J Cardiovasc Med 2015, 16: a Department of Experimental and Clinical Medicine, University of Florence, b SOD

Transcription

1 Narrative review Novel oral anticoagulants in atrial fibrillation: which novel oral anticoagulant for which patient? Domenico Prisco a,b, Caterina Cenci a, Elena Silvestri a,b, Lucia Ciucciarelli a,b and Giovanni Di Minno c Atrial fibrillation is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Current european society of cardiology guidelines recommend to stratify atrial fibrillation patients according to the CHA 2 DS 2 -VASc score and to administer anticoagulation, preferably with novel oral anticoagulants, that is, dabigatran, rivaroxaban, or apixaban, if the CHA 2 DS 2 - VASc score is at least 1. All novel anticoagulants have shown the same, if not greater, efficacy and safety as warfarin, with some advantages. The choice among the novel oral anticoagulants depends on their different pharmacokinetic profile, patients stroke and bleeding risk, comorbidities, drug tolerability and costs and, finally, patients preferences. J Cardiovasc Med 2015, 16: Keywords: atrial fibrillation, novel oral anticoagulants, stroke a Department of Experimental and Clinical Medicine, University of Florence, b SOD Patologia Medica, AOU Careggi, Florence and c Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy Correspondence to Caterina Cenci, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, Italy caterinacenci@gmail.com Received 10 August 2014 Revised 22 November 2014 Accepted 7 December 2014 Introduction Atrial fibrillation is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke, resulting from embolization of thrombi that form within the left atrium of the heart. The results of the Framingham Heart Study show that in patients with atrial fibrillation, who have never had an ischemic event and who are not receiving antithrombotic treatment, the stroke rate is 4.5% per year, but it is much higher in some patients. 1,2 Because the absolute benefit of antithrombotic therapy depends on the underlying risk of stroke, the current european society of cardiology (ESC) guidelines recommend to stratify atrial fibrillation patients according to the CHA 2 DS 2 -VASc score 3 5 (Tables 1 and 2). Patients with one or more major risk factors (e.g. previous stroke, transient ischemic attack, or systemic embolism, age >75 years), or with two or more clinically relevant nonmajor risk factors (e.g. heart failure or moderate-to-severe left ventricular systolic dysfunction, hypertension, diabetes mellitus, female sex, age years, vascular disease) should be considered for oral anticoagulation such as vitamin K antagonists (VKAs), or novel oral anticoagulants (NOACs); patients with one clinically relevant nonmajor risk factor only (CHA 2 DS 2 -VASc score ¼ 1) could be managed preferably with oral anticoagulation, although this indication is controversial; patients without risk factors (CHA 2 DS 2 -VASc score ¼ 0) 0) can be managed with no antithrombotic therapy, given the very low thromboembolic risk in such patients and the anticoagulant drug potential for bleeding. 3 On the contrary, the old CHADS 2 score 4,6 has several limitations, which have been underlined, namely due to the noninclusion of several common stroke risk factors, and to the fact that it classifies a significant number of patients in the intermediate-risk group, hence creating ambiguity over the most appropriate antithrombotic therapy. 