Alternatives to warfarin in atrial fibrillation. Heart 2008

Bayard YL, Ostermayer SH, Sievert H. Alternatives to warfarin in atrial fibrillation: drugs and devices. Heart 2008 Sep;94(9):1113-1116. (Editorial)
PMID: 18703688

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Heart 2008;94:1113-1116; doi:10.1136/hrt.2007.118844
Copyright © 2008 BMJ Publishing Group Ltd & British Cardiovascular Society

EDITORIALS
Alternatives to warfarin in atrial fibrillation: drugs and devices
Yves L Bayard1, Stefan H Ostermayer1, Horst Sievert1,2

1 CardioVascular Center Frankfurt, Sankt Katharinen, Frankfurt, Germany
2 Washington Hospital Center, Washington, DC, USA

Correspondence to:
Professor H Sievert, CardioVascular Center Frankfurt, Seckbacher Landstrasse 65, 60389 Frankfurt, Germany; Washington Hospital Center, 110 Irving Street NW, Suite 4B-1, Washington DC, 20010, USA;

Atrial fibrillation is a common cardiac arrhythmia with a higher prevalence in the elderly. It is more common in men than in women at all ages.1 It may cause a reduced cardiac output and formation of atrial thrombi, especially in the left atrial appendage.2 Atrial fibrillation is associated with a fivefold increased risk for stroke and embolism3 and accounts for as much as one-sixth of all ischaemic strokes.4 These strokes tend to be more severe than cerebral embolisms caused by other sources, probably owing to the larger size of thrombi in atrial fibrillation.5 6
In this editorial, we discuss different medical, surgical and catheter-based approaches to the prevention of stroke in patients with non-rheumatic atrial fibrillation.

   MEDICAL TREATMENT OF ATRIAL FIBRILLATION
 
Warfarin
Several randomised studies such as the AFFIRM and the RACE trial have demonstrated the benefit of anticoagulation treatment in patients with both rhythm- and rate-controlled atrial fibrillation.
With a stroke risk reduction of almost 70%, warfarin is highly effective in preventing embolic events in patients with atrial fibrillation and is better than other pharmacological approaches.7 Compared with aspirin, oral anticoagulation reduces the risk of stroke by 45%. However, it may increase the risk of major bleeding by about 70% compared with aspirin, accounting for severe bleeding in up to 2.3% of patients a year.8 Other disadvantages of warfarin are its narrow therapeutic range, pharmacological and food interactions and the need for frequent monitoring and dose adjustments. These may be some of the reasons why only 54% of all high-risk patients who are eligible for oral anticoagulation therapy actually receive warfarin.9 A recent review of the FDA Surveillance and Epidemiology Office showed that warfarin was among the top 10 drugs with the largest number of serious adverse event reports between 1990 to 2000.10 Furthermore, US death certificates indicate that anticoagulants ranked first in 2003 and 2004 in the number of total mentions of deaths for drugs causing adverse effects in therapeutic use. This led to the addition of a black-box warning about the risk of bleeding in the product labelling for warfarin in October 2006.
Combined antiplatelet therapy
Favourable results have been obtained by combining two antiplatelet agents acting through different mechanisms after percutaneous coronary interventions. The Active-W trial was designed to determine whether the combination of aspirin plus clopidogrel was non-inferior to warfarin in preventing vascular events in high-risk patients with atrial fibrillation.11 While there was no difference in the occurrence of haemorrhage, the risk for stroke or peripheral embolism was significantly higher in the combined antiplatelet patient group.
Direct thrombin inhibitors (DTIs)
DTIs represent a new class of anticoagulant agents, binding to thrombin and inhibiting its interactions with its substrates. Ximelagratan was the first DTI to be evaluated in large clinical phase III trials (SPORTIF III and V) with the primary end points of stroke and peripheral embolism. In contrast with warfarin, ximelagratan showed a rapid onset of action and its metabolism is independent of the hepatic cytochrome P450 enzyme system. Thus, it has a low potential for drug interactions and no known food interactions, making coagulation monitoring and dose adjustments unnecessary. In the SPORTIF III trial, primary events occurred in 2.3% of patients receiving warfarin and in 1.6% of those receiving ximelagratan (SPORTIF V 1.2% and 1.6%, respectively). Both studies demonstrated non-inferiority to warfarin for stroke risk reduction. Whereas the risk of major bleeding was equal with both agents, ximelagratan caused less minor bleeding than warfarin. However, ximelagratan did not get FDA approval for stroke prevention in patients with atrial fibrillation because serum alanine aminotransferase levels rose to three times the upper limit of normal in about 6% of patients (0.8% in the warfarin group).
So far, four DTIs are available in clinical practice: hirudin, argatroban, bivalirudin and desirudin. However, none of these have been approved by the FDA as a preventative drug for patients with atrial fibrillation.

