Patient population. Study drug administration and maintenance of the double blind. Study objectives. Study design

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1 Trial Design 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) Christian T. Ruff, MD, a,c Robert P. Giugliano, MD, SM, a,c Elliott M. Antman, MD, a,c Sharon E. Crugnale, MS, a,c Tomas Bocanegra, MD, b,c Michele Mercuri, MD, PhD, b,c James Hanyok, PharmD, b,c Indravadan Patel, MD, b,c Minggao Shi, PhD, b,c Dan Salazar, PhD, b Carolyn H. McCabe, BS, a,c and Eugene Braunwald, MD a,c Boston, MA; and Parsippany, NJ Background Vitamin K antagonists have been the standard 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, randomized, double-blind, double-dummy, multinational, noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin. Approximately 20,500 subjects will be randomized 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. Randomization 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 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. (Am Heart J 2010;160: e2.) Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. 1 It has been estimated that 2.2 million people in the United From the a TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, and b Daiichi Sankyo Inc, Parsippany, NJ. c for the ENGAGE AF-TIMI 48 Investigators. See Appendix B for complete listing. RCT #NCT Submitted March 12, 2010; accepted June 24, Reprint requests: Christian T. Ruff, MD, TIMI Study Group, 350 Longwood Ave, 1st Floor Offices, Boston, MA cruff@partners.org /$ - see front matter 2010, Mosby, Inc. All rights reserved. doi: /j.ahj States and 4.5 million people in the European Union suffer from AF. 2 The prevalence of AF is rapidly increasing as the population ages; the prevalence of AF in individuals N80 years is approximately 8%. 3 Thromboembolism is a feared and devastating complication of AF. Approximately 15% to 20% of all strokes occur in patients with AF. 4 Vitamin K antagonists (VKAs), such as warfarin, reduce the risk of stroke by 60% to 80% in patients with AF versus placebo. 5 However, less than half of eligible patients are treated with VKAs because of a number of limitations associated with the unpredictable pharmacokinetics and pharmacodynamics. 6-8 Even with frequent monitoring, patients taking VKAs spend more

2 636 Ruff et al American Heart Journal October 2010 than a third of the time outside the standard target therapeutic range (international normalized ratio [INR] ). 9 Thus, there is a recognized need for more predictable and convenient anticoagulants. Several new anticoagulants are being evaluated that inhibit thrombin (FIIa) or factor Xa (FXa). 10 Factor Xa is located in a critical position of the coagulation cascade, at the confluence of the intrinsic and extrinsic coagulation pathways. Direct FXa inhibitors inhibit both free FXa and FXa within the prothrombinase complex, which activates thrombin from prothrombin and serves as the primary site of amplification of the coagulation cascade. 11 Edoxaban (the free base of DU-176b) is an oral, smallmolecule, direct FXa inhibitor. The drug is rapidly absorbed, reaching a maximum concentration (C max )in 1 to 2 hours with a mean plasma half-life (t 1/2 )of8to 10 hours. 12,13 Edoxaban's disposition is characterized by linear pharmacokinetics, providing a predictable and consistent exposure within subjects. 12 Edoxaban is eliminated through multiple pathways, but the majority of systemically absorbed drug is eliminated via renal excretion. 12 Exposure to edoxaban increases in patients with renal dysfunction and in individuals with low body weight ( 60 kg). 