Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: NICE guidance 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Cost-effectiveness of apixaban versus other new oral anticoagulants for stroke prevention in atrial fibrillation. Does left atrial appendage closure with a cardiac plug system reduce the stroke risk in nonvalvular atrial fibrillation patients? A single-center case series. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Evaluation of the safety and efficacy of an edoxaban‐based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST‐AF PCI trial Comparative Efficacy and Safety of New Oral Anticoagulants in Patients With Atrial Fibrillation Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Probing oral anticoagulation in patients with atrial high rate episodes: Rationale and design of the Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH–AFNET 6) trial A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial Prevalence of intracardiac thrombi under phenprocoumon, direct oral anticoagulants (dabigatran and rivaroxaban), and bridging therapy in patients with atrial fibrillation and flutter. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). Incidence of left atrial abnormalities under treatment with dabigatran, rivaroxaban, and vitamin K antagonists Cost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillation Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. Efficacy and safety of percutaneous left atrial appendage closure to prevent thromboembolic events in atrial fibrillation patients with high stroke and bleeding risk Dual antiplatelet therapy versus oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation and low-to-moderate thromboembolic risk undergoing coronary stenting: design of the MUSICA-2 randomized trial. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial Left atrial thrombus resolution in atrial fibrillation or flutter: Results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF). Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation†. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists Rationale and design of the RE-LATED AF—AFNET 7 trial: REsolution of Left atrial-Appendage Thrombus—Effects of Dabigatran in patients with Atrial Fibrillation Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation (APACHE-AF): study protocol for a randomised controlled trial Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Stroke event rates in anticoagulated patients with paroxysmal atrial fibrillation.
Atrial fibrillation ( AF ) is the commonest sustained cardiac arrhythmia , whose importance has been realised given its strong association with stroke and systemic embolism that can be significantly reduced by oral anticoagulation . Until recently , the only oral anticoagulant ( OAC ) available was the vitamin K antagonist ( VKA ) class of drugs — for example , warfarin . Indeed , warfarin provides highly effective prophylaxis against thromboembolism as shown by extensive evidence from r and omised controlled trials , but its effectiveness is dependent upon good anticoagulation control ( as reflected by its high length of time in the therapeutic range).1 The risk of stroke in AF is not homogeneous , and depends upon the presence or absence of several risk factors . These risk factors have been used to formulate stroke risk stratification schemes , so that the focus has been to identify ‘ high-risk ’ patients who could be targeted for this ‘ inconvenient ’ drug , warfarin . The numerous practical limitations which affect a clinician 's willingness to prescribe warfarin , and a patient 's willingness to comply with it ( box 1 ) , have result ed in large numbers of high-risk patients either unprotected against stroke or suboptimally protected with antiplatelet therapy2—despite evidence that aspirin is less effective for stroke prevention and is not without its own bleeding risk , especially in the elderly.3 Box 1 # # # Limitations of warfarin The limitations of warfarin have driven efforts to establish new OACs which can circumvent the shortcomings of the VKAs . The new OACs fall into two classes : the oral direct thrombin inhibitors ( eg , dabigatran ) and the oral factor Xa inhibitors ( eg . rivaroxaban , apixaban).4 The National Institute for Health ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American – Australian – African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association AND ROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor blocker ARISTOTLE : Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation ATHENA : A placebo-controlled , double-blind , parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d . for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter ATRIA : AnTicoagulation and Risk factors In Atrial fibrillation AVERROES : Apixaban VErsus acetylsalicylic acid ( ASA ) to Reduce the Rate Of Embolic Stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment AVRO : A prospect i ve , r and omized , double-blind , Active-controlled , superiority study of Vernakalant vs. amiodarone in Recent Onset atrial fibrillation b.i.d : bis in die ( twice daily ) b.p.m . : beats per minute CABANA : Catheter ABlation vs . ANtiarrhythmic drug therapy for Atrial fibrillation CABG : coronary artery bypass graft CAP : Continued Access to Protect AF CHA2DS2-VASc : Congestive heart failure or left ventricular dysfunction Hypertension , Age ≥75 ( doubled ) , Diabetes , Stroke (doubled)-Vascular disease , Age 65–74 , Sex category ( female ) CHADS2 : Congestive heart failure , Hypertension , Age ≥75 , Diabetes , Stroke ( doubled ) CI : confidence interval CRAFT : Controlled R and omized Atrial Fibrillation Trial CrCl : creatinine clearance DAFNE : Dronedarone Atrial FibrillatioN study after Electrical cardioversion DIONYSOS : R and omized Double blind trIal to evaluate efficacy and safety of drOnedarone ( 400 mg b.i.d . ) vs . amiodaroNe ( 600 mg q.d . for 28 daYS , then 200 mg qd thereafter ) for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation EAST : Early treatment of Atrial fibrillation for Stroke prevention Trial EHRA : European Heart Rhythm Association ECG : electrocardiogram EMA : European Medicines Agency ERATO : Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation EURIDIS : EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm FAST : atrial Fibrillation catheter Ablation vs . Surgical ablation Treatment FDA : Food and Drug Administration Flec-SL : Flecainide Short-Long trial HAS-BLED : Hypertension , Abnormal renal/liver function , Stroke , Bleeding history or predisposition , Labile INR , Elderly , Drugs/alcohol concomitantly HF-PEF : heart failure with preserved ejection fraction HF-REF : heart failure with reduced ejection fraction HR : hazard ratio HRS : Heart Rhythm Society ICH : intracranial haemorrhage INR : international normalized ratio i.v . : intravenous J-RHYTHM : Japanese RHYTHM management trial for atrial fibrillation LAA : left atrial appendage LoE : level of evidence LVEF : left ventricular ejection fraction MANTRA-PAF : Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation NICE : National Institute for Health and Clinical Excellence NOAC : novel oral anticoagulant NSAID : non-steroidal anti-inflammatory drug NYHA : New York Heart Association OAC : oral anticoagulant or oral anticoagulation o.d . : omni die ( every day ) PALLAS : Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of st and ard therapy PCI : percutaneous coronary intervention PREVAIL : Prospect i ve R and omized EVAluation of the LAA closure device In patients with atrial fibrillation v s. Long-term warfarin therapy PROTECT AF : WATCHMAN LAA system for embolic PROTECTion in patients with Atrial Fibrillation PT : prothrombin time RAAFT : Radio frequency Ablation Atrial Fibrillation Trial RE-LY : R and omized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate 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 RRR : relative risk reduction TE : thromboembolism TIA : transient ischaemic attack t.i.d . : ter in die ( three times daily ) TOE : transoesophageal echocardiogram TTR : time in therapeutic range VKA : vitamin K antagonist Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition , taking into account the impact on BACKGROUND Apixaban ( 5 mg BID ) , dabigatran ( available as 150 mg and 110 mg BID in Europe ) , and rivaroxaban ( 20 mg once daily ) are 3 novel oral anticoagulants ( NOACs ) currently approved for stroke prevention in patients with atrial fibrillation ( AF ) . OBJECTIVE The objective of this study was to evaluate the cost-effectiveness of apixaban against other NOACs from the perspective of the United Kingdom National Health Services . METHODS A Markov model was developed to evaluate the pharmacoeconomic impact of apixaban versus other NOACs over a lifetime . Pair-wise indirect treatment comparisons were conducted against other NOACs by using ARISTOTLE ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ) , RE-LY ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) , and 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 ) trial results for the following end points : ischemic stroke , hemorrhagic stroke , intracranial hemorrhage , other major bleeds , clinical ly relevant nonmajor bleeds , myocardial infa rct ion , and treatment discontinuations . Outcomes were life-years , quality -adjusted life years gained , direct health care costs , and incremental cost-effectiveness ratios . RESULTS Apixaban was projected to increase life expectancy versus other NOACs , including dabigatran ( both doses ) and rivaroxaban . A small increase in therapeutic management costs was observed with apixaban due to projected gains in life expectancy and lower discontinuation rates anticipated on apixaban versus other NOACs through lifetime . The estimated incremental cost-effectiveness ratio was £ 9611 , £ 4497 , and £ 5305 per quality -adjusted life-year gained with apixaban compared with dabigatran 150 mg BID , dabigatran 110 mg BID , and rivaroxaban 20 mg once daily , respectively . Sensitivity analyses indicated that results were robust over a wide range of inputs . CONCLUSIONS Although our analysis was limited by the absence of head-to-head trials , based on the indirect comparison data available , our model projects that apixaban may be a cost-effective alternative to dabigatran 150 mg BID , dabigatran 110 mg BID , and rivaroxaban 20 mg once daily for stroke prevention in AF patients from the perspective of the United Kingdom National Health Services BACKGROUND Atrial fibrillation ( AF ) is the most common sustained cardiac arrhythmia and it is associated with an increased stroke risk , due mainly to cardiac embolism from the left atrial appendage ( LAA ) . Percutaneous LAA closure is a method to reduce stroke risk in AF without using anticoagulant agents . In this study we report data from an Italian experience with the LAA occluder Amplatzer Cardiac Plug ( ACP ) device ( Aga Medical Corporation , Plymouth , MN , USA ) . METHODS The study was design ed to evaluate the safety of LAA closure using ACP and the efficacy of the procedure in preventing strokes during a 1-year follow-up . Patients with permanent or paroxysmal AF , high stroke risk , and contraindication to warfarin therapy were selected for the procedure . RESULTS The LAA closure was attempted in 37 patients and succeeded in 34 cases ( 91.9 % ) . Four patients experienced serious complications ( one cardiac tamponade requiring pericardiocentesis , two device embolizations , one low-rate response AF requiring artificial pacing ) . During a 1-year follow-up , ischemic stroke occurred in one of 34 patients , result ing in a stroke rate of 2.94 % ; thus there was a stroke rate reduction of 50.2 % and 26.5 % compared to the expected stroke rate , according to CHADS2 and CHA2 DS2 VASc score . None of the patients who received ACP experienced major bleeding during the follow-up . CONCLUSION LAA closure using ACP is a relatively feasible procedure which can be performed by highly experienced operators to reduce stroke rate in patients with AF , high stroke risk , and contraindication to oral anticoagulants The Canadian Cardiovascular Society ( CCS ) published the complete set of 2010 Atrial Fibrillation ( AF ) Guidelines in the January , 2011 issue of the Canadian Journal of Cardiology . During its deliberations , the CCS Guidelines Committee engaged to a timely review of future evidence , with periodic composition of focused up date s to address clinical ly important advances . In 2011 , results were published from 3 pivotal AF trials : the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ( ROCKET-AF ) , the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ( ARISTOTLE ) study , and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of St and ard Therapy ( PALLAS ) , comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease risk-factor burden . Each of these large r and omized trials provided clear results with major implication s for AF management . Other important evidence that has emerged since the 2010 Guidelines includes findings about prediction instruments for AF-associated stroke and bleeding risk , stroke risk in paroxysmal-AF patients , risk-benefit considerations related to oral anticoagulation in patients with chronic kidney disease , and risk/benefit considerations in the use of antiplatelet agents , alone and in combination with each other or with oral anticoagulants , in AF patients . The Guidelines Committee judged that this extensive and important new evidence required focused updating of