7 Moreover, patients classified in the lowest-risk category (CHADS 2 score of 0) still have a nearly 2% annual risk for stroke. Therefore, the most recent guidelines by the american heart association 5 have also accepted, for the first time, the use of CHA 2 DS 2 -VASc score as in Europe, although they state, differently from the ESC guidelines, that for patients with a CHA 2 DS 2 -VASc of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered (see Table 2 for details). The approach to thromboprophylaxis in patients with atrial fibrillation, however, requires not only the evaluation of the risk of ischemic stroke but also the consideration of the risk of bleeding, in order to maximize the benefits of antithrombotic therapy and minimize adverse events. 8 Therefore, the latest ESC guidelines recommend using the HAS-BLED score 3 (see Table 1) for the bleeding risk stratification of atrial fibrillation patients, which implies caution and/or regular review of anticoagulant therapy in patients with a HAS-BLED score of at least 3. Until a few years ago, the VKAs were the only oral anticoagulant drugs available for the prevention of stroke in atrial fibrillation patients. Despite their proven efficacy, their employment is burdened by a number of Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: /JCM

2 2 Journal of Cardiovascular Medicine 2015, Vol 00 No 00 Table 1 Current European guidelines for stratification of atrial fibrillation patients (the CHA 2 DS 2 -VASc and HAS-BLED scores) CHA 2 DS 2 -VASc score Congestive heart failure/lv dysfunction: 1 point Hypertension: 1 point Age 75 years: 2 points Diabetes mellitus: 1 point Stroke/TIA/thromboembolism: 2 points Vascular disease (prior myocardial infarction, peripheral artery disease, aortic plaque): 1 point Age years: 1 point Sex category (i.e. female sex): 1 point Score 0: estimated stroke rate 0%/year Score 1: estimated stroke rate 1.3%/year HAS-BLED bleeding score Uncontrolled hypertension: 1 point Abnormal renal and liver function: 1 point each Stroke: 1 point Bleeding: 1 point Labile INRs: 1 point Elderly (e.g. age >65): 1 point Drugs and alcohol: 1 point each Maximum score 9 Score 0: 1.13 bleeds per 100 patients/year Score 1: 1.02 bleeds per 100 patients/year Score 2: 1.88 bleeds per 100 patients/year Score 3: 3.74 bleeds per 100 patients/year Score 4: 8.70 bleeds per 100 patients/year Score 5: bleeds per 100 patients/year Score 6: 0 bleeds per 100 patients/year Modified from ESC CHA 2 DS 2 -VASc score: Maximum score 9; score 0, estimated stroke rate 0%/year; score 1, estimated stroke rate 1.3%/year; score greater than 1, estimated stroke rate above 2%/year. HAS-BLED bleeding score: Maximum score 9; score 0, 1.13 bleeds per 100 patients/year; score 1, 1.02 bleeds per 100 patients/ year; score 2, 1.88 bleeds per 100 patients/year; score 3, 3.74 bleeds per 100 patients/year; score 4, 8.70 bleeds per 100 patients/year; score 5, bleeds per 100 patients/year; score 6, 0 bleeds per 100 patients/year. INRs, international normalized ratio; TIA, transient ischemic attack. limitations that contribute to complicate their practical use. 9 As a consequence, it is estimated that only about 50% of patients at high risk of stroke receive anticoagulation, 10 and it has recently been shown that the time in therapeutic range (TTR) for patients taking warfarin is between 51 and 58% in outpatient settings. 2 4,11 Therefore, in order to overcome the limitations of the currently available treatments, pharmaceutical research has turned to the development of NOACs that were able to maintain, or even improve, the efficacy and safety of old anticoagulants, addinggreatermaneuverability. Amongthe NOACs synthesized in recent years, three drugs have been approved by the US Food and Drug Administration (FDA) and the european medicine agency (EMA), and are currently available for the prevention of stroke in nonvalvular atrial fibrillation patients, that is, dabigatran, rivaroxaban, and apixaban, 12,13 whereas a fourth drug, edoxaban, is still waiting for approval by FDA/EMA. Novel oral anticoagulants in atrial fibrillation The main pharmacokinetic and pharmacodynamic characteristics of NOACs are reported in Table 3. 