13,14 Edoxaban is a substrate for the efflux transporter p-glycoprotein (P-gp), which is primarily located in the intestine, acting to pump drugs back into the intestinal lumen limiting systemic absorption of xenobiotics. Reduced dosages of drugs such as edoxaban that are substrates for P-gp may be needed when coadministered with strong P-gp inhibitors (eg, verapamil, quinidine). Edoxaban was studied in a phase 2 trial that randomized 1,146 subjects with AF (follow-up 3 months) to 1 of 4 fixed and blinded doses of edoxaban (30 mg once daily, 30 mg twice daily, 60 mg once daily, and 60 mg twice daily) or open-label warfarin titrated to INR 2.0 to Once-daily regimens were associated with less major bleeding than twice-daily regimens (30 mg twice daily vs 60 mg once daily: 2% vs 0.4%), and rates were similar to warfarin (0.4%). 15 Based on these findings, 2 dose exposures of edoxaban, 30 mg once daily and 60 mg once daily, were selected for comparison with warfarin in the prevention of thromboembolic events in the ENGAGE AF TIMI 48 trial (NCT ). Study objectives The primary objective of the ENGAGE AF TIMI 48 trial is to compare edoxaban to warfarin with regard to the composite primary end point of stroke and systemic embolic events (SEEs). Study design ENGAGE AF TIMI 48 is a large, multinational, randomized (1:1:1), double-blind, double-dummy noninferiority design trial comparing the efficacy and safety of 2 exposure strategies (high and low) of edoxaban to warfarin titrated to an INR of 2.0 to 3.0 (Figure 1). Randomization is stratified by CHADS 2 risk score 2 to 3 versus 4 to 6 and factors affecting drug exposure that require edoxaban dose adjustment (see section on drug administration). Enrollment commenced in November 2008 with a projected sample size of approximately 20,500 subjects in 1,400 sites and 46 countries (NCT ). Patient population The study population includes patients with AF at medium or high risk of thromboembolic events (CHADS 2 risk score 2). 16 Eligible subjects include men and women 21 years old who have a history of AF of any duration documented by any electrical tracing within the prior 12 months and for which anticoagulation is indicated and planned for the duration of the study. Both VKA-experienced (N60 days of continuous anticoagulation at anytime before randomization) and naive patients are eligible. Key exclusion criteria include AF due to a reversible disorder, severe renal dysfunction (creatinine clearance [CrCl] b 30 ml/min), subjects with a condition associated with a high risk of bleeding, and moderate or severe mitral stenosis. A complete list of enrollment criteria is provided in Table I. Study drug administration and maintenance of the double blind Subjects are randomized through an interactive voice/ Web response system (IVRS) (Figure 1). All subjects are dispensed 2 sets of study drug. The first set, edoxaban or matching placebo, is administered as a fixed dose regardless of the INR values. The second set, warfarin or matching placebo, contains different strengths of study drug (1, 2.5, and 5 mg [0.5 mg available in selected countries]) to be adjusted in accordance with INR values to maintain INRs between 2.0 and 3.0, inclusive. Patients are randomized to edoxaban 60 mg in the high-exposure group, 30 mg in the low-exposure group, or warfarin. If patients randomized to 1 of the 2 edoxaban groups have an anticipated increased drug exposure (any one or multiple of the following: creatinine clearance [CrCl] ml/min calculated with the Cockcroft-Gault formula, 17 body weight 60 kg, or concomitant administration of verapamil or quinidine [strong P-gp inhibitors]), they receive a 50% dose reduction (60 mg reduced to 30 mg in the high-exposure group; 30 mg reduced to 15 mg in the low-exposure group). This dose reduction can occur at randomization or at anytime during the trial if subjects develop moderate renal dysfunction, have a drop in body weight to 60 kg, or are prescribed verapamil or quinidine.