the 2010 Guidelines with respect to stroke prevention and rate/rhythm control . This report presents the details of the new recommendations , along with the background and rationale Background The optimal antithrombotic treatment after percutaneous coronary intervention ( PCI ) with stenting in patients with atrial fibrillation ( AF ) is unknown . In the ENGAGE AF‐TIMI 48 trial , edoxaban was noninferior to a vitamin K antagonist ( VKA ) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF . The effects of edoxaban in combination with single‐ or dual‐antiplatelet therapy in the setting of PCI are unexplored . Design The ENTRUST‐AF PCI trial is a multinational , multicenter , r and omized , open‐label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF . Patients are r and omized between 4 hours and 5 days after successful PCI to either an edoxaban‐based strategy ( experimental arm ; 60 mg [ or 30 mg according to dose reduction criteria ] once daily plus a P2Y12 antagonist [ default clopidogrel , 75 mg once daily ] for 12 months ) or a VKA‐based strategy ( control arm ; VKA plus a P2Y12 antagonist [ as above ] plus acetylsalicylic acid [ 100 mg once daily ] for 30 days to 12 months ) . The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis – defined major or clinical ly relevant nonmajor bleeding . The main efficacy end point is the composite of cardiovascular death , stroke , systemic embolic events , spontaneous myocardial infa rct ion , and definite stent thrombosis . Summary The ENTRUST‐AF PCI trial tests the hypothesis that an edoxaban‐based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual‐antiplatelet therapy in patients with AF in need of oral anticoagulation . The relative risk of ischemic events between groups will be compared Background — Dabigatran , an oral thrombin inhibitor , and rivaroxaban and apixaban , oral factor Xa inhibitors , have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation . We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled r and omized trials , using the method of adjusted indirect comparisons . Methods and Results — We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran  ( R and omized Evaluation of Long-Term Anticoagulation Therapy [ RELY ] ) , apixaban ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ ARISTOTLE ] ) , and rivaroxaban ( 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 ] ) , each compared with warfarin . The primary efficacy end point was stroke or systemic embolism ; the safety end point we studied was major hemorrhage . To address a lack of comparability between trial population s caused by the restriction of ROCKET-AF to high-risk patients , we conducted a subgroup analysis in patients with a CHADS2 score ≥3 . We found no statistically significant efficacy differences among the 3 drugs , although apixaban and dabigatran were numerically superior to rivaroxaban . Apixaban produced significantly fewer major hemorrhages than dabigatran and rivaroxaban . Conclusions — An indirect comparison of new anticoagulants based on existing trial data indicates that in patients with a CHADS2 score ≥3  dabigatran 150 mg , apixaban 5 mg , and rivaroxaban 20 mg result ed in statistically similar rates of stroke and systemic embolism , but apixaban had a lower risk of major hemorrhage compared with dabigatran and rivaroxaban . Until head-to-head trials or large-scale observational studies that reflect routine use of these agents are available , such adjusted indirect comparisons based on trial data are one tool to guide initial therapeutic choices BACKGROUND Vitamin K antagonists have been the st and ard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism . Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments . Edoxaban is a selective and direct factor Xa inhibitor that may provide effective , safe , and more convenient anticoagulation . STUDY DESIGN ENGAGE AF-TIMI 48 is a phase 3 , r and omized , double-blind , double-dummy , multinational , noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin .  Approximately 20,500 subjects will be r and omized to edoxaban high exposure ( 60 mg daily , adjusted for drug clearance ) , edoxaban low exposure ( 30 mg daily , adjusted for drug clearance ) , or warfarin titrated to an international normalized ratio of 2.0 to 3.0 . The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure . Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban . Eligibility criteria include electrical documentation of atrial fibrillation ≤12 months and a CHADS(2 ) score ≥2 . R and omization is stratified by CHADS(2 ) score and anticipated drug exposure . The primary objective is to determine  whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism . The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding . Recruitment began in November 2008 . The expected median follow-up is 24 months . CONCLUSIONS ENGAGE AF-TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation Background Oral anticoagulation prevents ischemic strokes in patients with atrial fibrillation ( AF ) . Early detection of AF and subsequent initiation of oral anticoagulation help to prevent strokes in AF patients . Implanted cardiac pacemakers and defibrillators allow seamless detection of atrial high rate episodes ( AHRE ) , but the best antithrombotic therapy in patients with AHRE is not known . Rationale Stroke risk is higher in pacemaker patients with AHRE than in those without , but the available data also show that stroke risk in patients with AHRE is lower than in patients with AF . Furthermore , only a minority of patients with AHRE will develop AF , many strokes occur without a temporal relation to AHRE , and AHRE can reflect other arrhythmias than AF or artifacts . An adequately powered controlled trial of oral anticoagulation in patients with AHRE is needed . Design The Non – vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes ( NOAH – AFNET 6 ) trial tests whether oral anticoagulation with edoxaban is superior to prevent the primary efficacy outcome of stroke or cardiovascular death compared with aspirin or no antithrombotic therapy based on evidence ‐based indications . The primary safety outcome will be major bleeding . NOAH – AFNET 6 will r and omize 3,400 patients with AHRE , but without documented AF , aged ≥65 years with at least 1 other stroke risk factor , to oral anticoagulation therapy ( edoxaban ) or no anticoagulation . All patients will be followed until the end of this investigator‐driven , prospect i ve , parallel‐group , r and omized , event‐driven , double‐blind , multicenter phase IIIb trial . Patients will be censored when they develop AF and offered open‐label anticoagulation . The sponsor is the Atrial Fibrillation NETwork ( AFNET ) . The trial is supported by the DZHK ( German