Future antithrombotic strategies
The difficulties of OAC treatment may also be overcome by the development of new anticoagulants that do not require regular monitoring and which have fewer drug interactions. Oral direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran.
They bind directly to thrombin, blocking its interaction with substrates and thereby preventing fibrin formation, thrombin-mediated activation of Factors V,VIII, XI, and XIII, and thrombin-induced platelet-ag-gregation . The use of these thrombin-inhibitors confirmed the efficiacy of anticoagulation for stroke prophylaxis. Ximelagatran, administered in a fixed dose without coagulation monitoring, protected high risk patients with atrial fibrillation against throm-
boembolism at least as effectively as well-controlled warfarin, and was associated with less bleeding. However, safety concerns regarding increased liver toxicity led the Food and Drug Administration to reject the sponsor’s application for ximelagatran. Very recently, the results of a phase 3 noninferiority trial on dabigatran etexilate against warfarin in AF have been published. In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Thus, the 150-mg dose appears to be more efficacious and the 110-mg dose appears to be safer than warfarin. Remarkably, the time in therapeutic range in the warfarin group was 64% which can be compared to contemporary studies but reflects optimal study conditions.
An attractive alternative to direct thrombin inhibition is selective inhibition of FXa. Several factor Xa inhibitors are under investigation, including rivaroxaban and apixaban. The recently published RECORD studies showed that rivaroxaban was more effective than enoxaparin in preventing venous thromboembolism after total knee or hip replacement. The ROCKET-AF study is a randomized, double-blind study that will compare the efficacy and safety of rivaroxaban 20 mg once daily with warfarin for the prevention of stroke in approximately 14 000 patients with AF. A phase III study, ARISTOTLE, which investigates apixaban 5 mg bid for the prevention of stroke
in patients with AF, is ongoing.
Nonpharmacologic approaches
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Patients at high risk of embolic stroke but with contraindications for OAC are in a need of an alternative approach that is not associated with a long-term risk of hemorrhage and other attendant circumstances. This is particularly true for those who survived intracranial hemorrhage but remain at high risk for cardiogenic embolism. The reasonable alternative may be the exclusion of the LAA cavity from circulation either by surgical or by percutaneous catheter-based procedures.
Currently, excision of the LAA at the time of mitral valve surgery is recommended to reduce future stroke risk. The efficiacy of LAA exclusion in patients undergoing elective coronary artery bypass graft surgery was shown in the LAA Occlusion Study (LAAOS). Thus, based on the surgical experience, the development of a less invasive percutaneous approach to close the LAA by implantation of a mechanical device was a logical consequence. In this issue, Park et al. give an overview on the latest developments in this field.
Thrombogenesis in atrial fibrillation
The absence of a regular contraction of the fibrillating atria leads to an increase of atrial pressure and dilatation, which together with hemoconcentration, endothelial dysfunction, and a prothrombotic state is the prerequisite for thrombus formation. Echocardiography and autopsy studies have shown that more than 90% of all thrombi in patients with AF originaing in the left atrium, form in the left atrial appendage (LAA). The pathogenesis of LAA thrombus formation has not been fully elucidated, but the precondition is likely to result from a hypercoagulable state explained by Virchow’s triad of thrombogenesis – ie, abnormal changes of the vessel wall, blood flow, and blood constituents . Nowadays, this is translated as follows: “Abnormal blood flow” means reduced flow up to stasis due to the lack of contraction in combination with the increase of volume and size of the LAA, “abnormal blood constituents” are represented by activated coagulation factors and platelets, and “abnormal vessel wall” in this case means structural and functional changes of endothelial or endocardial cells. Dense spontaneous echocardiographic contrast (SEC) in the left atrium and left atrial appendage aris-
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es when blood flow velocity is low and this phenomenon is an independent risk factor for stroke.
The density of SEC increases and LAA velocities progressively decline significantly together with the accumulation of clinical risk factors for stroke evaluated by the CHADS2 score (see below). There are various connections between morphologic and functional changes of the left atrium and the state of activation of blood coagulation, inflammation and extracellular matrix turnover, which can be demonstrated in patients with AF and are prone to an increased risk of cardiac еmbolism.
Summary
With an aging population, AF is a growing public health problem with significant clinical consequences. Despite conclusive evidence from randomized controlled clinical trials, the use of OAC for the prevention of ischemic stroke in AF is suboptimal probably due to both, the real-world limitations of warfarin and the disregard for risk guided treatment. In patients with an overall risk of stroke or cardiovascular events that is substantially higher than that of major bleeding the proven absolute risk reductions of stroke cannot substantially be offset by small but statistically significant increases in major hemorrhage. Therefore, prophylaxis must be better tailored to the patient’s stroke and bleeding risk profile to steer safely between the Scylla of thrombosis or embolism and the Charybdis
of bleeding. Moreover, appropriate facilities to monitor INR such as anticoagulation clinics and non-phar-
mocological alternatives are necessary. However, there are promising new antithrombotic agents with potential benefits including fixed dosing, rapid onset of action, and no requirement for therapeutic monitoring at various stages of development and clinical evaluation. Finally, the alternative to close the left atrial appendage as the main source of cardiogenic emboli with a less invasive percutaneous procedure may help to reduce major stroke rates in the future.
1.Brian F. Gage, MD, MSc; Carl van Walraven, MD, FRCPC, MSc; Lesly Pearce, MS; Robert G. Hart, MD; Peter J. Koudstaal, MD; B.S.P. Boode, MD; Palle Petersen, MD, PhD / Selecting Patients With Atrial Fibrillation for Anticoagulation//Circulation. 2004;110
2. B y B R I A N K . C O U RT N E Y, M D , M S E E , a n d PA U L D O R I A N , M D , F R C P C/ Stroke Prophylaxis in Non-Valvular Atrial Fibrillation// CARDIOLOGY Rounds J A N U A R Y 2 0 0 8 v o l u m e
X I I I , i s s u e 2
3. A John Camm/ Stroke Prevention in Atrial Fibrillation – The Unmet Need and Morbidity Burden// E U R O P E A N C A R D I O L O G Y 2011-Р 187-195
4. B. Leithäuser, F. Jung*, J.-W. Park/ Oral anticoagulation for prevention of cardioembolic stroke in patients with atrial fibrillation: Focussing the elderly// Cardiopulmonary Pathophysiology 13: 307-317
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