   SURGICAL APPROACH TO ATRIAL FIBRILLATION
 
The first surgical attempt to remove the left atrial appendage as a possible source for a thromboembolic event was made by Madden in 1948.12 Nowadays, surgical obliteration or resection of the left atrial appendage is usually not performed as a stand-alone procedure because of its invasive character. Besides, it might not prevent thromboembolism from the structure dependably, as it is often incomplete.13 However, surgical ligation of the left atrial appendage is part of the Maze procedure and recommended by the American College of Cardiology and the American Heart Association guidelines during mitral valve surgery.14 15
In the "Maze" operation introduced by Cox, several small incisions are made in the atria to interrupt atrial fibrillation re-entry pathways.16 In a report of 197 patients who underwent the Maze procedure, the mean rate of freedom from atrial fibrillation was 89% after 10 years of follow-up.17 Despite these good results, the Maze procedure is not commonly used, as it is complicated and time consuming. Operations that were modified from the original Maze procedure were shown to be less effective than the original procedure.18 Complications of the Maze operation include atrial dysfunction due to extensive injury to the atrial walls, and different types of atrial arrhythmias as a possible consequence of partial denervation of the sympathetic and parasympathetic systems of the heart.19

   CATHETER ABLATION OF ATRIAL FIBRILLATION
 
Foci triggering atrial fibrillation in the right and the left atrium and in the pulmonary veins can be identified. Nowadays, catheter ablation of these foci can be achieved in most patients. However, the recurrence rate of atrial fibrillation was found to be as high as 35% within 2 weeks after the procedure and up to 42% in the first month.20 In a larger series of 589 patients, late recurrence of atrial fibrillation was reported to be 16%, 21% and 22% at 1, 2 and 3 years, respectively.21 Thus, many patients continue to require oral anticoagulation after ablative treatment of atrial fibrillation.

   LEFT ATRIAL APPENDAGE TRANSCATHETER OCCLUSION
 
A meta-analysis of several surgical, echocardiographic and autopsy studies showed that 90% of all cardiogenic thrombi in non-rheumatic atrial fibrillation originate from the left atrial appendage.22 The risk for embolic stroke is especially high when left atrial appendage flow velocity is below 20 cm/s (13.1% a year) and in subjects with dense spontaneous echocardiographic contrast (18.2% a year).23 Percutaneous closure of the left atrial appendage offers a minimally invasive way to exclude the structure from circulation and thereby prevent cardioembolic events.
A profound anatomical and histological examination of the left atrial appendage and its relationship to surrounding structures is described by Su and colleagues in this issue of the journal (see article on page 1166).24 The study showed a wide anatomical variability of the oval-shaped left atrial appendage orifice as well as proximity of the paper-thin structure to the left upper pulmonary vein, the mitral valve, the left anterior descending artery and the circumflex artery. It is important to consider these findings when attempting transcatheter closure of the left atrial appendage.
This intervention was performed for the first time in 2001 using the percutaneous left atrial appendage transcatheter occlusion (PLAATO) system (ev3, Plymouth, Minnesota, USA).25 The results of the PLAATO study showed that this new procedure is feasible and that it can be performed at acceptable risk.26 Another device that has been especially developed to fit the left atrial appendage anatomy is the WATCHMAN filter system (Atritech, Plymouth, Minnesota, USA). Amplatzer septal devices (AGA Medical Corporation, Golden Valley, Minnesota, USA) have also been used for left atrial appendage occlusion.

