Skip Navigation

European Journal of Echocardiography 2004 5(4):239-242; doi:10.1016/j.euje.2004.04.008
© 2004 by European Society of Cardiology
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in Eur J Echocardiogr
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sallach, J.A
Right arrow Articles by Klein, A.L
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sallach, J.A
Right arrow Articles by Klein, A.L
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2004, The European Society of Cardiology

Subtherapeutic anticoagulation: the bane of conventional anticoagulation for cardioversion of atrial fibrillation

J.A Sallach and A.L Klein*

The Cleveland Clinic Foundation, Department of Cardiology, 9500 Euclid Avenue, Desk F15, Cleveland, OH 44195-5001, USA

Received 27 April 2004; .

kleina{at}ccf.org

* Corresponding author. Tel.: +1-216-444-3932; fax: +1-216-445-2309.

Please see page 257 for the article by Corrado et al. (doi: 10.1016/S1525-2167(03)00075-1) to which this editorial pertains.

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, affecting slightly less than 1% of the general population.1 Patients with AF suffer from a decrease in functional capacity secondary to a combination of palpitations, dyspnea, myocardial ischemia, congestive heart failure and hypotension.2,3 In addition, unorganized atrial electrical and mechanical activity result in blood stasis and the formation of atrial thrombi placing the patient at risk of systemic thromboembolism.4 It is therefore important, if feasible, to attempt cardioversion (CV) to normal sinus rhythm (NSR) in these patients.

The most concerning complication of CV in AF is systemic thromboembolism, and more specifically stroke. In 1960, Goldman reported a 1.5% embolization event rate in 400 AF patients undergoing chemical CV who had not received anticoagulation.5 This study proposed for the first time that anticoagulant therapy initiated prior to CV could stabilize pre-existing thrombus allowing it to organize and adhere to the atrial wall. The first report of thromboembolism associated with electrical CV occurred in 1963 when Lown et al. examined 50 AF patients.6 In this series, 94% of patients had rheumatic heart disease and systemic embolization was reported in 1.7%. Anticoagulation therapy was restricted only to patients with mitral stenosis. A few years later, Lown reported the results of a series of 350 patients undergoing electrical CV for AF.7 This study documented a 0.9% incidence of systemic embolization. Interestingly, only 29% of patients received anticoagulant agents and all embolic events occurred in those not receiving warfarin. The first prospective controlled study of anticoagulation in patients undergoing electrical CV was performed in 1969 by Bjerkelund and Orning.8 In 437 patients with atrial arrhythmia, systemic thromboembolism occurred in 5.3% of patients not receiving anticoagulation compared to 0.8% of patients receiving long-term anticoagulant therapy. This study demonstrated that although anticoagulation prior to CV significantly decreases the risk of embolization, it does not eliminate it.

The current recommendations for the management of anticoagulation around the time of CV were published by the American College of Chest Physicians initially in 19929 and then updated in 2001.10 These conventional-therapy guidelines recommend that patients with AF of >48 h duration be treated with therapeutic levels of warfarin (INR 2-3) for 3 weeks prior to CV and continued until NSR has been maintained for at least 4 weeks. However, with the advent of widespread use of transesophageal echocardiography (TEE) in the 1990s, it was hypothesized that AF patients free of left atrial thrombi may safely undergo a short-term course of anticoagulation followed by early CV, thereby reducing the risk of stroke and bleeding events. In 1995, Manning et al. reported a study of 94 patients with AF >48 h duration, scheduled to undergo clinically indicated CV who had not received long-term anticoagulation.11 TEE revealed 14 atrial thrombi in 12 patients (13%), all of whom did not undergo CV. Seventy-eight (95%) of 82 patients without thrombi were successfully cardioverted to NSR and none suffered an embolic event. Although this study suggested that TEE allowed exclusion of thrombi and early safe CV without long-term anticoagulation, it did not determine if early TEE-guided CV was safer than conventional therapy. The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) pilot study was the first prospective, randomized trial to examine patients with AF of >2 days duration undergoing clinically indicated CV.12 A total of 126 patients from 10 international clinical sites were randomized to conventional anticoagulation or a TEE-guided approach with short-term anticoagulation. CV was postponed in 7 (13%) patients due to atrial thrombi identified on TEE. The TEE-guided strategy resulted in early CV without embolization in all patients without atrial thrombi detected on TEE. In addition, CV was performed much earlier with this strategy than with the conventional method (0.6 weeks vs. 4.7 weeks). Based on the results of this pilot study, the ACUTE multicenter trial prospectively enrolled 1222 patients with AF of >48 h duration and assigned them to TEE-guided (n = 619) or conventional therapy (n = 603).13 Although there was no difference in the rate of embolization at 8 weeks follow-up, the TEE-guided group had a significantly lower rate of hemorrhagic events. In addition, this group had a significantly shorter time to CV compared to the conventional-therapy group (3.0±5.6 vs. 30.6±10.6 days, p<0.001). At 8 weeks follow-up, there were no differences in the rates of death, maintenance of NSR, or in functional status between the two groups. This randomized trial suggested that a TEE-guided approach with a short period of anticoagulation may be considered a clinically efficacious alternative to conventional therapy in AF patients scheduled for electrical CV.

