Michael D. Ezekowitz

Edoxaban versus Warfarin in Patients with Atrial Fibrillation

BACKGROUNDnEdoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.nnnMETHODSnWe conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding.nnnRESULTSnThe annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32).nnnCONCLUSIONSnBoth once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).

Management and Outcomes of Major Bleeding during Treatment with Dabigatran or Warfarin

Background— The aim of this study was to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin. Methods and Results— Two independent investigators reviewed bleeding reports from 1034 individuals with 1121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27 419 patients treated for 6 to 36 months. Patients with major bleeds on dabigatran (n=627 of 16 755) were older, had lower creatinine clearance, and more frequently used aspirin or non-steroid anti-inflammatory agents than those on warfarin (n=407 of 10 002). The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%; pooled odds ratio, 0.68; 95% confidence interval, 0.46–1.01; P=0.057). After adjustment for sex, age, weight, renal function, and concomitant antithrombotic therapy, the pooled odds ratio for 30-day mortality with dabigatran versus warfarin was 0.66 (95% confidence interval, 0.44–1.00; P=0.051). Major bleeds in dabigatran patients were more frequently treated with blood transfusions (423/696, 61%) than bleeds in warfarin patients (175/425, 42%; P<0.001) but less frequently with plasma (dabigatran, 19.8%; warfarin, 30.2%; P<0.001). Patients who experienced a bleed had shorter stays in the intensive care unit if they had previously received dabigatran (mean 1.6 nights) compared with those who had received warfarin (mean 2.7 nights; P=0.01). Conclusions— Patients who experienced major bleeding on dabigatran required more red cell transfusions but received less plasma, required a shorter stay in intensive care, and had a trend to lower mortality compared with those who had major bleeding on warfarin. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00262600, NCT00291330, NCT00680186, NCT00329238 and NCT00558259.

Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation

AIMSnX-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion.nnnMETHODS AND RESULTSnWe assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P < 0.001). Major bleeding occurred in six patients (0.6%) in the rivaroxaban group and four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67).nnnCONCLUSIONnOral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion.nnnNAME OF THE TRIAL REGISTRYnClinicaltrials.gov;nnnTRIAL REGISTRATION NUMBERnNCT01674647.

2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design

This is a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). This is endorsed by the governing bodies of the ACC Foundation, the AHA, the ECAS, the EHRA, the STS, the APHRS, and the HRS.

Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options-a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.

Variations in Cause and Management of Atrial Fibrillation in a Prospective Registry of 15 400 Emergency Department Patients in 46 Countries The RE-LY Atrial Fibrillation Registry

Background— Atrial fibrillation (AF) is the most common sustained arrhythmia; however, little is known about patients in a primary care setting from high-, middle-, and low-income countries. Methods and Results— This prospective registry enrolled patients presenting to an emergency department with AF at 164 sites in 46 countries representing all inhabited continents. Patient characteristics were compared among 9 major geographic regions. Between September 2008 and April 2011, 15 400 patients were enrolled. The average age was 65.9, standard deviation 14.8 years, ranging from 57.2, standard deviation 18.8 years in Africa, to 70.1, standard deviation 13.4 years in North America, P<0.001. Hypertension was globally the most common risk factor for AF, ranging in prevalence from 41.6% in India to 80.7% in Eastern Europe, P<0.001. Rheumatic heart disease was present in only 2.2% of North American patients, in comparison with 21.5% in Africa and 31.5% in India, P<0.001. The use of oral anticoagulation among patients with a CHADS2 score of ≥2 was greatest in North America (65.7%) but was only 11.2% in China, P<0.001. The mean time in the therapeutic range was 62.4% in Western Europe, 50.9% in North America, but only between 32% and 40% in India, China, Southeast Asia, and Africa, P<0.001. Conclusions— There is a large global variation in age, risk factors, concomitant diseases, and treatment of AF among regions. Improving outcomes globally requires an understanding of this variation and the conduct of research focused on AF associated with different underlying conditions and treatment of AF and predisposing conditions in different socioeconomic settings.

Edoxaban versus enoxaparin–warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial

BACKGROUNDnEdoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available.nnnMETHODSnWe did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434.nnnFINDINGSnBetween March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA2DS2-VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status.nnnINTERPRETATIONnENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups.nnnFUNDINGnDaiichi Sankyo provided financial support for the study.

Changes in renal function in patients with atrial fibrillation: An analysis from the RE-LY trial

BACKGROUNDnVitamin K-dependent factors protect against vascular and renovascular calcification, and vitamin K antagonists may be associated with a decreased glomerular filtration rate (GFR).nnnOBJECTIVESnThis study analyzed changes in GFR during long-term treatment with warfarin or dabigatran etexilate (DE) in patients enrolled in the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial.nnnMETHODSnOf the 18,113 patients in the RE-LY study randomized to receive DE (110 mg or 150 mg twice daily) or warfarin, 16,490 patients with atrial fibrillation had creatinine values measured at baseline and at least 1 follow-up visit. Changes in GFR for up to 30 months were evaluated.nnnRESULTSnGFR declined in all treatment groups. After an average of 30 months, the mean ± SE decline in GFR was significantly greater with warfarin (-3.68 ± 0.24 ml/min) compared with DE 110 mg (-2.57 ± 0.24 ml/min; pxa0= 0.0009 vs. warfarin) and DE 150 mg (-2.46 ± 0.23 ml/min; pxa0= 0.0002 vs. warfarin). A decrease in GFR >25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; pxa0= 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; pxa0=xa00.0056) than with warfarin in the observation period >18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic rangexa0<65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes.nnnCONCLUSIONSnPatients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus DE, and it was amplified by diabetes and previous vitamin K antagonist use. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600).

Comprehensive risk reduction in patients with atrial fibrillation: Emerging diagnostic and therapeutic options Executive summary* of the report from the 3rd AFNET/EHRA consensus conference

There are exciting new developments in several areas of atrial fibrillation (AF) management that carry the hope of improving outcomes in AF patients. This paper is an executive summary that summarises the proceedings from the 3rd AFNET/EHRA consensus conference on atrial fibrillation, held in Sophia Antipolis from November 7th to 9th 2010, shortly after the release of the new ESC guidelines on AF. The conference was jointly organised by the German Atrial Fibrillation competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA). This executive summary report covers four sections: 1. Risk factors and risk markers for AF, 2. Pathophysiological classification of AF, 3. Relevance of monitored AF duration for AF-related outcomes, and 4. Perspectives and needs for implementing better antithrombotic therapy.

Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.

Background Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown. Methods and Results We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P<0.0001), more likely to be white (92% versus 89%, P=0.005), more likely to have private insurance (33% versus 25%, P<0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P<0.0001). They had more new‐onset atrial fibrillation (8.8% versus 4.1%, P<0.0001), lower CHADS2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P<0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P<0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow‐up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P<0.0001). Conclusions Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted. Clinical Trial Registration URL: Clinicaltrials.gov. Unique identifier: NCT01165710.