trials warfarin increased the risk of major bleeding, and outside the trial this risk was greater depending on how the warfarin therapy was monitored and on the risk of haemorrhage [23].
Pulmonary Vein Antrum Isolation Results
Another important finding of our study is that ICE-guided pulmonary vein antrum isolation is a safe and effective treatment for AF. Our success rate was high (82.5%) and our complication rate was low in terms of the data pre- viously reported by Marrouche et al. [11]. In our series we did not observe any severe pulmonary vein stenosis.
We had only one case of an embolic complication which occurred at the end of the ablation procedure in a 74-year-old woman with a history of tran- sient ischaemic attack after electrical cardioversion. We hypothesised that this complication was due to the use of a larger trans-septal sheath (8.5 Fr).
After this event we changed to 8-Fr trans-septal sheaths and saw no further embolic complications.
In 7 patients an iatrogenic post-AF-ablation atrial tachycardia/flutter was documented. This is similar to the data previously published by other groups.
Study Limitation
This is a retrospective analysis of consecutive patients. The lack of a matched control group may have affected the results. However, we consider our study to be a pilot and its aim was to evaluate two different therapeutic approach- es. Of course, further randomised studies are needed to establish the safety of interrupting oral anticoagulation therapy after radiofrequency catheter ablation of AF in all patients.
Conclusions
ICE-guided pulmonary vein antrum isolation seems to prevent cerebrovas- cular accidents in patients with symptomatic drug-refractory AF who are not receiving anticoagulation therapy. ICE-guided pulmonary vein antrum isola- tion is an effective and safe treatment for AF.
References
1. Wolf PA, Dawber TR, Thomas HE et al (1978) Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 28:973–977 2. Flegel KM, Shipley MJ, Rose G (1987) Risk of stroke in non rheumatic atrial fibril-
lation. Lancet 1:526–529
3. Man-Son-Hing M, Laupacis A, O’Connor AM et al (1999) A patient decision aid regarding antithrombotic therapy for stroke prevention in atrial fibrillation: a ran- domized controlled trial. JAMA 282:737–743
4. Petersen P, Boysen G, Godtfredsen J et al (1989) Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1:175–179 5. Anonymous (1994) Risk factors for stroke and efficacy of antithrombotic therapy
in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449–1457
6. Anonymous (1990) The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 323:1505–1511
7. Anonymous (1991) Stroke Prevention in Atrial Fibrillation Study. Final results.
Circulation 84:527–539
8. Anonymous (1994) Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 343:687–691
9. Haïssaguerre M, Jaïs P, Shah DC et al (1998) Spontaneous initiation of atrial fibril- lation by ectopic beats originating in the pulmonary veins. N Engl J Med 339:659–666
10. Chen SA, Hsieh MH, Tai CT et al (1999) Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 100:1879–1886
11. Marrouche NF, Martin DO, Wazni O et al (2003) Phased array intracardiac echocar- diography monitoring during pulmonary vein isolation in patients with atrial fibrillation: impact on outcome and complications. Circulation 107:2710–2716 12. Evans A, Perez I, Yu G et al (2000) Secondary stroke prevention in atrial fibrillation.
Stroke 32:2106–2111
13. Evans A, Perez I, Yu G et al (2001) Should stroke subtype influence anticoagulation decision to prevent recurrence in stroke patients with atrial fibrillation? Stroke 32:2828–2832
14. Lightowlers S, McGuire A (1998) Cost-effectiveness of anticoagulation in non rheu- matic atrial fibrillation in the primary prevention of ischemic stroke. Stroke 29:1827–1832
15. Connolly SJ, Laupacis A, Gent M et al (1991) Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 18:349–355
16. Ezekowitz MD, Bridgers SL, James KE et al (1992) Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 327:1406–1412
17. Hart RG, Benavente O, McBride R (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 131:492–501 18. Hart RG, Pearce LA, McBride R et al (1999) Factors associated with ischemic stroke
during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 30:1223–1229
19. Hart RG, Halperin JL, Pearce LA et al (2003) Stroke Prevention in Atrial Fibrillation Investigators. Lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann Intern Med 138:831–838
20. Sherman DG, Kim SG, Boop BS et al; National Heart, Lung, and Blood Institute AFFIRM Investigators (2005) Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study. Arch Intern Med 165:1185–1191
21. Go AS, Hylek EM, Philipps KA et al (2000) Implication of stroke risk criteria on the anticoagulation decision in non valvular atrial fibrillation. The anticoagulation and risk factors in atrial fibrillation (ATRIA study). Circulation 102:11–13
22. De Piccoli B, Rigo F, Ragazzo M et al (2001) Transthoracic and transesophageal echocardiographic indices predictive of sinus rhythm maintenance after cardio- version of atrial fibrillation. Echocardiography 18:545–552
23. Gage BF, van Walraven C, Pearce L et al (2004) Selecting patients with atrial fibrilla- tion for anticoagulation: stroke risk stratification in patients taking aspirin.
Circulation 110:2287–2292