The current study by Corrado et al. showed that prior to electrical CV of AF, subtherapeutic levels of anticoagulation using the conventional anticoagulant approach may expose patients to systemic thromboembolism.14 The study is important because it demonstrates the difficulties in maintaining therapeutic anticoagulation prior to CV using conventional-therapy guidelines.9 Left atrial appendage (LAA) thrombus was identified on TEE in 4 (9.8%) of 41 patients with at least 1 subtherapeutic INR, a disturbingly high prevalence. However, this value is very consistent with the findings of Shen et al. who retrospectively examined the prevalence of atrial thrombi in 182 AF patients who were anticoagulated for ≥3 weeks with at least 1 subtherapeutic INR.15 On pre-CV TEE, LAA thrombi were identified in 18 (9.9%) patients. In the current study by Corrado et al., patients with thrombi were found to have lower INR values, a higher prevalence of atrial spontaneous echo contrast (SEC) and lower LAA emptying velocities. It is important to note that the mere presence of atrial thrombus on TEE portends a poor prognosis as shown previously.16 Of the 4 patients with atrial thrombus in this study, follow-up at 1 year documented 2 TIAs, 2 major bleeds and 2 deaths compared to only 1 TIA in the 37 patients without atrial thrombus.

Based on this study, it is therefore essential to maintain therapeutic levels of anticoagulation in the 3 weeks preceding CV. When conventional guidelines are used, subtherapeutic INR values are extremely common and frequently result in prolongation of prophylactic anticoagulation prior to CV. Schlicht et al. demonstrated a widespread failure to follow the ACCP's Third Consensus Conference of Antithrombotic Therapy recommendations.9,17 In 51 retrospectively identified patients who underwent elective CV, 14 (27.5%) patients failed to receive a complete 3-week course of anticoagulation prior to their procedure. Similarly, in 1152 patients undergoing CV, Carlsson et al.18 have shown that the ACCP guidelines are not followed in 59% of patients ≥65 years of age. The ACUTE trial highlighted some of the difficulties in following the conventional approach.13 Only 33 (55.2%) of 603 patients in the conventional-treatment group ever underwent electrical CV.13 Of the remaining 270 patients who did not undergo CV, 127 (47%) had a spontaneous or chemical CV. The other 143 (53%) patients never underwent CV of any kind often due to subtherapeutic anticoagulation. Subtherapeutic levels of anticoagulation unnecessarily expose patients to an increased risk of systemic thromboembolization. There is also no consensus on how patients with subtherapeutic INR values during the 3 weeks prior to CV should be managed. Although many physicians will "reset the 3-week clock" of anticoagulation, this may lead to an increased risk of bleeding and an escalated cost of therapy. Recently in an economic evaluation of the ACUTE Trial, Klein et al. showed that conventional therapy resulted in 24% higher cumulative costs than TEE-guided therapy, primarily due to bleeding complications.19 Although no guidelines on patient selection for TEE in AF of >48 h duration currently exist, it has been suggested that patients with a subtherapeutic INR should undergo TEE and immediate CV if atrial thrombi are not present (Table 1).20


