Editorial
Anticoagulant therapy in atrial fibrillation: vitamin K antagonists or novel oral anticoagulant drugs? Nicoletta Rivaa, Christian Borg Xuerebb and Walter Agenoa J Cardiovasc Med 2015, 16:139–141 a
Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy and bDepartment of Psychology, Faculty for Social Wellbeing, University of Malta, Malta Correspondence to Nicoletta Riva, Department of Clinical and Experimental Medicine, University of Insubria. Via Guicciardini 9, 21100 Varese, Italy Tel: +39 0332 278831; fax: +39 0332 278118; e-mail: [email protected] Received 29 July 2014 Revised 5 August 2014 Accepted 6 August 2014
Atrial fibrillation carries a five-fold increased risk of stroke and it is estimated that more than 20% of stroke in elderly patients may be attributable to atrial fibrillation.1 The use of vitamin K antagonists (VKAs) significantly reduces the rate of stroke by 64%,2 but it is hampered by the risk of severe bleeding episodes which occur in 2–13% of the patients.3 As a consequence, only half of the atrial fibrillation patients at high thromboembolic risk receive anticoagulant treatment in clinical practice.4 Recently, novel, direct, target-specific oral anticoagulant drugs have been shown to be at least as effective and at least as safe as VKAs. Current guidelines recommend anticoagulation in patients with atrial fibrillation and risk factors for stroke, summarized by the CHA2DS2-VASc score (congestive heart failure, hypertension, age greater than 65 years, diabetes mellitus, previous stroke or systemic embolism, vascular disease, and female sex).5 The therapeutic options include the VKAs or the novel oral anticoagulants (NOACs), the latter recommended by the European Society of Cardiology as ‘broadly preferable to VKA in the vast majority of patients with non-valvular atrial fibrillation, when used as studied in the clinical trials’.5 The availability of different therapeutic options should now allow better individualized treatment, balancing between the thromboembolic and the bleeding risks, along with patients’ values and preferences. Fu et al.6 reported the results of a network meta-analysis of randomized controlled trials, assessing four NOACs (dabigatran, apixaban, edoxaban and rivaroxaban) in patients with non-valvular atrial fibrillation. The authors initially evaluated the efficacy and safety of the NOACs through a direct comparison versus warfarin, and subsequently performed indirect comparisons among the NOACs. In the prevention of stroke and systemic embolism, the NOACs were at least non-inferior to VKAs, and three dosages were superior [dabigatran 150 mg twice 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
daily (b.i.d.), apixaban 5 mg b.i.d., and edoxaban 60 mg once daily (q.d.)]. If considering only ischemic stroke, dabigatran 150 mg b.i.d. proved to be superior and edoxaban 30 mg q.d. inferior to VKAs. Moreover, the NOACs had similar or less major bleeding events compared with warfarin. Among the four dosages that were associated with less major bleeding (dabigatran 110 mg b.i.d., apixaban 5 mg b.i.d., and edoxaban 30 mg q.d. and 60 mg q.d.), edoxaban 30 mg q.d. was significantly better than the other NOACs. Considering the different patterns of bleeding complications, all NOACs caused fewer intracranial haemorrhages, whereas three dosages were associated with more gastrointestinal bleeding (dabigatran 150 mg b.i.d., rivaroxaban 20 mg q.d., and edoxaban 60 mg q.d.). The choice of the most appropriate anticoagulant therapy in atrial fibrillation is still debated. VKAs have been the only available oral anticoagulant drugs for more than 60 years; however, they have the disadvantages of a variable anticoagulant response, food and drug interactions and a narrow therapeutic window, which explain the need for frequent monitoring.7 These pharmacological drawbacks also influence patients’ lifestyles, which may result in refusal or a negative perception of VKAs.8 Nonetheless, there are some categories of patients that are still candidates for VKAs. Firstly, patients with valvular atrial fibrillation, defined as the presence of rheumatic valve diseases, mainly mitral stenosis, or prosthetic heart valves.5 Systemic embolism is very common in atrial fibrillation associated with rheumatic valve diseases and has been reported in up to 31% of patients with mitral stenosis and 22% with mitral regurgitation.9 Therefore, patients with haemodynamically significant mitral stenosis were excluded from the major NOAC trials.10–13 Additionally, dabigatran showed increased rates of both thromboembolic and bleeding complications, when compared with warfarin in patients with mechanical heart valves,14 and the regulatory agencies released alerts against its use in this setting. Secondly, chronic kidney disease (CKD) is a risk factor for both thromboembolic and bleeding events in atrial fibrillation.15 While the VKAs undergo almost entirely hepatic transformation into inactive metabolites, the NOACs have higher renal excretion, which ranges from approximately 30% (apixaban and rivaroxaban), to 50% (edoxaban) and 80% (dabigatran).7,16 Although a dose DOI:10.2459/JCM.0000000000000212
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
140 Journal of Cardiovascular Medicine 2015, Vol 16 No 2
reduction is recommended in CKD, there are very limited data for patients with severe renal failure (defined as creatinine clearance
