Summary
Background
Current guidelines recommend unfractionated heparin (UFH) or low-molecular-weight heparin plus an oral anticoagulant for the prevention of thromboembolism in patients undergoing electric cardioversion of atrial fibrillation (AF). Selective factor Xa inhibitors, such as fondaparinux, which has a favourable benefit-risk profile in the prevention and treatment of venous thromboembolism and the management of acute coronary syndromes, have not been systematically evaluated in this setting.
Aim
To evaluate the efficacy and safety of fondaparinux versus standard treatment in patients undergoing echocardiographically-guided cardioversion of AF.
Methods
In this multicentre, randomized, open-label, controlled, two-parallel-group, phase II pilot study, patients with AF undergoing electric cardioversion following transoesophageal echocardiography (TEE) were randomized to fondaparinux or standard therapy (UFH plus vitamin K antagonist [VKA]). Patients showing an atrial thrombus in the first TEE (clot-positive) were randomized to treatment with fondaparinux or standard care for 4 weeks before cardioversion.
Results
The primary endpoint (combined rate of cerebral neurological events, systemic thromboembolism, all-cause death and major bleeding events) occurred in 3 of 174 (1.7%) patients on fondaparinux and 2 of 170 (1.2%) patients on UFH + VKA. The rate of thrombus disappearance among clot-positive patients was higher in the fondaparinux arm (11 of 14; 78.6%) than in the UFH + VKA arm (7 of 14; 50.0%). Incidences of adverse events were similar (45.4% with fondaparinux and 46.5% with UFH + VKA).
Conclusion
In this pilot study in patients with TEE-guided cardioversion, the use of fondaparinux appeared to be well tolerated, with similar efficacy to UFH + VKA. Furthermore, a trend to greater thrombus resolution was observed.
Résumé
Justification
Les recommandations actuelles suggèrent la prescription d’une héparine non fractionnée ou une héparine de bas poids moléculaire et un traitement anticoagulant oral au décours afin de prévenir le risque thromboembolique artériel des patients en fibrillation atriale avec une indication à une cardioversion électrique. Les inhibiteurs sélectifs du facteur Xa, tels le fondaparinux, ont un profil bénéfice-risque favorable dans la prévention et le traitement de la thrombose veineuse périphérique et dans la prise en charge des syndromes coronaires aigus, mais n’ont pas été évalués dans la fibrillation atriale.
Objectifs
Évaluer l’efficacité et la sécurité du fondaparinux versus un traitement standard chez les patients ayant une indication à une cardioversion électrique d’une fibrillation atriale guidée par échocardiographie transœsophagienne.
Méthode
Cette étude randomisée, multicentrique, ouverte, contrôlée avec deux groupes parallèles est une étude pilote de phase II, incluant des patients en fibrillation atriale, ayant une indication à une cardioversion électrique au décours d’une échographie transœsophagienne. Ces patients ont été randomisés entre un groupe fondaparinux et un groupe traitement standard (héparine non fractionnée + AVK). Les patients ayant un thrombus dans l’oreillette ou l’auricule gauche lors de la première échocardiographie transœsophagienne (groupe clot positive) ont été randomisés pour un traitement par fondaparinux ou un traitement standard 4 semaines au décours de la cardioversion.
Résultats
Le critère de jugement principal (critère combiné événements neurologiques cérébrovasculaires, embolie artérielle systémique, décès de toute cause et saignement majeur) est survenu chez 3 des 174 patients, (1,7 %) du groupe fondaparinux et 2 des 170 patients (1,2 % à des patients sous héparine non fractionnée + AVK). Le taux de disparition de la thrombose atriale gauche dans le groupe clot positive était plus élevé dans le fondaparinux (11/14, 78,6 %) versus 7/14, 50 % dans le groupe héparine non fractionnée + AVK. L’incidence des événements indésirables était similaire dans les deux groupes (45,4 % dans le groupe fondaparinux, 45 % dans le groupe héparine non fractionnée + AVK).
Conclusion
Dans cette étude pilote de cardioversion guidée par ETO, l’utilisation de fondaparinux apparaît comme bien tolérée avec une efficacité similaire au traitement conventionnel héparine non fractionnée + AVK. Une tendance à un taux de réduction accru de la thrombose auriculaire gauche a été observée.