Centre for Cardiovascular Research ) , the BMBF ( German Ministry of Education and Research ) , and Daiichi Sankyo Europe . Conclusion NOAH – AFNET 6 will provide robust information on the effect of oral anticoagulation in patients with atrial high rate episodes detected by implanted devices . Graphical abstract Figure . No Caption available Aims The choice between initiating a non-vitamin K antagonist oral anticoagulant ( NOAC ) and a vitamin K antagonist ( VKA ) in patients with atrial fibrillation ( AF ) may be challenging . To assist in this decision , we developed a risk score to identify patients for whom a therapeutic benefit of NOACs over VKA is predicted . Methods and results ENGAGE AF-TIMI 48 was a r and omized clinical trial of edoxaban vs. warfarin in 21 105 patients with AF . Cox proportional hazard models identified factors associated with a serious net clinical outcome ( NCO ) of disabling stroke , life-threatening bleeding , and all-cause mortality in VKA naïve patients from the warfarin arm . These were used to develop an integer risk score . Performance was assessed by C-indices and validation by bootstrapping . Kaplan-Meier analyses were stratified by three score categories and treatment arm . Over a median of 2.7 years , 457  NCO events occurred in 2898 patients with a total person-time of 7549.5 years ( 6.05%/year ) . The risk prediction model ( C = 0.693 ) for the NCO was translated into a 17-point integer score , with annualized event rates for the low , intermediate , and high-risk categories in the warfarin arm of 3.5 % , 9.9 % , and 20.8 % , respectively . Therapeutic benefit of higher- and lower-dose edoxaban over warfarin was demonstrated in the high- and intermediate-risk , with equal benefit in the low-risk categories ( P-interaction 0.008 and 0.014 , respectively ) . Conclusion In VKA naive patients with AF , the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA Direct oral anticoagulants ( DOACs ) are effective for stroke prevention in nonvalvular atrial fibrillation ( AF ) .  Cardioversion ( CV ) is frequently performed in patients with AF or flutter . To further explore the safety profile of DOACs in the context of CV , we sought to assess the prevalence of intracardiac thrombi under DOAC therapy in comparison with treatment with vitamin K antagonists . A total of 672 transesophageal echocardiograms performed in 643 patients with a history of nonvalvular AF were analyzed .  The median CHA2DS2-VASc score was 4 . Cases were stratified according to anticoagulation with dabigatran ( n = 79 ) , rivaroxaban ( n = 122 ) , phenprocoumon ( n = 180 ) , or bridging therapy ( n = 287 ) . In a subgroup analysis , only patients receiving phenprocoumon with an international normalized ratio ≥2 on the day of the investigation or on DOAC therapy for ≥3 weeks were considered . The prevalence of intracardiac thrombi  under phenprocoumon was significantly higher than under DOACs ( phenprocoumon , 17.8 % ; all DOACs , 3.9 % ; dabigatran , 3.8 % ; rivaroxaban , 4.1 % ) and showed no significant difference to bridging therapy ( 12.5 % ) . In patients with sufficient short-term anticoagulation , similar differences between DOAC and phenprocoumon groups were observed ( phenprocoumon , 18.4 % ; all DOACs , 3.8 % ; dabigatran , 0 % ; rivaroxaban , 6.6 % ) . The influence of anticoagulation medication on thrombus rates was confirmed after adjusting for baseline intergroup differences regarding left atrial size and CHA2DS2-VASc score . In conclusion , the prevalence of intracardiac thrombi was lower under DOAC therapy than under phenprocoumon in this high-risk patient cohort . Safety of CV during DOAC treatment requires further prospect i ve evaluation OBJECTIVES The purpose of this study was to assess the safety and efficacy of left atrial appendage ( LAA ) closure in nonvalvular atrial fibrillation ( AF ) patients ineligible for warfarin therapy . BACKGROUND The PROTECT AF ( Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation ) trial demonstrated that LAA closure with the Watchman device ( Boston Scientific , Natick , Massachusetts ) was noninferior to warfarin therapy . However , the PROTECT AF trial only included patients who were c and i date s for warfarin , and even patients r and omly assigned to the LAA closure arm received concomitant warfarin  for 6 weeks after Watchman implantation . METHODS A multicenter , prospect i ve , nonr and omized study was conducted of LAA closure with the Watchman device in 150 patients with nonvalvular AF and CHADS₂ ( congestive heart failure , hypertension , age ≥75 years , diabetes mellitus , and prior stroke or transient ischemic attack ) score ≥1 , who were considered ineligible for warfarin . The primary efficacy endpoint was the combined events of ischemic stroke , hemorrhagic stroke , systemic embolism , and cardiovascular/unexplained death . RESULTS The mean CHADS₂ score and CHA₂DS₂-VASc ( CHADS₂ score plus 2 points for age ≥75 years and 1 point for vascular disease , age 65 to 74 years , or female sex ) score were 2.8 ± 1.2 and 4.4 ± 1.7 , respectively . History of hemorrhagic/bleeding tendencies ( 93 % ) was the most common reason for warfarin in eligibility . Mean duration of follow-up was 14.4 ± 8.6 months . Serious procedure- or device-related safety events occurred in 8.7 % of patients ( 13 of 150 patients ) . All-cause stroke or systemic embolism occurred in 4 patients ( 2.3 % per year ) : ischemic stroke in 3 patients ( 1.7 % per year ) and hemorrhagic stroke in 1 patient ( 0.6 % per year ) . This ischemic stroke rate was less than that expected ( 7.3 % per year ) based on the CHADS₂ scores of the patient cohort . CONCLUSIONS LAA closure with the Watchman device can be safely performed without a warfarin transition , and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation . ( ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology [ ASAP ] ; NCT00851578 ) Background Non-vitamin K antagonist oral anticoagulants ( NOACs ) such as dabigatran or rivaroxaban are alternatives to vitamin K antagonists ( VKAs ) for prevention of stroke and systemic embolism in patients with atrial fibrillation ( AF ) and atrial flutter ( AFL ) . Incidences of risk factors for left atrium ( LA ) and left atrial appendage ( LAA ) thrombus formation , such as dense spontaneous echo contrast ( SEC ) , low LAA velocity ( LAAV ) < 20 cm/s under treatment with dabigatran and rivaroxaban in comparison with VKAs are unknown . Methods We studied 306 patients with AF ( 94 % ) and AFL ( 6 % ) undergoing transesophageal echocardiography .  