14,15 Dabigatran etexilate is a pro-drug that acts as a direct thrombin inhibitor. Its efficacy in preventing stroke and systemic embolism and its safety in nonvalvular atrial fibrillation patients were demonstrated in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) trial. 16,17 This trial included about patients who were randomized to receive dabigatran etexilate 150 mg twice daily, 110 mg twice daily, or warfarin. Rivaroxaban is a direct selective inhibitor of factor Xa, whose efficacy and safety in nonvalvular atrial fibrillation patients were compared to warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study. 18 This trial included about atrial fibrillation patients who were randomized to receive rivaroxaban 20 mg once daily [reduced to 15 mg once daily in patients with renal impairment, e.g. with a creatinine clearance (CrCl) of ml/min], or warfarin. Apixaban is a direct inhibitor of factor Xa, whose efficacy and safety in the prevention of stroke in nonvalvular atrial fibrillation patients were compared with warfarin in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. 19 This trial included about patients who were randomized to receive apixaban 5 mg twice daily (reduced to 2.5 mg twice daily in patients with at least two among creatinine 1.5 mg/dl, age 80 years, and body weight 60 kg) or warfarin. 20 Edoxaban is the newest NOAC drug waiting for approval by FDA/EMA for stroke and systemic embolism Table 2 Comparison between American and European current guidelines CHA 2 DS 2 -VASc score AHA 2014 ESC 2012 ASA 2012 CHA 2 DS 2 -VASc 0 None None CHA 2 DS 2 -VASc 1 Anticoagulation or aspirin or none Anticoagulation CHA 2 DS 2 -VASc >1 Anticoagulation Anticoagulation CHADS 2 0 CHADS 2 1 CHADS 2 2 Aspirin or no treatment Aspirin or anticoagulation Anticoagulation Modified from AHA 2014, 5 ESC 2012, 3 and ASA

3 Novel oral anticoagulants in atrial fibrillation Prisco et al. 3 Table 3 Pharmacokinetics and pharmacodynamics of novel oral anticoagulants Drug characteristics Dabigatran (RELY) Rivaroxaban (ROCKET-AF) Apixaban (ARISTOTLE) Edoxaban (ENGAGE-TM) Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor bioavailability (%) Time to peak levels (h) h after ingestion Half-life (h) Excretion 80% renal 2/3 liver, 1/3 renal 25% renal, 75% fecal 50 renal, 50 liver (4% CYP3A4) Dose 150 mg BD or 110 mg BD 20 mg OD or 15 mg OD 5 mg BD or 2.5 mg BD 60 mg OD or 30 mg OD Pro-drug Yes No No No Liver metabolism CYP3A4 involved No Yes Minimal Yes Absorption with food No effect þ39% more No effect 6 22% more GI tolerability Dyspepsia (5 10%) No problem No problem No problem Modified from Skjoth et al. 14 and EHRA ARISTOTLE, apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation; BD, bis in die; GI, gastrointestinal; OD, once daily; RELY, randomized evaluation of long-term anticoagulation therapy; ROCKET-AF, rivaroxaban once daily oral direct factor xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. prevention in nonvalvular atrial fibrillation. It is an oral, reversible, direct factor Xa inhibitor, and its efficacy and safety were tested in a large trial comparing two dose regimens [60 mg once daily or 30 mg once daily, adjusted to a 50% dose in patients with estimated CrCl of ml/min, or a body weight of <60 kg, or the concomitant use of potent P-glycoprotein (P-gp) inhibitors such as verapamil or quinidine] with warfarin. 