Background
Electrical cardioversion to restore sinus rhythm is a common procedure for patients with persistent atrial fibrillation (AF). In patients with AF lasting > 2 days, thromboembolic events have been reported in 5–7% of those who undergo cardioversion in the absence of anticoagulation . The occurrence of thromboembolism is related to both dislodgement of atrial thrombi and post-cardioversion left atrial stunning . Transoesophageal echocardiography (TEE) offers optimal imaging of the atria and allows for accurate identification and exclusion of thrombi . Furthermore, a TEE-guided approach to early cardioversion of AF in conjunction with periprocedural therapeutic anticoagulation with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) has a similar safety profile to conventional anticoagulant therapy (i.e. 1 month of effective oral anticoagulation before cardioversion) . Hence, current guidelines for the management of AF of > 48 hours’ duration recommend ≥ 3 weeks of efficient anticoagulation with an oral anticoagulant (international normalized ratio [INR] 2.0–3.0) before cardioversion followed by ≥ 4 weeks of treatment afterwards, i.e. the “conventional strategy” . Alternatively, a TEE-guided strategy can be followed, in which the 3-week period of anticoagulation can be shortened if TEE reveals no left atrial or left atrial appendage (LAA) thrombus or sludge .
The use of UFH requires frequent monitoring and dose adjustment of anticoagulation whereas LMWH rapidly achieves adequate anticoagulation levels and does not require regular anticoagulation monitoring. However, enoxaparin, which has been shown to be non-inferior to UFH in patients undergoing TEE-guided cardioversion , needs to be administered twice daily. In contrast, the antithrombotic fondaparinux sodium has the advantage of once-daily application. This selective factor Xa inhibitor has shown a favourable benefit-risk profile in trials in the prevention and treatment of venous thromboembolism and in the management of acute coronary syndromes, and its use is now recommended in evidence-based guidelines as an alternative to heparin . Furthermore, fondaparinux carries a very low risk of thrombocytopoenia .
The aim of the SAfety of Fondaparinux in transoesophageal echocardiography-guided Electric cardioversion of Atrial Fibrillation (SAFE-AF) study was to evaluate the efficacy and safety of fondaparinux versus standard therapy (UFH + vitamin K antagonist [VKA]) for the prevention of thromboembolic complications, death and major bleeding events in patients undergoing cardioversion of non-valvular AF.
Methods
Study design
SAFE-AF was an international, multicentre, randomized, open-label, controlled, two-parallel-group, phase II pilot study to evaluate the efficacy and safety of fondaparinux for anticoagulation of patients with AF undergoing electrical cardioversion following TEE ( Fig. 1 ). After stratification into clot-positive and clot-negative patients according to the presence or absence of thrombus in the left atrial cavity or LAA on TEE, patients were randomized to receive either fondaparinux or UFH followed by VKA. The TEE scans were assessed by the treating physicians.
In the fondaparinux arm, clot-negative patients received fondaparinux 7.5 mg once daily subcutaneously (body weight < 100 kg) or 10 mg once daily (body weight > 100 kg) for the first 7–10 days after randomization, followed by 3 weeks of fondaparinux 2.5 mg once daily until day 28 ± 4. Clot-positive patients were given fondaparinux 5–10 mg, depending on weight and renal function, for 28 ± 4 days. In patients whose second TEE showed that the thrombi had disappeared, cardioversion was performed and the patients were treated in the same manner as clot-negative patients.
In the UFH + VKA arm, both clot-negative and clot-positive patients received an initial intravenous bolus injection of 70 IU/kg (≥ 5000 IU) of UFH followed by a continuous infusion with an initial rate of 15 IU/kg per hour. The infusion dose was adjusted to maintain an activated partial thromboplastin time at 1.5–2 times the reference control value and was continued for ≥ 72 hours. VKA treatment was started as soon as possible and adjusted to achieve a target INR of 2–3. In clot-positive patients, TEE was repeated after 28 days and cardioversion was performed if the thrombi had disappeared. Post-cardioversion VKA treatment was continued for 28 days.
Clot-positive patients with persistent thrombi at the second TEE from both groups were excluded from the study except for follow-up on day 90 ± 7.
Patients
Male and female patients aged ≥ 18 years were eligible to participate in this study if they qualified for cardioversion and had AF meeting at least one of the following criteria: acute clinical symptoms (e.g. palpitations, chest pain, dyspnoea, fatigue, light-headedness, syncope) for ≥ 48 hours and < 1 year and AF recorded on a baseline electrocardiogram; newly discovered AF persisting for ≥ 7 days; or recurrent AF persisting for ≥ 7 days and < 1 year. Key exclusion criteria were: duration of current episode of AF > 1 year; acute neurological deficit; treatment with antithrombotic agents (including low-dose anticoagulation > 96 hours before randomization); treatment with oral non-steroidal anti-inflammatory drugs or aspirin > 325 mg/day for > 72 hours before randomization; treatment with two antiplatelet drugs; active and clinically significant bleeding within the past month; major surgery within the past 3 months; uncontrolled arterial hypertension; bacterial endocarditis; calculated creatinine clearance < 30 mL/min; body weight < 50 kg, and planned surgery or intervention within the next 65 days.