Patients received VKAs ( n = 138 ) , dabigatran ( n = 68 ) , or rivaroxaban ( n = 100 ) for at least 3 weeks prior to investigation . Time in therapeutic range was 67 % for VKA . Mean CHADS2 score and CHA2DS2-VASc score were 1.3 and 2.5 , respectively . Left atrial abnormality was defined as either dense SEC , low LAAV < 20 cm/s , or thrombus . Results Any LA abnormality occurred in 9 , 3 , and 5 % of patients receiving VKA , dabigatran , and rivaroxaban , respectively . The most frequent abnormality was LAA thrombus ( VKA : 4 % , dabigatran : 0 % , rivaroxaban : 2 % ) and low LAAV of less than 20 cm/s ( VKA : 4 % , dabigatran : 1 % , rivaroxaban : 1 % ) , followed by dense SEC ( VKA : 2 % , dabigatran : 1 % , rivaroxaban : 2 % ) . Results of uni- and multivariate analyses revealed a numerically lower but not significantly different frequency of any LA abnormality under dabigatran ( OR 0.4 , 95 % Cl 0.08 − 1.88 , p = 0.25 ) and rivaroxaban ( OR 0.65 , 95 % Cl 0.22 − 1.98 , p = 0.45 ) compared to VKA . Conclusion With respect to the incidence of LA abnormalities , dabigatran and rivaroxaban are not inferior to VKA Aims Warfarin , a vitamin K antagonist ( VKA ) , has been the st and ard of care for stroke prevention in patients with atrial fibrillation ( AF ) .  Aspirin is recommended for low-risk patients and those unsuitable for warfarin . Apixaban is an oral anticoagulant that has demonstrated better efficacy than warfarin and aspirin in the ARISTOTLE and AVERROES studies , respectively , and causes less bleeding than warfarin . We evaluated the potential cost-effectiveness of apixaban against warfarin and aspirin from the perspective of the UK payer perspective . Results and methods A lifetime Markov model was developed to evaluate the pharmacoeconomic impact of apixaban compared with warfarin and aspirin in VKA suitable and VKA unsuitable patients , respectively . Clinical events considered in the model include ischaemic stroke , haemorrhagic stroke , intracranial haemorrhage , other major bleed , clinical ly relevant non-major bleed , myocardial infa rct ion , cardiovascular hospitalization and treatment discontinuations ; data from the ARISTOTLE and AVERROES trials and published mortality rates and event-related utility rates were used in the model . Apixaban was projected to increase life expectancy and quality -adjusted life years ( QALYs ) compared with warfarin and aspirin . These gains were expected to be achieved at a drug acquisition-related cost increase over lifetime . The estimated incremental cost-effectiveness ratio was £ 11 909 and £ 7196 per QALY gained with apixaban compared with warfarin and aspirin , respectively . Sensitivity analyses indicated that results were robust to a wide range of inputs . Conclusions Based on r and omized trial data , apixaban is a cost-effective alternative to warfarin and aspirin , in VKA suitable and VKA unsuitable patients with AF , respectively BACKGROUND At the end of 2 previous trials , an excess of stroke and bleeding was observed in patients with AF r and omized to a new oral anticoagulant ( NOAC ) who transitioned to a vitamin K antagonist ( VKA ) .  OBJECTIVES The ENGAGE AF-TIMI 48 ( Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infa rct ion 48 ) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF . An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period . METHODS All patients on the blinded study drug at the trial 's conclusion were included in this analysis . In pre-specified analyses , stroke , bleeding , and death that occurred through 30 days after the end-of-trial visit were stratified by r and omized treatment allocation and open-label anticoagulant selected post-trial . RESULTS Of the 13,642 patients taking the blinded study drug at the end of the trial , 9,304 ( 68.2 % ) were transitioned to open-label VKA and 4,258 patients ( 31.2 % ) to an NOAC . There were 21 strokes evenly distributed across the 3 r and omized treatment arms : warfarin 7 ( 1.90%/year ) , edoxaban high dose 7 ( 1.89%/year ) , edoxaban low dose 7 ( 1.85%/year ) . Major bleeding was also similar across the 3 treatment arms : warfarin 11 ( 2.98%/year ) , edoxaban high dose 10 ( 2.69%/year ) , edoxaban low dose 18 ( 4.76%/year ) . In patients transitioned to VKA , 85 % of patients had at least 1 INR ≥ 2 by day 14 after the transition and 99 % by day 30 . CONCLUSIONS The ENGAGE AF-TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants . ( Global Study to Assess the Safety and Effectiveness of Edoxaban [ DU-176b ] vs St and ard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ EngageAFTIMI48 ] ; NCT00781391 ) Aims The r and omized PROTECT AF trial demonstrated non-inferiority of left atrial appendage ( LAA ) closure to oral anticoagulation with warfarin . Current guidelines give a class IIb recommendation for LAA closure . We evaluated the efficacy and safety of LAA closure in a consecutive series of non-valvular atrial fibrillation patients with contraindications to long-term oral anticoagulation or at high bleeding risk . Methods and results 101 consecutive non-valvular atrial fibrillation patients ( age 74.7 ± 7.5 years ) at high risk for stroke ( CHA2DS2-VASc Score 4.4 ± 1.6 ) and high bleeding risk ( HAS-BLED Score 4.2 ± 1.3 ) received LAA closure with either the Watchman closure device ( n = 38 ) or the Amplatzer cardiac plug ( n = 63 ) . Dual antiplatelet therapy with aspirin and clopidogrel was recommended for 3–6 months after device implantation , followed by long-term antiplatelet therapy with aspirin . No anticoagulation was given after device implantation . Mean follow-up was 400 days . One patient ( 1 % ) experienced a transient ischemic attack , and two patients ( 2 % ) suffered from ischemic stroke . While on recommended antiplatelet therapy , bleeding occurred in 12/101 patients ( 12 % ) . Bleeding was significantly reduced with 3 compared with 6 months dual antiplatelet therapy ( 3.0 vs. 16.2 % , p < 0.05 ) while ischemic or thrombotic events were similar . Conclusion Left atrial appendage closure in patients with non-valvular atrial fibrillation and high risk for stroke and bleeding events effectively prevented stroke and reduced cerebral ischemic events compared to expected stroke rate according to CHA2DS2-VASc Score . Dual antiplatelet therapy for 3 months reduced the rate of bleeding events compared to 6 months therapy with no increase of thrombotic events BACKGROUND Oral anticoagulation ( OAC ) is the recommended therapy for patients with atrial fibrillation ( AF ) because it reduces the risk of stroke and other thromboembolic events . Dual antiplatelet therapy ( DAPT ) is required after percutaneous coronary intervention and stenting ( PCI-S ) . In patients with AF requiring PCI-S  , the association of DAPT and OAC carries an increased risk of bleeding , whereas OAC therapy or DAPT alone may not protect against the risk of developing new ischemic or thromboembolic events . OBJECTIVE The MUSICA-2 study will test the hypothesis that DAPT compared with triple therapy ( TT ) in patients with nonvalvular AF at low-to-moderate risk of stroke ( CHADS2 score ≤2 ) after PCI-S reduces the risk of bleeding and is not inferior to TT for preventing thromboembolic complications . DESIGN The MUSICA-2 is a multicenter , open-label r and omized trial that will compare TT with DAPT in patients with AF and CHADS2 score ≤2 undergoing PCI-S.  