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LMWH Safe and Effective for A.Fib. Reversion?
Anna M. Wodlinger, Pharm.D., BCPS
Review: Stellbrink C, Nixdorff U, Hofmann T, Lehmacher W, Daniel WG, Hanrath P, et al. on behalf of the ACE Study Group. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109: 997-1003.
Anticoagulation for TEE-guided Cardioversion
Electrical cardioversion to normal sinus rhythm is one of the treatment options for patients with atrial fibrillation (AF). To prevent systemic thromboembolism from occurring in the peri-cardioversion period, guidelines have traditionally recommended anticoagulant therapy for 3-4 weeks prior to and for 3-4 weeks following cardioversion.1,2 A recent study suggests that a transesophageal echocardiography (TEE) performed prior to cardioversion can identify thrombus formation in the left atrium and, in patients in whom no thrombus exists, allow for immediate cardioversion. While this decreases the overall anticoagulation period from 8 weeks to 4 weeks, it requires that patients be hospitalized for administration of unfractionated heparin (UFH) until their warfarin is therapeutic. This increases the overall cost of the procedure and has lead clinicians to wonder whether the use of LMWH’s as outpatient bridge therapy would be safe and effective.
The ACE study was a prospective, randomized, open-label trial in which patients with AF undergoing cardioversion were randomized to receive either UFH plus phenprocoumon or enoxaparin therapy.4 One study group received UFH (bolus 80 IU/kg then infusion adjusted to aPTT) for at least 72 hours and then phenprocoumon therapy (adjusted to INR 2-3) for the remainder of the study period, and the other study group received enoxaparin 1mg/kg subcutaneously twice daily for 3-8 days followed by a fixed dose of 40mg twice daily (if body weight < 65 kg) or 60mg twice daily (if body weight > 65kg) for the rest of the study period. In patients undergoing TEE-guided cardioversion in which no thrombus was detected, cardioversion was performed within the first 3 days once full anticoagulation was achieved and anticoagulation was then continued for 28 days. In patients who did not undergo TEE-guided cardioversion or if a thrombus was detected on TEE, anticoagulation was administered for 21 days prior to cardioversion and then continued for 28 days following cardioversion. The primary objective of the study was to demonstrate noninferiority of enoxaparin compared with UFH + phenprocoumon in the composite endpoint of cerebral-ischemic neurological events, systemic thromboembolism, death from any cause and major bleeding complications.
In the per-protocol analysis, the primary endpoint occurred in 3.2% of the enoxaparin group (n=216) compared to 5.7% of the UFH + phenprocoumon (n=212) group (probability value for noninferiority = 0.016; 95% CI for difference in incidence rates -6.9 to 1.8%). Overall, there were very few embolic events (0.8% vs 1.6%), hemorrhagic events (9.3% vs 10.9%), and death (3 vs 5 patients) in the enoxaparin and UFH + phenprocoumon groups, respectively. The authors concluded that enoxaparin may be the preferred drug for TEE-guided cardioversion because it was noninferior to UFH + phenprocoumon with regard to embolic events, death and bleeding and requires less monitoring and hospitalization costs.
Although, this is the first prospective, randomized study to compare a LMWH with traditional anticoagulation procedures for electrical cardioversion of AF there are several limitations that must be considered when applying the results to clinical practice:
The study is a noninferiority trial and therefore has only proven that enoxaparin is not inferior to UFH + phenprocoumon. It has not proven that the therapies are equal or that one is superior to another. Additionally, it was slightly underpowered (needed 500 patients for a 70% power and only 496 were randomized to therapy) and so results should be interpreted cautiously.
The fixed dose of enoxaparin utilized in this study has never been proven effective for conditions that require full anticoagulation.
The study administered phenprocoumon which is an anticoagulant commonly prescribed in Germany. Warfarin is the anticoagulant most often prescribed worldwide.
Enoxaparin was not used as "bridge" therapy to warfarin and therefore application of the study is difficult since many clinicians would not advocate using enoxaparin for 28 days. It also decreases the potential cost-benefit since enoxaparin is more expensive than warfarin therapy.
In summary, as the first prospective study to evaluate the use of LMWH in TEE-guided cardioversion this is a landmark study. There are significant limitations of the study that affect its interpretation and application and therefore, more studies are needed to confirm the efficacy and safety of LMWH use in TEE-guided cardioversion.
1. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary -- a report of the American College of Cardiology, American heart Association task force on practice guidelines, and the European Society of Cardiology committee for practice guidelines and policy conferences (committee to develop guidelines for the management of patients with atrial fibrillation). J Am Coll Cardiol 2001; 38: 1231-1265.
2. Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 2001; 119: 194S-206S.
3. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. NEJM 2001; 344:1411-1420.
4. Stellbrink C, Nixdorff U, Hofmann T, et al. on behalf of the ACE Study Group. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) Trial. Circulation 2004; 109: 997-1003.
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