Implantation technique
The implantation technique is similar in all devices. Before the procedure, patients receive a loading dose of 300 mg clopidogrel. After trans-septal puncture, they are given 5000 to 10 000 units of heparin to keep the activated clotting time greater than 250 s. The procedure is performed under transoesophageal echocardiographic (TOE) guidance. After trans-septal access, angiography is performed to assess the size of the appendage and its orifice diameter. A device is chosen with a diameter 20–50% larger than the diameter of the left atrial appendage ostium to guarantee adequate anchoring of the device. The delivery catheter and the trans-septal sheath are withdrawn, revealing the implant, which is allowed to expand and thereby fills in the appendage. Angiography is performed to assess for leaks and positioning. If sealing is not adequate, the device may be collapsed, repositioned and re-expanded, or completely removed while trans-septal access is maintained and replaced with a device of a different size. In the next step, a stability test is performed: The delivery catheter is moved back and forth slightly under angiography and TOE control. Until final release, the devices are completely retrievable. The final seal is evaluated by contrast fluoroscopy in the left atrium once the device is completely released.

PLAATO
The implant consists of a self-expandable nitinol cage covered with polytetrafluoroethylene. Different sizes (15–32 mm) are available to ensure optimal sealing. The membrane occludes the orifice of the appendage and allows tissue incorporation into the device. Three rows of anchors along the struts help to stabilise the device in the left atrial appendage.
Two studies with similar protocols were conducted using the PLAATO device: the PLAATO Feasibility study26 and the European PLAATO Registry study. The device has successfully been implanted in more than 270 patients (aged 71 (9) years) who were not eligible for oral anticoagulation treatment. In 2% of the patients in whom the procedure was attempted, the left atrial appendage was too large or the anatomy was too challenging to find a suitable position for the implant.
The most common complication was cardiac tamponade which occurred in 3% and pericardial effusion in 2%. In most of these patients, pericardiocentesis was performed in the catheter laboratory and there were no sequelae. One patient, however, also underwent median sternotomy and died 1 month later owing to probable cerebral haemorrhage after anticoagulation was restarted.
Device embolisation occurred in one patient immediately after implant release. It was snared and removed from the aortic bifurcation, and another occluder was successfully implanted during the same procedure.
The expected annual stroke risk in the PLAATO patients was calculated using the CHADS2 Score.27 The PLAATO patients were at high risk for stroke, with a mean CHADS2 Score of 2.9. The mean expected annual stroke rate of PLAATO patients was 6.5% assuming they were taking aspirin only.28 In a follow-up period of almost 300 patient-years, nine patients experienced a stroke, resulting in an annual stroke rate of 3%. This corresponds to a risk reduction of more than 50%.
Nine patients died during follow-up for various reasons that were not related to the device or the procedure.
Three patients developed a thrombus on the device It was diagnosed within the first 6 months after implantation and was firmly attached to the device in all of them. Under continuous administration of aspirin and clopidogrel or low molecular weight heparin, respectively, these thrombus formations resolved within 3–6 months without sequelae. No mobile clots, mitral valve damage or pulmonary vein obstruction were seen on TOE during follow-up.
About 200 patients received a PLAATO device after the device was CE approved in 2005. Although it showed good results, the PLAATO system was stopped in December 2006 because a randomised study of PLAATO occluder versus warfarin could not be conducted for financial reasons.