21 An overview of the main outcomes of these trials is reported in Table 4. 21,22 As a whole, in addition to ensuring the same, if not greater, efficacy and safety of warfarin, these new drugs offer many advantages over VKAs thanks to their different pharmacokinetics and pharmacodynamics (Table 3). For example, their rapid onset and offset of action, similar to that of low-molecular-weight heparins, avoids the need for bridging therapies when starting treatment or when invasive procedures are needed, and their specific targets imply few significant drug interactions (Table 5) 23 ; this last property is particularly important in elderly patients who are the major users of oral anticoagulants and often assume polypharmacy. Moreover, the efficacy of NOACs is not influenced by age, sex, or body weight, unlike warfarin, hence offering the possibility of using fixed doses with a predictable anticoagulant response that does not require a routine laboratory monitoring to maintain patients in a therapeutic range Taking into account these aspects, the current guidelines recommend to choose NOACs over VKAs for anticoagulation in nonvalvular atrial fibrillation patients, unless there is a contraindication to their use 3 (see list below for details), in particular, severe renal impairment (CrCl Table 4 Overview of main outcomes of phase III clinical trials of novel oral anticoagulants versus warfarin Trial Primary outcome (stroke or systemic embolism) Hemorrhagic stroke Intracranial hemorrhage Myocardial infarction All-cause mortality Major bleeding RELY 150 mg: RR 0.65, for Dabigatran 110 mg: RR 0.90, for noninferiority ROCKET-AF rivaroxaban ARISTOTLE apixaban ENGAGE-TM edoxaban HR 0.88, for noninferiority, P ¼ 0.12 for HR 0.79, for noninferiority, P ¼ 0.01 for 60 mg: HR 0.79, for noninferiority, P ¼ 0.02 for 30 mg: HR 1.07, P ¼ for noninferiority, P ¼ 0.44 for 150 mg: RR 0.26, 110 mg: RR 0.31, 150 mg: RR 0.41, 110 mg: RR 0.30, 150 mg: RR 1.27, P ¼ mg: RR 1.29, P < mg: RR 0.88, P ¼ mg: RR 0.91, P ¼ mg: RR 0.93, P ¼ mg: RR 0.80, P ¼ HR 0.59, P ¼ HR 0.67, P ¼ 0.02 HR 0.81, P ¼ 0.12 HR 0.85, P ¼ HR 1.04, P ¼ 0.58 HR 0.51, HR 0.42, HR 0.88, P ¼ 0.37 HR 0.89, P ¼ HR 0.69, 60 mg: HR 0.54, 30 mg: HR 0.33, 60 mg: HR 0.47, 30 mg: HR 0.30, 60 mg: HR 0.94 P ¼ mg: HR 1.19, P ¼ mg: HR 0.92, P ¼ mg: HR 0.87, P ¼ mg: HR 0.8, 30 mg: HR 0.47, Modified from Albert. 22 ARISTOTLE, apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation; HR, hazard ratio; RELY, randomized evaluation of long-term anticoagulation therapy; ROCKET-AF, rivaroxaban once daily oral direct factor xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation.

4 4 Journal of Cardiovascular Medicine 2015, Vol 00 No 00 Table 5 Clinically relevant drug drug interactions of novel oral anticoagulants Dabigatran Rivaroxaban Apixaban Edoxaban Antiacids, PPI # Concentration No interaction No interaction No interaction Should be administered 2h No dose adjustment No dose adjustment No dose adjustment before antiacids and PPI P-gp inhibitors " Concentration " Concentration " Concentration " Concentration Reduce dabigatran dose Avoid administration Caution with strong No dose adjustment with with verapamil with potent inhibitors inhibitors digoxin and amiodarone dronedarone Dose adjustment recommended with quinidine, verapamile, dronedarone No dose adjustment with amiodarone and digoxin No dose adjustment with amiodarone and digoxin P-gp inducers # Concentration # Concentration # Concentration # Concentration rifampicin Avoid administration Avoid administration Consider dose adjustment of rifampicin if co-administering with another inhibitor With rifampicin; caution with With rifampicin; Caution with phenytoin, carbamazepine