Abstract
While long-term anticoagulation prevents ischemic stroke in high-risk patients with atrial fibrillation (AF), the optimal initial anti-thrombotic regime in acute AF is less well defined. We randomized 96 patients with new onset acute AF in an emergency admission ward to receive (1) once-daily preparation of low molecular weight heparin (LMWH), tinzaparin or (2) conventional intravenous unfractionated heparin (target APTT 50–70 s). 5 patients in unfractionated heparin group compared with no patients in LMWH group (0%, P = 0.04) developed ischemic stroke/transient ischemic attack during the first 48 h. An initial subcutaneous LMWH was safe and effective in ischemic stroke prevention in patients with acute AF.
Introduction
Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and is associated with increased risk of thrombo-embolism and ischemic stroke (Citation1). Although long-term oral anticoagulation in high-risk patients has been unequivocally demonstrated in large randomized control trials to be effective in preventing this complication, much less attention has been paid on the thromboprophylaxis in the setting of acute symptomatic AF, particularly in ‘low risk’ patients. Nonetheless, warfarin is expected to be ineffective in acute setting given its slow therapeutic action. Consequently, the role and optimal regime of thromboprophylaxis during acute AF remains largely undefined. Recently, low molecular weight heparin (LMWH) with a more predictable antithrombotic response than intravenous unfractionated heparin may potentially simplify the management of acute AF.
Methods
We conducted an open labeled, randomized trial in ‘low-risk’ patients with acute symptomatic AF in an emergency admission ward setting to compare the clinical efficacy and safety of a once-daily preparation of LMWH, tinzaparin with conventional intravenous unfractionated heparin. This local research ethics committee approved the study, and all patients gave informed consent. Briefly, 96 patients with CHADS2 score ≤ 2 presented with acute symptomatic AF for the first time to our emergency department, were recruited. Patients were excluded if they had previously documented AF, a ventricular rate >200 beats per minute, pre-excitation syndrome, hypotension, congestive heart failure, the presence of implanted pacemaker and/or implantable cardioverter-defibrillator, recent myocardial infarction, unstable angina, stroke or thrombo-embolism within the last six months, allergy or contraindication to the study medications, or other major medical conditions including renal failure, respiratory failure, and bleeding disorders. As a result, 50 patients were randomized to intravenous unfractionated heparin (loading bolus of 50 iu/kg followed by infusion of 500 iu every day, which was adjusted every 6 hours to achieve a target activated partial thromboplastin time of 50 to 70 s), and 46 patients were to subcutaneous tinzaparin (Innohep, Leo Pharmaceutical Products, Ballerup, Denmark), given at a fixed dose of 175 iu/kg every 24 h. Oral anti coagulation was initiated on the second day, and the dose was adjusted to international normalized ratio (INR) between 2 and 3. Parenteral antithrombotic treatment was continued until the international normalized ratio was 1.8 or above. Ischemic stroke was defined as a neurological deficit of sudden onset that persisted for more than 24 h, which corresponded to a vascular territory in the absence of primary hemorrhage, and could not be explained by other causes (trauma, infection, vasculitis). It was confirmed by computerized axial tomography or magnetic resonance imaging of the brain. Transient ischemic attack was defined as a neurological deficit of sudden onset that lasted for less than 24 h. Analyses were performed according to the intention-to-treat principle. Summary data were expressed as mean ± standard error of the mean or numbers and percentage of patients. Statistical comparisons of demographic and clinical features between the two groups were performed using chi-square test, Fisher's exact test, and t-test as appropriate.
Results
summarizes the clinical characteristics of patients randomized to intravenous unfractionated heparin and LMWH at presentation. With the exception that patients randomized to LMWH had a higher mean left ventricular ejection fraction than those to intravenous unfractionated heparin (67 ± 2% versus 60 ± 2, P = 0.03), there were no significant differences in baseline characteristics between them. In addition, the use of ventricular rate control agents did not differ significantly between the two groups. Altogether 5 patients (5.2%) developed ischemic strokes/transient ischemic attacks (2 ischemic strokes and 3 transient ischemic attacks) during the first 48 h. Their mean age was 74 ± 1.4 years, and 3 were men. Two of them had CHADS2 score of 0, another 2 patients with CHADS2 of 1, and 1 patient with 2. All of them were assigned to intravenous unfractionated heparin group (P = 0.04), with sub-therapeutic activated partial thromboplastin time (), and none of them had sinus conversion before the onset of ischemic stroke.
Table I. Baseline characteristics of the patients.
Table II. Characteristics of patients with ischemic stroke/transient ischemic attack.
Discussion
Prior studies have shown that ischemic stroke tends to cluster in the initial presentation of AF (Citation2,Citation3). Indeed, the presence of left atrial thrombi have been detected in up to 14% of patients with AF <2 days with trans-esophageal echocardiography (Citation4) and hence a possibility of thrombo-embolic risk even in patients with acute AF (Citation4,Citation5). Since oral anticoagulation requires at least several days to achieve a therapeutic level, parenteral antithrombotic agents has been advocated during acute AF management. Nevertheless, the optimal antithrombotic therapy in patients presented with acute AF has not been addressed previously. In this study, up to 5.2% of patients developed ischemic stroke within the first 48 h after admission, and all these episodes of ischemic stroke occurred in patients treated with intravenous unfractionated heparin while the level of anticoagulation was sub-therapeutic. These findings highlight the risks of systemic thrombo-embolism in patients with acute AF, and the importance of incorporation of adequate antithrombotic therapy as an integral part of the acute management of AF. The present study also suggests that the use of LMWH with a more rapid onset and stable therapeutic effect may be advantageous in the management of acute AF. Furthermore, no major adverse effects or bleeding complication was observed with either regime of antithrombotic therapy.
Limitations
First, the study is limited by the small sample size, and all patients are from a single center. Second, although we show that patients receiving LMWH have a lower risk of ischemic stroke/transient ischemic attack, this would be related to the inadequate levels of anticoagulation in patients receiving intravenous unfractionated heparin. Nonetheless, our data does highlight the under-recognized thrombo-embolic risk in low-risk patients with acute AF.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the writing and content of the paper.
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