Watchman
At present, the Watchman occluder is the only device specifically designed for left atrial appendage occlusion. It became available within clinical trials shortly after the PLAATO occluder and has been implanted since 2002 in Europe and since 2003 in the USA.
The Watchman device is made of a nitinol frame structure and a 160 µm polyethylene membrane that covers the atrial facing surface of the device. It is equipped with a row of fixation barbs around its perimeter. The implant is constrained within a delivery catheter and is available in 21, 24, 27 and 30 mm sizes. In contrast with the PLAATO studies, patients had to be eligible for warfarin treatment. Within the Watchman feasibility study,29 75 patients were enrolled, of whom 66 (88%) were successfully implanted. In 9% of the patients, the left atrial appendage anatomy did not allow device placement. Compared with the PLAATO studies, Watchman patients were younger (mean age 68.5 vs 71 years), had a lower CHADS2 score (1.8 vs 2.9) and received warfarin after implantation for at least 45 days.
The initial device embolised in two patients. After modification of the device barbs, no more embolisations occurred with the second-generation device. Five pericardial effusions (6.7%) and one major air embolism were noted. There were no sequelae. In a follow-up time of 101 patient-years, a thrombus on the occluder was noted in four patients. One of these patients sustained a transient ischaemic attack. In another patient with a transient ischaemic attack, no thrombus was noted on the device. However, there were no strokes or peripheral embolisms during follow-up.
Since February 2005, the Watchman occluder has been evaluated in the PROTECT AF (Protection in Patients With Atrial Fibrillation) trial, a prospective, randomised study assessing whether the safety and efficacy of left atrial appendage closure is non-inferior to that of warfarin. Transcatheter occlusion of the left atrial appendage followed by 45 days of warfarin intake is randomised against long-term warfarin intake in a 2:1 ratio. In contrast with the PLAATO studies, all patients have to be eligible for long-term oral anticoagulation treatment. So far, more than 500 patients have been enrolled in the study.
In our experience, the Watchman occluder is easier to implant and seems to adapt better to left atrial appendage anatomy than the rather rigid PLAATO device.

Amplatzer
The Amplatzer atrial septal defect (ASD) and patent foramen ovale (PFO) occluders are the most commonly used devices for ASD and PFO closure, as they are easy to handle, show good closure results and are fully retrievable at any time of the procedure. The devices consist of a double disc system and are available in diameters up to 40 mm. They are manufactured from a wire frame mesh with Dacron patches inside. The two discs are linked together by a short connecting waist. In the case of the ASD occluder, the diameter of the waist corresponds to the size of the ASD in order to allow "stenting" of the defect and to provide additional stability.
The ease of handling of these devices, on the one hand, and the fact that the anatomy of the left atrial appendage might allow stenting of the structure’s neck with an Amplatzer device, on the other, encouraged Meier and colleagues to use these devices for left atrial appendage occlusion.30 Unlike the Watchman and PLAATO methods, most of the procedures were performed without echocardiographic guidance. Left atrial appendage occlusion using the Amplatzer was successfully performed in 23/27 patients (85.2%) aged 58–95 years. In four patients, the device embolised immediately after release. Two patients had to undergo surgery for this complication, whereas catheter retrieval was possible in the other two patients. Another device embolisation occurred during follow-up. The device could be successfully removed from the descending aorta by catheter technique. Complete appendage occlusion was achieved in all but one patient. In a follow-up of 30 patient-years, no strokes occurred.

   CONCLUSION
 
Anticoagulation treatment with warfarin is still the first-line treatment in patients with non-rheumatic atrial fibrillation. Rate or rhythm control may alleviate the symptoms of atrial fibrillation, but this treatment does not eliminate the risk of stroke. Aspirin alone and combined antiplatelet therapy are significantly less effective in preventing embolic events than oral anticoagulation. Several DTIs are currently under investigation, and maybe, these agents will replace warfarin as the "gold standard" in blood-thinning treatment for patients with non-rheumatic atrial fibrillation in the future. However, the concern of possible liver toxicity after long-term intake of these drugs has to be resolved.
Surgical ligation of the atrial appendage is often incomplete. After catheter ablation the risk of thrombus formation and embolism persists. Neither method is an alternative to warfarin.
Left atrial appendage occlusion by the catheter technique seems to be a safe alternative for those patients who cannot tolerate blood-thinning treatment or are not willing to take such drugs for the rest of their lives. Whether this method can match oral anticoagulation for stroke risk reduction and adverse event rate might be shown by the current PROTECT AF study, in which the Watchman occluder implantation is randomised against warfarin.

   FOOTNOTES
 
Competing interests: None.