phenytoin, carbamazepine Caution with ketoconazole, clarithromycin, chloramphenicol CYP3A4 inhibitors " Concentration " Concentration " Concentration " Concentration Caution with strong inhibitors Caution with strong inhibitors Caution with strong inhibitors Caution with strong inhibitors ritonavir CYP3A4 inducers # Concentration ## Concentration ## Concentration # Concentration rifampicin rifampicin rifampicin Consider dose adjustment of rifampicin if co-administering with another inhibitor Modified from Potpara and Lip. 23 P-gp, P-glycoprotein; PPI, proton pump inhibitor. between 15 and 30 ml/ min) or end-stage renal disease (CrCl <15 ml/ min or patients undergoing hemodialysis). Contraindications to NOACs assumption: (1) Moderate/severe mitral valve stenosis (2) Mechanical prosthetic valve (3) Active bleeding (4) Pregnancy (5) Liver disease associated with coagulopathy, severe hepatic impairment (child Pugh C) or moderate hepatic impairment (child Pugh B: only for rivaroxaban) (6) Renal insufficiency, for example, CrCl below 30 ml/ min (for dabigatran) and CrCl below 15 ml/min for rivaroxaban and apixaban There are, however, some clinical conditions in which VKAs still represent the first choice for anticoagulation in atrial fibrillation patients. 27 Because NOACs are indicated in the case of nonvalvular atrial fibrillation, the definition of valvular atrial fibrillation needs to be specified. 28 There is a wide consensus that atrial fibrillation patients with moderate-to-severe mitral stenosis, together with those with prosthetic mechanical heart valves, should receive warfarin, whereas no recommendation exists for other valvulopathies (such as aortic stenosis or mitral regurgitation). It is reasonable that for valvulopathies that do not require anticoagulation in the absence of atrial fibrillation, NOACs may be an option when they are associated with atrial fibrillation, but this issue is not completely defined. A possible solution to this unanswered question can be derived from the analysis of the exclusion criteria of NOAC phase III clinical trials. In the RELY trial, 16 patients having a hemodynamic valve disease or a prosthetic valve were excluded; in the ROCKET-AF trial, 18 atrial fibrillation patients with hemodynamically significant mitral valve stenosis and prosthetic heart valve were not included in the study population, whereas patients treated with annuloplasty with or without prosthetic ring, commissurotomy, and/or valvuloplasty were permitted; in the ARIS- TOTLE trial, 19 atrial fibrillation patients with moderate or severe mitral stenosis, as well as those who had a prosthetic valve, were excluded. Finally, in the ENGAGE trial, 21 patients with moderate or severe mitral stenosis, unresected atrial myxoma, or a mechanical heart valve were excluded, whereas patients with other valve diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease were allowed in the study population. Therefore, the study population of these trials also included to varying extents patients with atrial fibrillation and some concomitant valve diseases, other than moderate-to-severe mitral stenosis. For example, in a post-hoc analysis of the ARISTOTLE trial, % of the entire trial population (about 5000 patients) had concomitant valve diseases and some of these patients had more than one valvular abnormality. The efficacy and safety of apixaban in these patients were no different from those observed in the overall study population, and this result also applies to rivaroxaban in the ROCKET-AF trial. 30 So, it is reasonable to assume that the positive outcomes of efficacy and safety of NOACs can be referred also to this category of patients.