The study was conducted in accordance with all applicable regulatory requirements, with the principles of Good Clinical Practice, all applicable patient privacy requirements and the guiding principles of the Declaration of Helsinki, including, but not limited to: institutional review board/independent ethics committee review and favourable opinion/approval of study protocol and any subsequent amendments; patient written informed consent, and investigator reporting requirements. All patients were free to withdraw from the study at any point.
Study endpoints
The primary objective of the study was to compare subcutaneous fondaparinux with UFH + VKA with respect to the occurrence of the primary combined endpoint of cerebral neurological events, systemic thromboembolism, all-cause death and major bleeding events occurring during the whole treatment period, i.e. from randomization to 4 days after the last administration of study drug. The secondary objectives of the study were to compare, up to day 90 ± 7, the effects of fondaparinux versus UFH + VKA on the components of the combined endpoint, thrombus resolution, alternative bleeding definitions (please see below), success of electrical cardioversion and hospitalizations.
Major bleeding was defined as a bleed that was clinically overt and at least one of the following: fatal; symptomatic intracranial, retroperitoneal, intraocular; led to a decrease in haemoglobin of ≥ 3.0 g/dL (with each blood transfusion unit counting for 1.0 g/dL of haemoglobin) or required transfusion of ≥ 2 units of red blood cells. Other clinically overt bleeding events that did not meet the criteria for major bleeding were categorized as minor bleeding. Bleeding events were also analysed using other criteria, as defined in the following studies: Thrombolysis in Myocardial Infarction (TIMI) and Anticoagulation in Cardioversion using Enoxaparin (ACE) .
All events were reviewed by an independent and blinded adjudication committee (see the Appendix A for details).
Statistical analysis
This was a pilot study and as such was not powered to enable formal statistical comparisons between randomized treatment therapies but did not preclude the analysis of data as observed. The aim was to randomize approximately 350 patients (175 per treatment group) into the study. With this sample size, the half-width of the 95% confidence interval (CI) for the estimated event rate (e.g. for the primary endpoint of efficacy) was at most 3.3 percentage points (absolute width) for an anticipated event rate of 5%. This sample size was expected to provide sufficient accuracy to describe the primary endpoint event rate, allowing for descriptive between-group comparisons and comparisons with historical data.
A generalized linear model stratified according to the absence or presence of a thrombus during first TEE was planned to provide an adjusted estimate of the primary endpoint. However, the adjusted estimates could not be calculated due to the low event rate. Thus, the unadjusted event rates (percentages of patients with an event in each treatment group), including their two-sided 95% CIs and the difference between the treatment groups with the associated two-sided 95% CIs are presented.
Results
Patient disposition
The study was conducted in 34 European study centres (see the Appendix A for locations). A total of 349 patients were enrolled, 175 of whom were randomized to fondaparinux and 174 to standard care with UFH + VKA. One patient in the fondaparinux group did not receive treatment because of a prohibited medication, and four patients in the UFH + VKA group withdrew consent. The safety/modified intention-to-treat (mITT) population therefore comprised 174 patients in the fondaparinux group (14 clot-positive and 160 clot-negative at first TEE) and 170 in the UFH + VKA group (14 clot-positive and 156 clot-negative at first TEE). The patient flow diagram is given in Fig. 2 . Baseline characteristics and echocardiographic variables were similar in the two treatment groups and are summarized in Tables 1–3 .
| Fondaparinux ( n = 174) | UFH + VKA ( n = 170) | |
|---|---|---|
| Male | 105 (60.3) | 110 (64.7) |
| Age (years) | 68.2 ± 11.1 | 66.8 ± 11.9 |
| Body mass index (kg/m 2 ) | 29.3 ± 5.7 | 28.7 ± 5.8 |
| Underlying heart disease | ||
| Arterial hypertension | 135 (77.6) | 121 (71.2) |
| Heart failure | 30 (17.2) | 43 (25.3) |
| Coronary artery disease | 24 (13.8) | 26 (15.3) |
| Duration of current AF episode (days) | 23.3 ± 53.3 | 18.4 ± 38.0 |
| Most frequent symptoms of current episode | ||
| Dyspnoea | 100 (57.5) | 108 (63.5) |
| Palpitations | 88 (50.6) | 84 (49.4) |
| Pattern of atrial fibrillation | ||
| Newly discovered | 138 (79.3) | 124 (72.9) |
| Recurrent | 36 (20.7) | 46 (27.1) |
| Time since first AF episode (months) | 52.0 ± 60.4 | 53.6 ± 76.4 |
| Total number of AF episodes a | 1 (1–100) | 1 (1–105) |
| CHADS 2 score b | 1.6 ± 1.1 | 1.5 ± 1.1 |
| CHA 2 DS 2 -VASc score c | 2.4 ± 1.3 | 2.2 ± 1.3 |
| Concomitant antiarrhythmics | 160 (92.0) | 156 (91.8) |
| Concomitant amiodarone | 51 (29.3) | 38 (22.4) |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