The primary end point is the incidence of stroke or any systemic embolism or major adverse cardiac events : death , myocardial infa rct ion , stent thrombosis , or target vessel revascularization at 1 year of PCI-S. The secondary end point is the combination of any cardiovascular event with major or minor bleeding at 1 year of PCI-S. The calculated sample size is 304 patients . CONCLUSIONS The MUSICA-2 will attempt to determine the most effective and safe treatment in patients with nonvalvular AF and CHADS2 score ≤2 after PCI-S. Restricting TT for AF patients at high risk for stroke may reduce the incidence of bleeding without increasing the risk of thromboembolic complications Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation ( AF ) . We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation . Methods and results Patients r and omized 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 ) trial ( n = 14 264 ) were grouped by baseline AF category : paroxysmal or persistent . Multivariable adjustment was performed to compare thrombo-embolic events , bleeding , and death between groups , in high-risk subgroups , and across treatment assignment ( rivaroxaban or warfarin ) . Of 14 062 patients , 11 548 ( 82 % ) had persistent AF and 2514 ( 18 % ) had paroxysmal AF . Patients with persistent AF were marginally older ( 73 vs. 72 , P = 0.03 ) , less likely female ( 39 vs. 45 % , P < 0.0001 ) , and more likely to have previously used vitamin K antagonists ( 64 vs. 56 % , P < 0.0001 ) compared with patients with paroxysmal AF . In patients r and omized to warfarin , time in therapeutic range was similar ( 58 vs. 57 % , P = 0.94 ) . Patients with persistent AF had higher adjusted rates of stroke or systemic embolism ( 2.18 vs. 1.73 events per 100-patient-years , P = 0.048 ) and all-cause mortality ( 4.78 vs. 3.52 , P = 0.006 ) . Rates of major bleeding were similar ( 3.55 vs. 3.31 , P = 0.77 ) . Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment ( rivaroxaban vs. warfarin , Pinteraction = 0.6 ) . Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation , those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF BACKGROUND Data on left atrial/left atrial appendage ( LA/LAA ) thrombus resolution after non-vitamin K antagonist ( VKA ) oral anticoagulant treatment are scarce . The primary objective of X-TRA was to explore the use of rivaroxaban for the resolution of LA/LAA thrombi in patients with nonvalvular atrial fibrillation ( AF ) or atrial flutter , with the CLOT-AF registry providing retrospective data after st and ard-of-care therapy in this setting . METHODS X-TRA was a prospect i ve , single-arm , open-label , multicenter study that investigated rivaroxaban treatment for 6 weeks for LA/LAA thrombus resolution in patients with nonvalvular AF or atrial flutter and LA/LAA thrombus confirmed at baseline on a transesophageal echocardiogram ( TEE ) .  CLOT-AF retrospectively collected thrombus-related patient outcome data after st and ard-of-care anticoagulant treatment for 3 to 12 weeks in patients with nonvalvular AF or atrial flutter who had LA/LAA thrombi on TEE recorded in their medical file . RESULTS In X-TRA , patients were predominantly ( 95.0 % ) from Eastern European countries . The adjudicated thrombus resolution rate was 41.5 % ( 22/53 modified intention-to-treat [ mITT ] patients , 95 % CI 28.1%-55.9 % ) based on central TEE assessment s. Resolved or reduced thrombus was evident in 60.4 % ( 32/53 mITT patients , 95 % CI 46.0%-73.6 % ) of patients . In CLOT-AF , the reported thrombus resolution rate was 62.5 % ( 60/96 mITT patients , 95 % CI 52.0%-72.2 % ) and appeared better in Western European countries ( 34/50 ; 68.0 % ) than in Eastern European countries ( 26/46 ; 56.5 % ) . CONCLUSION X-TRA is the first prospect i ve , multicenter study examining LA/LAA thrombus resolution with a non-VKA oral anticoagulant in VKA-naïve patients or in patients with suboptimal VKA therapy . Rivaroxaban could be a potential option for the treatment of LA/LAA thrombi AIMS Edoxaban is an oral , once-daily factor Xa inhibitor that is non-inferior to well-managed warfarin in patients with atrial fibrillation ( AF ) for the prevention of stroke and systemic embolic events ( SEEs ) . We examined the efficacy and safety of edoxaban vs. warfarin in patients who were vitamin K antagonist ( VKA ) naive or experienced . METHODS AND RESULTS ENGAGE AF-TIMI 48 r and omized 21 105 patients with AF at moderate-to-high risk of stroke to once-daily edoxaban vs. warfarin .  Subjects were followed for a median of 2.8 years . The primary efficacy endpoint was stroke or SEE . As a pre-specified subgroup , we analysed outcomes for those with or without prior VKA experience ( > 60 consecutive days ) . Higher-dose edoxaban significantly reduced the risk of stroke or SEE in patients who were VKA naive [ hazard ratio ( HR ) 0.71 , 95 % confidence interval ( CI ) 0.56 - 0.90 ] and was similar to warfarin in the VKA experienced ( HR 1.01 , 95 % CI 0.82 - 1.24 ; P interaction = 0.028 ) . Lower-dose edoxaban was similar to warfarin for stroke or SEE prevention in patients who were VKA naive ( HR 0.92 , 95 % CI 0.73 - 1.15 ) , but was inferior to warfarin in those who were VKA experienced ( HR 1.31 , 95 % 1.08 - 1.60 ; P interaction = 0.019 ) . Both higher-dose and lower-dose edoxaban regimens significantly reduced the risk of major bleeding regardless of prior VKA experience ( P interaction = 0.90 and 0.71 , respectively ) . CONCLUSION In patients with AF , edoxaban appeared to demonstrate greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced . Edoxaban significantly reduced major bleeding compared with warfarin regardless of prior VKA exposure Aims Oral anticoagulation with vitamin K antagonists ( VKAs ) for stroke prevention in atrial fibrillation ( AF ) is effective but has significant limitations . AZD0837 , a new oral anticoagulant , is a prodrug converted to a selective and reversible direct thrombin inhibitor ( AR-H067637 ) . We report from a Phase II r and omized , dose-guiding study ( NCT00684307 ) to assess safety , tolerability , pharmacokinetics , and pharmacodynamics of extended-release AZD0837 in patients with AF . Methods and results Atrial fibrillation patients ( n = 955 ) with ≥1 additional risk factor for stroke were r and omized to receive AZD0837 ( 150 , 300 , or 450 mg once daily or 200 