5 Novel oral anticoagulants in atrial fibrillation Prisco et al. 5 Moreover, VKAs are preferred to NOACs in patients with acute coronary syndrome (ACS) and implantation of drug-eluting stent (DES) for which a triple antithrombotic therapy is needed, because there is no evidence on the use of NOACs in this category of patients. Triple therapy with dual antiplatelet therapy and NOACs at least doubles the risk of major bleeding after an ACS. 15 In a post-hoc substudy of the RELY trial, the association of single and dual antiplatelet drug increased bleeding risk by about 60 and 130%, respectively. 31 Considering these assumptions, the current european heart rhythm association (EHRA) guidelines 15 give precise indications in different coronary artery disease scenarios. In the case of an ACS (acute setting) in atrial fibrillation patients on NOACs, it is recommended to temporarily discontinue this therapy, considering the short half-lives of these drugs and the fact that in clinical studies the interruption of NOAC therapy before percutaneous coronary intervention (PCI) was suggested. This allows a safe initiation of the newer P2Y12 inhibitors such as ticagrelor and prasugrel, which have been shown to be superior over clopidogrel in ACS, but for which the bleeding risk when associated with NOACs is not well known. In the stable (ACS >1 year) coronary artery disease scenario, anticoagulation with VKAs without additional antiplatelet agents is considered sufficient for most atrial fibrillation patients, but NOACs may be safe and effective alternatives to VKAs 15 and, among them, as reported below, a factor Xa inhibitor might be preferred. As regards cardioversion, no prospective data are available concerning the safety under NOAC treatment: observational data from the three phase III studies of NOACs versus warfarin seem to confirm their efficacy and safety for periprocedural anticoagulation. 15 However, as there is no easily available specific coagulation assay for any NOAC that provides information on effective anticoagulation over the past 3 weeks and because patient compliance may be variable, warfarin may be preferable in this clinical situation. Finally, for patients on VKAs, it is important to consider the quality of therapy conduction (e.g. TTR) and the treatment compliance before moving on to a NOAC. In fact, in the case of well conducted therapy (TTR 70%), the current guidelines recommend maintaining VKAs, which are also preferred in noncompliant patients, because the short half-life of NOACs makes missing a dose very dangerous, whereas, on the contrary, periodic measurements of the international normalized ratio can be a stimulus to a better adherence to therapy, as well as an important monitoring tool for the physician. 32 Which novel oral anticoagulant for which patient? Considering their proven similar efficacy and safety (see Table 4 for details 21,22 ) with a better performance, as regards this last aspect, for dabigatran 110 mg twice daily and apixaban, 33 the choice between the three available NOACs at present must take into account their differences in the pharmacokinetic profile (Table 3), 14,15 comorbidities, drug tolerability and costs, and, finally, patients preferences and their ischemic and bleeding risk profile. For example, patients with a high risk of ischemic stroke and low risk of bleeding should assume dabigatran 150 mg twice daily, which is more effectivethanwarfarininpreventing ischemic stroke and systemic embolism; on the contrary, a patient considered to be at a high risk of bleeding should be managed with apixaban or dabigatran 110 mg twice daily. Anyway, one should consider that all the NOACs significantly decrease the risk of intracranial bleeding with respect to warfarin. Even in the absence of head-to-head trials, the analysis of drug profiles and of the results of the phase III studies allows some considerations to address a choice in clinical practice. First of all, because NOACs are dependent on renal excretion to varying extents, estimated CrCl should be determined before starting treatment with NOACs in all patients. 34 Dabigatran is contraindicated in patients with CrCl less than 30 ml/min, whereas, in patients with CrCl between 15 and 30 ml/min, rivaroxaban and apixaban should be used with caution, through dose adjustment and routine measurement of renal function, even if there is no experience in this subset of patients because they were excluded from the main randomized controlled trials. In patients with moderate renal impairment (CrCl between 30 and 50 ml/min), dabigatran and rivaroxaban should be used at reduced doses, whereas apixaban, which has the lowest rate of renal excretion, can be taken at the usual doses, at least in patients aged 80 years or less and weighing at least 60 kg (see Table 6 for details 34 ). This characteristic may lead many physicians to prefer apixaban in patients with impaired renal function. Apixaban may also represent the best choice in patients with a recent and/or recurrent history of gastrointestinal bleeding, as well as in patients with disease condition(s) predisposing to higher risk of gastrointestinal bleeding (active peptic ulcer disease, recent biopsy or trauma, gastritis), because the results of clinical trials demonstrated an increased risk of gastrointestinal bleeding in patients assuming dabigatran and rivaroxaban, but not in those taking apixaban 32 (see Table 7 for details). In patients with severe hepatic dysfunction, all NOACs are contraindicated, and, in those assuming a strong CYP3A4 inhibitor, a dose reduction or special caution may be required for apixaban and rivaroxaban, which are metabolized by this cytochrome, but not for dabigatran. 27 All these drugs, however, are substrates of the transporter protein P-gp, so a dose reduction may be required in patients treated with strong P-gp inhibitors (see Table 5 for details on relevant drug drug interactions 23 ).