View this table:
[in this window]
[in a new window]

  		Table 1 TEE or not TEE? Patient selection criteria in atrial fibrillation of longer than 48 h duration

 
When considering the results of this study, it is important to bear in mind several significant limitations. Most importantly, this was a single center retrospective study consisting of a very small group of patients. It is, therefore, much more difficult to accurately characterize the cohort in question. In addition, the nature of this study prevents assessment of INR values at regularly scheduled intervals. Subsequently, a single subtherapeutic INR value over the entire 3-week period may not accurately represent the overall efficacy of anticoagulation therapy. Statistical analysis was based on a single subtherapeutic measurement. Perhaps a mean or median INR value would be more clinically useful. The study also failed to speculate as to why these patients had subtherapeutic INR values, which would be essential in attempting to prevent recurrence of this problem. It is also necessary to remember that a core echocardiography laboratory was not used in the interpretation of TEE thrombus images. Furthermore, the grading of the degree of thrombosis consisted only of SEC or thrombi. We now know that a distinct intermediary stage of thrombosis termed "sludge" is frequently observed in the LAA of AF patients.21 Although part of a spectrum of clot formation, it is a distinct clinical entity.

In summary, this study stresses the importance of therapeutic INR values in patients undergoing CV for AF. Clinicians must remain cognizant of the fact that subtherapeutic INR values prior to CV are associated with a relatively high prevalence of atrial thrombi. It is, therefore, essential to strictly follow the current ACCP anticoagulation guidelines for CV of AF greater than 48 h duration. Alternatively, patients who unsuccessfully complete 3 weeks of conventional anticoagulation therapy may be considered for early TEE-guided therapy.