mg twice daily ) or VKA ( international normalized ratio 2–3 , target 2.5 ) for 3–9 months . Approximately 30 % of patients were naïve to VKA treatment . Total bleeding events were similar or lower in all AZD0837 groups ( 5.3–14.7 % , mean exposure 138–145 days ) vs. VKA ( 14.5 % , mean exposure 161 days ) , with fewer clinical ly relevant bleeding events on AZD0837 150 and 300 mg once daily . Adverse events were similar between treatment groups ; with AZD0837 , the most common were gastrointestinal disorders ( e.g. diarrhoea , flatulence , or nausea ) . d-Dimer , used as a biomarker of thrombogenesis , decreased in all groups in VKA-naïve subjects with treatment , whereas in VKA pre-treated patients , d-dimer levels started low and remained low in all groups . As expected , only a few strokes or systemic embolic events occurred . In the AZD0837  groups , mean S-creatinine increased by ∼10 % from baseline and returned to baseline following treatment cessation . The frequency of serum alanine aminotransferase ≥3 × upper limit of normal was similar for AZD0837 and VKA . Conclusion AZD0837 was generally well tolerated at all doses tested . AZD0837 treatment at an exposure corresponding to the 300 mg od dose in this study provides similar suppression of thrombogenesis at a potentially lower bleeding risk compared with dose-adjusted VKA . This study is registered with Clinical Trials.gov , number NCT00684307 Background Dabigatran etexilate , a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant ( NOAC ) , has been shown to effectively prevent thromboembolic events in patients with non-valvular atrial fibrillation ( AF ) . However , there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage ( LAA ) thrombi in AF patients . Objective The primary objective of the RE-LATED AF trial is to assess whether dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin K antagonist phenprocoumon . Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate within 6 weeks of treatment and change in LAA thrombus volume under treatment . Furthermore , this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon . Methods The study is design ed as a prospect i ve , r and omized , open-label , controlled , explorative , blinded endpoint ( PROBE ) trial . Patients with AF and left atrial appendage thrombus confirmed by transoesophageal echocardiography ( TEE ) will be r and omized to receive either dabigatran ( 150 mg bid ) or phenprocoumon ( INR 2–3 ) for the resolution of LAA thrombus formation for at least 21 days . Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at weeks 4 and 6 , if the LAA thrombus has not been resolved before . A total of 110 patients are planned to be r and omized . Conclusion This is the first prospect i ve , multicentre , r and omized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF Background There is a marked lack of evidence on the optimal prevention of ischaemic stroke and other thromboembolic events in patients with non-valvular atrial fibrillation and a recent intracerebral haemorrhage during treatment with oral anticoagulation .  These patients are currently treated with oral anticoagulants , antiplatelet drugs , or no antithrombotic treatment , depending on personal and institutional preferences . Compared with warfarin , the direct oral anticoagulant apixaban reduces the risk of stroke or systemic embolism , intracranial haemorrhage , and case fatality in patients with atrial fibrillation . Compared with aspirin , apixaban reduces the risk of stroke or systemic embolism in patients with atrial fibrillation , and has a similar risk of intracerebral haemorrhage . Novel oral anticoagulants have not been evaluated in patients with atrial fibrillation and a recent intracerebral haemorrhage . To inform a phase III trial , the phase II Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation ( APACHE-AF ) trial aims to obtain estimates of the rates of vascular death or non-fatal stroke in patients with atrial fibrillation and a recent anticoagulation-associated intracerebral haemorrhage treated with apixaban and in those in whom oral anticoagulation is avoided . Methods / Design APACHE-AF is a phase II , multicentre , open-label , parallel-group , r and omised clinical trial with masked outcome assessment . One hundred adults with a history of atrial fibrillation and a recent intracerebral haemorrhage during treatment with anticoagulation in whom clinical equipoise exists on the optimal stroke prevention strategy will be enrolled in 14 hospitals in The Netherl and s . These patients will be r and omly assigned in a 1:1 ratio to either apixaban or to avoiding oral anticoagulation . Patients in the control group may be treated with antiplatelet drugs at the discretion of the treating physician . The primary outcome is the composite of vascular death or non-fatal stroke during follow-up . We aim to include 100 patients in 2.5 years . All patients will be followed-up for the duration of the study , but at least for 1 year . Recruitment commenced in September 2014 and is ongoing . This trial is funded by the Dutch Heart Foundation ( 2012 T077 ) and ZonMW (015008048).Trial registration NTR4526 ( 16 April 2014 ) BACKGROUND Warfarin reduces the risk for ischemic stroke in patients with atrial fibrillation ( AF ) but increases the risk for hemorrhage . Dabigatran is a fixed-dose , oral direct thrombin inhibitor with similar or reduced rates of ischemic stroke and intracranial hemorrhage in patients with AF compared with those of warfarin . OBJECTIVE To estimate the quality -adjusted survival , costs , and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular AF . DESIGN Markov decision model . DATA SOURCES The RE-LY ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) trial and other published studies of anticoagulation . The cost of dabigatran was estimated on the basis of pricing in the United Kingdom . TARGET POPULATION Patients aged 65 years or older with nonvalvular AF and risk factors for stroke ( CHADS₂ score ≥1 or equivalent ) and no contraindications to anticoagulation . TIME HORIZON Lifetime . PERSPECTIVE Societal . INTERVENTION Warfarin anticoagulation ( target international normalized ratio , 2.0 to 3.0 ) ; dabigatran , 110 mg twice daily ( low dose ) ; and dabigatran , 150 mg twice daily ( high dose ) . OUTCOME MEASURES Quality -adjusted life-years ( QALYs ) , costs ( in 2008 U.S. dollars ) , and incremental cost-effectiveness ratios . RESULTS OF BASE-CASE ANALYSIS The quality -adjusted life expectancy was 10.28 QALYs with warfarin , 10.70 QALYs with low-dose dabigatran , and 10.84 QALYs with high-dose dabigatran . Total costs were $ 143 193 for warfarin , $ 164 576 for low-dose dabigatran , and $ 168 398 for high-dose dabigatran . The incremental cost-effectiveness