6 6 Journal of Cardiovascular Medicine 2015, Vol 00 No 00 Table 6 Selection of appropriate novel oral anticoagulants for atrial fibrillation patients with renal impairment Mild CrCl ml/min Moderate CrCl ml/min Severe CrCl ml/min Dabigatran 150 mg twice daily X X a NA Dabigatran 110 mg twice daily NA Rivaroxaban 20 mg once daily X Rivaroxaban 15 mg once daily X X b Apixaban 5 mg twice daily X X Apixaban 2.5 mg twice daily X b,c Edoxaban 60 mg once daily X NA Edoxaban 30 mg once daily X d Modified from Gong and Kim. 34 CrCl, creatinine clearance. a A dose reduction to 110 mg twice daily should be considered if there is high bleeding risk. b There are no outcome data for NOACs in patients with advanced chronic kidney disease (CrCL <30 ml/min), and the current ESC guidelines recommend against their use in such patients. c The recommended criteria for dose reduction with apixaban include two of the following: age at least 80 years, weight 60 kg or less, creatinine at least 1.5 mg/dl. d In the phase III trial, patients with a body weight of 60 kg or less, CrCl below 50 ml/min, or on concomitant treatment with verapamil, quinidine, or dronedarone were offered a reduced dose. In elderly patients (>75 years), it has been demonstrated that dabigatran and apixaban, but not rivaroxaban, require a dose reduction. In particular, it has been shown that the risk benefit of dabigatran 150 mg versus warfarin is more favorable than the 110-mg regimen among patients aged below 75 years thanks to the better efficacy of the higher dose of the drug but is less favorable in those aged at least 75 years in whom a trend towards a higher bleeding rate has been demonstrated (5.19 versus 4.37% per year; P ¼ 0.07). 32 Thus, some regulatory authorities have recommended the lower 110-mg dose of dabigatran in patients over 80 years of age and suggested considering the lower dose also in those aged years. 35 As regards apixaban, the recommended criteria for dose reduction include two of the following: age at least 80 years, weight 60 kg or less, creatinine at least 1.5 mg/dl. Anyway, in this frail subgroup of patients, characterized by an elevated risk of both thrombotic and bleeding events, apixaban 5 mg might be the drug of choice thanks to its better safety profile and because it offers the optimal balance between the prevention of ischemic events and the risk of major bleeding. On the contrary, rivaroxaban, which offers the advantage of the once-daily dosing, could be taken into account in patients assuming polypharmacy to improve their adherence to treatment. In patients with recent (<1 year) ACS and new-onset atrial fibrillation, if a NOAC was indicated over warfarin, a factor Xa inhibitor (apixaban or rivaroxaban) might be preferred based on the reported trend to a higher incidence of myocardial infarction with dabigatran 150 mg in the RELY trial 12 versus warfarin, although associated with a lower mortality. On the contrary, a nonsignificant reduction of myocardial infarction in atrial fibrillation patients has been shown with both apixaban and rivaroxaban 36 ; so, according to some authors, they might represent the best choice in this subset of patients. However, the issue of an increased risk of myocardial infarction related to dabigatran (or in general to directed thrombin inhibitors) 37 has not been completely clarified and cannot be considered a reason per se to exclude the use of dabigatran in ACS patients. 38 Rivaroxaban was also evaluated in nonatrial fibrillation patients with ACS, 39 randomized to receive rivaroxaban 2.5 mg twice daily or 5 mg twice daily, or placebo, in addition to standard dual antiplatelet therapy. The results of this study showed that rivaroxaban at both regimens reduces the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke at the expense of an increasing risk of major bleeding and intracranial hemorrhage, but not of fatal bleeding. However, the doses of the drug tested in this trial were much lower than those used in atrial fibrillation patients, so this result does not provide guidance for the use of rivaroxaban in atrial fibrillation patients who also experienced an ACS. 39 On the contrary, after ACS, dual antiplatelet therapy on top of apixaban at a dose proven to be protective in atrial fibrillation significantly increases major and fatal bleeding risk, including intracranial hemorrhage, without any clear evidence of reduction in ischemic events, including stroke. 40 As mentioned above, in the clinical scenario of atrial fibrillation patients with stable coronary disease, there is evidence that NOACs may be safe and effective alternatives to VKAs. Table 7 Focus on gastrointestinal bleeding events (novel oral anticoagulants versus warfarin) 16,18,19,21 Drug GIB events NOAC (%/year) GIB events warfarin (%/year) RR (95% CI) GIB NOAC/W Dabigatran 110 mg , P ¼ 0.43 Dabigatran 150 mg , Rivaroxaban 20 mg , Apixaban 5 mg , P ¼ 0.33 Edoxaban 30 mg , Edoxaban 60 mg , P ¼ 0.03 CI, confidence interval; GIB, gastrointestinal bleeding; NOAC, novel oral anticoagulant.