   REFERENCES
 
1. Go AS, Hylek EM, Phillips KA. 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;285:2370–5.[Abstract/Free Full Text]
2. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9.[Abstract/Free Full Text]
3. Lip GYH, Edwards SJ, Stroke prevention with aspirin, warfarin, and Ximelagratan in patients with non-valvular atrial fibrillation: a systematic review and metaanalysis. Thrombosis Res 2006;118:321–33.[CrossRef][Medline]
4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8.[Abstract/Free Full Text]
5. Anderson DC, Kappelle LJ, Eliasziw M, et al.Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 2002;33:1963–7.[Abstract/Free Full Text]
6. Harrison MJ, Marshall J. Atrial fibrillation, TIAs and completed strokes. Stroke 1984;15:441–2.[Abstract/Free Full Text]
7. Hart RG, Halperin JL, Pearce LA, et al.Lessons from the stroke prevention in atrial fibrillation trials. Ann Intern Med 2003;138:831–8.[Abstract/Free Full Text]
8. Levine MN, Raskob G, Landefeld S, et al.Hemorrhagic complications of anticoagulant treatment. Chest 2001;119:108S–21S.[CrossRef][Medline]
9. Waldo AL, Becker RC, Tapson VF, et al.Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol 2005;46:1729–36.[Abstract/Free Full Text]
10. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007;167:1414–9.[Abstract/Free Full Text]
11. The ACTIVE Writing group. On behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial. Lancet 2006;367:1903–12.[CrossRef][Medline]
12. Madden J. Resection of the left auricular appendix. JAMA 1948;140:769–72.
13. Katz ES, Tsiamtsiouris T, Applebaum RM, et al.Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiographic study. J Am Coll Cardiol 2000;36:468–71.[Abstract/Free Full Text]
14. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. J Thorac Cardiovasc Surg 1991;101:584–92.[Abstract]
15. Bonow RO, Carabello B, de Leon AC, et al.ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on management of patients with valvular heart disease). J Am Coll Cardiol 1998;32:1486–582.[Free Full Text]
16. Cox JL, Canavan TE, Schuessler RB, et al.The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101:406–26.[Abstract]
17. Gaynor SL, Schuessler RB, Bailey MS, et al.Surgical treatment of atrial fibrillation: predictors of late recurrence. J Thorac Cardiovasc Surg 2005;129:104–11.[Abstract/Free Full Text]
18. Barnett SD, Ad N. Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg 2006;131:1029–35.[Abstract/Free Full Text]
19. Pasic M, Musci M, Siniawski H, et al.The Cox maze iii procedure: parallel normalization of sinus node dysfunction, improvement of atrial function, and recovery of the cardiac autonomic nervous system. J Thorac Cardiovasc Surg 1999;118:287–95.[Abstract/Free Full Text]
20. Oral H, Knight BP, Ozaydin M, et al.Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol 2002;40:100–4.[Abstract/Free Full Text]
21. Pappone C, Rosanio S, Augello G, et al.Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003;42:185–97.[Abstract/Free Full Text]
22. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9.[Abstract/Free Full Text]
23. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high-risk subjects with nonvalvular atrial fibrillation. Ann Intern Med 1998;128:639–47.[Abstract/Free Full Text]
24. Su P, McCarthy KP, Ho SY. Occluding the left atrial appendage: anatomical considerations. Heart 2008;94:1166–70.[Abstract/Free Full Text]
25. Sievert H, Lesh MD, Trepels T, et al.Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation: early clinical experience. Circulation 2002;105:1887–9.[CrossRef][Medline]
26. Ostermayer SH, Reisman M, Kramer PH, et al.Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005;46:9–14.[Abstract/Free Full Text]
27. Gage BF, Waterman AD, Shannon W, et al.Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70.[Abstract/Free Full Text]
28. Gage BF, van Walraven C, Pearce L, et al.Selecting patients with atrial fibrillation for anticoagulation – stroke risk stratification in patients taking aspirin. Circulation 2004;110:2287–92.[CrossRef][Medline]
29. Sick PB, Schuler G, Hauptmann KE, et al.Initial worldwide experience with the WATCHMAN left atrial appendage system. for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2007;49:1490–5.[Abstract/Free Full Text]
30. Meier B, Palacios I, Windecker S, et al.Transcatheter left atrial appendage occlusion with Amplatzer devices to obviate anticoagulation in patients with atrial fibrillation. Catheter Cardiovasc Interv 2003;60:417–22.[CrossRef][Medline]

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