   References
Top
 References
 

  1. Go A.S, Hylek E.M, Phillips K.A, Chang Y, Henault L.E, Selby J.V, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA (2001) 285:2370–2375.[Abstract/Free Full Text]
  2. Gosselink A.T, Crijns H.J, van den Berg M.P, van den Broek S.A, Hillege H, Landsman M.L, et al. Functional capacity before and after cardioversion of atrial fibrillation: a controlled study. Br Heart J (1994) 72:161–166.[Abstract/Free Full Text]
  3. Gosselink A.T, Bijlsma E.B, Landsman M.L, Crijns H.J, Lie K.I. Long-term effect of cardioversion on peak oxygen consumption in chronic atrial fibrillation: a 2-year follow-up. Eur Heart J (1994) 15:1368–1372.[Abstract/Free Full Text]
  4. Abbott W.M, Maloney R.D, McCabe C.C, Lee C.E, Wirthlin L.S. Arterial embolism: a 44 year perspective. Am J Surg (1982) 143:460–464.[CrossRef][Web of Science][Medline]
  5. Goldman M.J. The management of chronic atrial fibrillation: indications for and method of conversion to sinus rhythm. Prog Cardiovasc Dis (1960) 2:465–479.[CrossRef][Web of Science]
  6. Lown B, Perlroth M.G, Kaidbey S, Abe T, Harken D.E. "Cardioversion" of atrial fibrillation. A report on the treatment of 65 episodes in 50 patients. N Engl J Med (1963) 269:325–331.[Web of Science][Medline]
  7. Lown B. Electrical reversion of cardiac arrhythmias. Br Heart J (1967) 29:469–489.[Free Full Text]
  8. Bjerkelund C.J, Orning O.M. The efficacy of anticoagulant therapy in prevent embolism related to DC electrical conversion of atrial fibrillation. Am J Cardiol (1969) 23:208–216.[CrossRef][Web of Science][Medline]
  9. Laupacis A, Albers G, Dunn M, Feinberg W. Antithrombotic therapy in atrial fibrillation. Third ACCP Conference on Antithrombotic Therapy. Chest (1992) 102(Suppl):426S–433S.[CrossRef][Medline]
  10. Albers G.W, Dalen J.E, Laupacis A, Manning W.J, Petersen P, Singer D.E. Antithrombotic therapy in atrial fibrillation. Chest (2001) 119(Suppl. 1):194S–206S.[CrossRef][Web of Science][Medline]
  11. Manning W.J, Silverman D.I, Keighley C.S, Oettgen P, Douglas P.S. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol (1995) 25:1354–1361.[Abstract]
  12. Klein A.L, Grimm R.A, Black I.W, Leung D.Y, Chung M.K, Vaughn S.E, et al. Cardioversion guided by transesophageal echocardiography: the ACUTE Pilot Study: a randomized controlled trial: assessment of cardioversion using transesophageal echocardiography. Ann Intern Med (1997) 126:200–209.[Abstract/Free Full Text]
  13. Klein A.L, Grimm R.A, Murray R.D, Apperson-Hansen C, Asinger R.W, Black I.W, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med (2001) 344:1411–1420.[Abstract/Free Full Text]
  14. Corrado C, Beretta S, Sormani L, Tadeo G, Foglia-Manzillo G, Tagliagambe L.M, et al. Prevalence of atrial thrombi in patients with atrial fibrillation/flutter and subtherapeutic anticoagulation prior to cardioversion. Eur J Echocardiogr (2004) 5:257–261.[Abstract/Free Full Text]
  15. Shen X, Li H, Rovang K, Hee T, Holmberg M.J, Mooss A.N, et al. Prevalence of intra-atrial thrombi in atrial fibrillation patients with subtherapeutic international normalized ratios while taking conventional anticoagulation. Am J Cardiol (2002) 90:660–662.[CrossRef][Web of Science][Medline]
  16. Leung D.Y, Davidson P.M, Cranney G.B, Walsh W.F. Thromboembolic risks of left atrial thrombus detected by transesophageal echocardiogram. Am J Cardiol (1997) 79:626–629.[CrossRef][Web of Science][Medline]
  17. Schlicht J.R, Davis R.C, Naqi K, Cooper W, Rao B.V. Physician practices regarding anticoagulation and cardioversion of atrial fibrillation. Arch Intern Med (1996) 156:290–294.[Abstract/Free Full Text]
  18. Carlsson J, Tebbe U, Rox J, Harmjanz D, Haerten K, Neuhaus K.L, et al. Cardioversion of atrial fibrillation in the elderly. ALKK-Study Group. Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausaerzte. Am J Cardiol (1996) 78:1380–1384.[CrossRef][Web of Science][Medline]
  19. Klein A.L, Murray R.D, Becker E.R, Culler S.D, Weintraub W.S, Jasper S.E, et al. Economic analysis of a transesophageal echocardiography-guided approach to cardioversion of patients with atrial fibrillation: the ACUTE economic data at eight weeks. J Am Coll Cardiol (2004) 43:1217–1224.[Abstract/Free Full Text]
  20. Asher C.R, Klein A.L. The ACUTE trial. Transesophageal echocardiography to guide electrical cardioversion in atrial fibrillation. Assessment of cardioversion using transesophageal echocardiography. Cleve Clin J Med (2002) 69:713–718.[Abstract/Free Full Text]
  21. Parakh K, Murray R.D, Swadi O, Jasper S.E, Thambidorai S.K, Klein A.L. Left atrial and atrial appendage viscid spontaneous echo contrast by transesophageal echocardiography: clinical and prognostic significance. Circulation (2002) 106(19):II-706. [Abstract].

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?

Related articles in Eur J Echocardiogr:

Prevalence of atrial thrombi in patients with atrial fibrillation/flutter and subtherapeutic anticoagulation prior to cardioversion
G Corrado, S Beretta, L Sormani, G Tadeo, G Foglia-Manzillo, L.M Tagliagambe, and M Santarone
Eur J Echocardiogr 2004 5: 257-261. [Abstract] [FREE Full Text]  




This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in Eur J Echocardiogr
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sallach, J.A
Right arrow Articles by Klein, A.L
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sallach, J.A
Right arrow Articles by Klein, A.L
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?