7 Novel oral anticoagulants in atrial fibrillation Prisco et al. 7 Table 8 A possible guide for the choice of the best novel oral anticoagulant Clinical situation High risk of bleeding (HAS-BLED 3) Previous GIB or dyspepsia High risk of ischemic stroke Previous stroke or TIA Stable coronary artery disease (previous myocardial infarction) Renal impairment Elderly (>75 years) Polypharmacy/compliance Best NOAC Dabigatran 110 mg Apixaban Apixaban Dabigatran 150 mg Dabigatran Apixaban Rivaroxaban Apixaban Rivaroxaban Apixaban (2.5 mg if two of the following: age 80 years, weight 60 kg, creatinine 1.5 mg/dl) Dabigatran 110 mg Apixaban (2.5 mg if two of the following: age 80 years, weight 60kg, creatinine 1.5mg/dl) Rivaroxaban Rivaroxaban Modified from Savelieva and Camm. 42 CI, confidence interval; GIB, gastrointestinal bleeding; NOAC, novel oral anticoagulant. In general, no preference is given to any of the NOACs. If dabigatran is chosen, a lower dose (110 mg twice daily) and low-dose aspirin (or clopidogrel in case of allergy to aspirin) might be an option, especially in patients with high atherothrombotic risk and low bleeding risk. 15 In atrial fibrillation patients suffering an ischemic stroke while taking a different anticoagulant, dabigatran 150 mg twice daily should be preferred among the other NOACs because this is the only regimen which has demonstrated a significantly superior efficacy compared with warfarin in preventing ischemic stroke. 16,41 On the contrary, for secondary stroke prevention, rivaroxaban and apixaban may also be considered. 15 Considering all these aspects, Table 8 shows a possible guide for the choice of the best NOAC in different clinical situations. 42 According to our own experience, although limited by the fact that the three novel anticoagulant drugs (dabigatran, rivaroxaban, and apixaban) have become available in Italy for only a relatively brief period, a careful selection of patients, based on clinical judgment, and planning an appropriate and personalized follow-up are crucial to prevent serious complications. This approach may be much more important than the choice of a specific drug. Anyway, we believe that apixaban, due to some characteristics (lowest renal clearance, no relevant gastrointestinal side effects, less major bleeding), may be an attractive choice for some atrial fibrillation patients with such problems. Currently, several postmarketing registries such as global registry on long-term oral antithrombotic treatment in patients with atrial fibrillation ( and Global Anticoagulant Registry in the FIELD (GAR- FIELD) 43 are underway with the purpose of collecting data on the outcome of real-world patients. A first report of GARFIELD has shown an increasing number of atrial fibrillation patients on antithrombotic agents in comparison with surveys of previous years, even if there are still many patients on aspirin or without any antithrombotic. 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