Anticoagulant therapy in atrial fibrillation: vitamin K antagonists or novel oral anticoagulant drugs? Nicoletta Rivaa, Christian Borg Xuerebb and Walter Agenoa J Cardiovasc Med 2015, 16:139–141 a
Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy and bDepartment of Psychology, Faculty for Social Wellbeing, University of Malta, Malta Correspondence to Nicoletta Riva, Department of Clinical and Experimental Medicine, University of Insubria. Via Guicciardini 9, 21100 Varese, Italy Tel: +39 0332 278831; fax: +39 0332 278118; e-mail: [email protected] Received 29 July 2014 Revised 5 August 2014 Accepted 6 August 2014
Atrial fibrillation carries a five-fold increased risk of stroke and it is estimated that more than 20% of stroke in elderly patients may be attributable to atrial fibrillation.1 The use of vitamin K antagonists (VKAs) significantly reduces the rate of stroke by 64%,2 but it is hampered by the risk of severe bleeding episodes which occur in 2–13% of the patients.3 As a consequence, only half of the atrial fibrillation patients at high thromboembolic risk receive anticoagulant treatment in clinical practice.4 Recently, novel, direct, target-specific oral anticoagulant drugs have been shown to be at least as effective and at least as safe as VKAs. Current guidelines recommend anticoagulation in patients with atrial fibrillation and risk factors for stroke, summarized by the CHA2DS2-VASc score (congestive heart failure, hypertension, age greater than 65 years, diabetes mellitus, previous stroke or systemic embolism, vascular disease, and female sex).5 The therapeutic options include the VKAs or the novel oral anticoagulants (NOACs), the latter recommended by the European Society of Cardiology as ‘broadly preferable to VKA in the vast majority of patients with non-valvular atrial fibrillation, when used as studied in the clinical trials’.5 The availability of different therapeutic options should now allow better individualized treatment, balancing between the thromboembolic and the bleeding risks, along with patients’ values and preferences. Fu et al.6 reported the results of a network meta-analysis of randomized controlled trials, assessing four NOACs (dabigatran, apixaban, edoxaban and rivaroxaban) in patients with non-valvular atrial fibrillation. The authors initially evaluated the efficacy and safety of the NOACs through a direct comparison versus warfarin, and subsequently performed indirect comparisons among the NOACs. In the prevention of stroke and systemic embolism, the NOACs were at least non-inferior to VKAs, and three dosages were superior [dabigatran 150 mg twice 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
daily (b.i.d.), apixaban 5 mg b.i.d., and edoxaban 60 mg once daily (q.d.)]. If considering only ischemic stroke, dabigatran 150 mg b.i.d. proved to be superior and edoxaban 30 mg q.d. inferior to VKAs. Moreover, the NOACs had similar or less major bleeding events compared with warfarin. Among the four dosages that were associated with less major bleeding (dabigatran 110 mg b.i.d., apixaban 5 mg b.i.d., and edoxaban 30 mg q.d. and 60 mg q.d.), edoxaban 30 mg q.d. was significantly better than the other NOACs. Considering the different patterns of bleeding complications, all NOACs caused fewer intracranial haemorrhages, whereas three dosages were associated with more gastrointestinal bleeding (dabigatran 150 mg b.i.d., rivaroxaban 20 mg q.d., and edoxaban 60 mg q.d.). The choice of the most appropriate anticoagulant therapy in atrial fibrillation is still debated. VKAs have been the only available oral anticoagulant drugs for more than 60 years; however, they have the disadvantages of a variable anticoagulant response, food and drug interactions and a narrow therapeutic window, which explain the need for frequent monitoring.7 These pharmacological drawbacks also influence patients’ lifestyles, which may result in refusal or a negative perception of VKAs.8 Nonetheless, there are some categories of patients that are still candidates for VKAs. Firstly, patients with valvular atrial fibrillation, defined as the presence of rheumatic valve diseases, mainly mitral stenosis, or prosthetic heart valves.5 Systemic embolism is very common in atrial fibrillation associated with rheumatic valve diseases and has been reported in up to 31% of patients with mitral stenosis and 22% with mitral regurgitation.9 Therefore, patients with haemodynamically significant mitral stenosis were excluded from the major NOAC trials.10–13 Additionally, dabigatran showed increased rates of both thromboembolic and bleeding complications, when compared with warfarin in patients with mechanical heart valves,14 and the regulatory agencies released alerts against its use in this setting. Secondly, chronic kidney disease (CKD) is a risk factor for both thromboembolic and bleeding events in atrial fibrillation.15 While the VKAs undergo almost entirely hepatic transformation into inactive metabolites, the NOACs have higher renal excretion, which ranges from approximately 30% (apixaban and rivaroxaban), to 50% (edoxaban) and 80% (dabigatran).7,16 Although a dose DOI:10.2459/JCM.0000000000000212
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
140 Journal of Cardiovascular Medicine 2015, Vol 16 No 2
reduction is recommended in CKD, there are very limited data for patients with severe renal failure (defined as creatinine clearance