ratios  compared with warfarin were $ 51 229 per QALY for low-dose dabigatran and $ 45 372 per QALY for high-dose dabigatran . RESULTS OF SENSITIVITY ANALYSIS The model was sensitive to the cost of dabigatran but was relatively insensitive to other model inputs . The incremental cost-effectiveness ratio increased to $ 50 000 per QALY at a cost of $ 13.70 per day for high-dose dabigatran but remained less than $ 85 000 per QALY over the full range of model inputs evaluated . The cost-effectiveness of high-dose dabigatran improved with increasing risk for stroke and intracranial hemorrhage . LIMITATION Event rates were largely derived from a single r and omized clinical trial and extrapolated to a 35-year time frame from clinical trials with approximately 2-year follow-up . CONCLUSION In patients aged 65 years or older with nonvalvular AF at increased risk for stroke ( CHADS₂ score ≥1 or equivalent ) , dabigatran may be a cost-effective alternative to warfarin depending on pricing in the United States . PRIMARY FUNDING SOURCE American Heart Association and Veterans Affairs Health Services Research & Development Service Atrial fibrillation ( AF ) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists ( VKAs ) . Vitamin K antagonist use is limited , in part , by the high incidence of complications when patients ' international normalized ratios ( INRs ) deviate from the target range . The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor , apixaban , is noninferior to warfarin at reducing the combined endpoint of stroke ( ischemic or hemorrhagic ) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke . We have r and omized 18,206 patients from over 1,000 centers in 40 countries . Patients were r and omly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind , double-dummy design .  International normalized ratios are monitored and warfarin ( or placebo ) is adjusted aim ing for a target INR range of 2 to 3 using a blinded , encrypted point-of-care device . Minimum treatment is 12 months , and maximum expected exposure is 4 years . Time to accrual of at least 448 primary efficacy events will determine treatment duration . The key secondary objectives are to determine if apixaban  is superior to warfarin  for the combined endpoint of stroke ( ischemic or hemorrhagic ) and systemic embolism , and for all-cause death . These will be tested after the primary objective using a closed test procedure . The noninferiority boundary is 1.38 ; apixaban will be declared noninferior if the 95 % CI excludes the possibility that the primary outcome rate with apixaban is > 1.38 times higher than with warfarin . ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism ; whether apixaban has particular benefits in the warfarin-naïve population ; whether it reduces the combined rate of stroke , systemic embolism , and death ; and whether it impacts bleeding AIMS To test the hypothesis that stroke and systemic embolic events ( SEE ) in the stroke prevention using an oral thrombin inhibitor in atrial fibrillation ( SPORTIF ) III and V trials are different between paroxysmal and persistent atrial fibrillation ( AF ) . METHODS Data analysis from two cohorts of patients enrolled in the prospect i ve SPORTIF III and V clinical trials ( n = 7329 ) ; 836 subjects ( 11.4 % ) with paroxysmal AF [ mean age 70.1 years ( SD = 9.5 ) ] were compared with 6493 subjects with persistent AF for this ancillary study . RESULTS The annual event rates for stroke/SEE are 1.73 % for persistent AF and 0.93 % for paroxysmal AF . In a multivariate analysis , after adjusting for stroke risk factors , gender and aspirin usage , the differences remained statistically significant with a higher hazard ratio ( HR ) for stroke/SEE in persistent AF [ vs. paroxysmal AF , HR 1.87 , 95 % confidence interval ( CI ) 1.04 - 3.36 ; P = 0.037 ] . In ' high risk ' patients ( with > or=2 stroke risk factors ) annual event rates for stroke/SEE were 2.08 % for persistent AF and 1.27 % for paroxysmal AF ( adjusted HR = 1.68 , 95 % CI 0.91 - 3.1 , P = 0.098 ) . Elderly patients had annual event rates for stroke/SEE of 2.38 % for persistent AF and 1.13 % for paroxysmal AF ( adjusted HR = 2.27 , 95 % CI 0.92 - 5.59 , P = 0.075 ) . Vitamin K antagonist (VKA)-naive paroxysmal AF patients had a 1.89%/year stroke/SEE rate , compared with 0.61 % for previous VKA takers ( HR = 0.33 , 95 % CI 0.11 - 1.01 , P = 0.052 ) . CONCLUSION In this large clinical trial cohort of anticoagulated AF patients , those with paroxysmal AF had stroke rates which were lower than for patients with persistent AF , although both groups had broadly similar stroke risk factors . Subjects with paroxysmal AF at ' high risk ' had stroke/SEE rates that were not significantly different to persistent AF subjects
Warfarin Versus Thrombin Inhibitor ( Dabigatran ) The RE-LY trial ( 9 , 18 ) showed that treatment with dabigatran , 150 mg , is superior to warfarin in reducing the incidence of the composite outcome of stroke or systemic embolism .
No statistically significant difference was observed between the 2 therapies with regard to major bleeding , myocardial infa rct ion , or
Atrial fibrillation ( AF ) is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function ( 1 ) .
It is the most common sustained cardiac arrhythmia , and according to estimates , 12.1 million Americans will have AF by 2050 ( 2 ) .
Patients with AF have increased risk for embolic stroke , heart failure , and cognitive impairment ; reduced quality of life ; and higher overall mortality ( 35 ) .
Strokes related to AF have been characterized as more severe ( 6 , 7 ) and translate to a substantial economic burden , costing Medicare approximately $ 8 billion annually ( 8) .
Antithrombotic therapies are the mainstays for preventing thromboembolic events in patients with AF .
Oral anticoagulation with vitamin K antagonists ( VKAs ) has long been the gold st and ard therapy for stroke prevention in these patients .
However , the challenges of monitoring VKA therapy and the many associated food and drug interactions have fueled the development of novel therapeutic options .
Currently , 4 direct-acting oral anticoagulants ( DOACs ) are approved for stroke prevention in patients with nonvalvular AF : the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban , rivaroxaban , and edoxaban .
In addition , procedural interventions , such as left atrial appendage ( LAA ) occlusion devices , are an alternative treatment for patients who are at high risk for bleeding while receiving anticoagulation therapy .
This systematic review up date s previous review s ( 13 ) and aims to compare the effectiveness of the available medical and procedural therapies in preventing thromboembolic events and bleeding complications in patients with AF .