3 American Heart Journal Volume 160, Number 4 Ruff et al 637 Figure 1 } Protocol schema for ENGAGE AF TIMI 48 Trial. Approximately 20,500 patients will be enrolled with history of AF documented on an electrical recording within the past 12 months for whom anticoagulation is planned for the duration of the trial. Subjects are randomized 1:1:1 to edoxaban high exposure (60 mg once daily or dose adjusted to 30 mg once daily for anticipated need to avoid excessive exposure), edoxaban low exposure (30 mg once daily or dose adjusted to 15 mg once daily for anticipated need to avoid excessive exposure) or warfarin titrated to an INR of 2.0 to 3.0. Randomization is stratified by CHADS 2 score 2 to 3 versus 4 to 6 and drug clearance. The primary outcome is whether edoxaban is noninferior to warfarin in the prevention of stroke and SEEs with a noninferiority margin of HR, Hazard ratio; SEE, systemic embolic event. INR blinding Because the anticoagulant activities of warfarin and other VKAs are monitored by measuring the INR, once subjects start study drug, INR measurements are performed using a point-of-care device supplied to each study site. The INR results generated by the point-of-care device are masked by a code number, which is reported by the investigators to a central IVRS. True INR values are provided by the IVRS for subjects assigned to active warfarin, whereas sham values are provided for subjects assigned to edoxaban. This is necessary because edoxaban does not elevate INR values to the same extent as warfarin and it is not titrated to a target INR in this study. The sham values mimic real INR values in the warfarin arm and are based on a regression algorithm that includes age, gender, dose of placebo warfarin, and previous INR variation (personal communication, Dr Anders Olden, Romelanda, Sweden). The treating physician/investigator determines the necessary dose titrations of study drug warfarin to maintain an INR of 2.0 to 3.0. The Data Monitoring Committee (DMC) and Study Oversight Committee review overall and country-, site-, and patient-specific (Study Oversight Committee only) INR data. The Trial Operations Committee has an action plan to ensure appropriate time in therapeutic range (TTR). Follow-up procedures Subjects return for study visits at days 8, 15, and 29 and every month thereafter until the end of the trial (median 24 months anticipated), consistent with current recommendations. 18 During follow-up visits, subjects are assessed for adverse events, study end points, INR measured in a blinded fashion, and periodic safety laboratory tests (creatinine, liver function) sent to the central laboratory. Concomitant medications All decisions regarding concomitant medications are left to the discretion of the treating physician with a few notable exceptions. If indicated, a single antiplatelet

4 638 Ruff et al American Heart Journal October 2010 Table I. Inclusion and exclusion criteria Inclusion criteria 1. Male or female subjects with age 21 y 2. Able to provide written informed consent 3. History of AF documented by any electrical tracing (routine 12-lead ECG, continuous ECG recording, rhythm strip, intracardiac electrogram, pacemaker or implantable cardiac defibrillator interrogation) within the prior 12 m and for which anticoagulation therapy is indicated and planned for the duration of the study. Subjects with AF include subjects with paroxysmal, persistent, or permanent AF and subjects with or without previous VKA (including warfarin) experience (it is anticipated that 40% of subjects will be VKA naive) 4. CHADS 2 index score 2. The CHADS 2 scoring 16 is calculated by assigning 1 point each for a history of congestive heart failure, hypertension, age 75 y, or diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Exclusion criteria 1. Transient AF secondary to other reversible disorders (eg, thyrotoxicosis, cardiac or thoracic surgery, pneumonia, severe anemia) 2. Moderate or severe mitral stenosis, unresected atrial myxoma, or a mechanical heart valve (subjects with bioprosthetic heart valves and/or valve repair can be included) 3. History of left atrial appendage exclusion 4. Intracardial mass or left ventricular thrombus 5. Subjects in whom chronic anticoagulation therapy will be discontinued if a planned pharmacologic, electrical, or surgical therapy were to be successful in converting and maintaining normal sinus rhythm 6. Any contraindication for anticoagulant agents 7. Conditions associated with high risk of bleeding such as history of intracranial, intraocular, spinal, retroperitoneal, or intraarticular bleeding; overt gastrointestinal bleeding or active ulcer within the previous year; recent severe trauma, major surgery, or deep organ biopsy within the previous 10 d; active infective endocarditis; uncontrolled hypertension (blood pressure N170/100 mm Hg); or hemorrhagic disorder including known or suspected hereditary or acquired bleeding or coagulation disorder 8. Dual-antiplatelet therapy (eg, aspirin plus thienopyridine) or anticipated need to receive such therapy unless all but 1 of the antiplatelet medications can be safely stopped before randomization and while receiving study drug 9. Chronic cyclosporine therapy 10. Concomitant use of medications that increase the risk of bleeding (eg, fibrinolytics, nonstudy anticoagulants other than those used as a bridge to/from study drug, chronic nonaspirin NSAID use for 4 d/wk, and potent P-gp inhibitors) 11. Acute MI, stroke, acute coronary syndrome, or percutaneous coronary intervention within the previous 30 d 12. Active liver disease or persistent (confirmed by repeat assessments 1 wk apart) elevation of liver enzymes/bilirubin Alanine transaminase or aspartate transaminase 2 times the ULN Total bilirubin 1.5 times the ULN (however, subjects whose elevated total bilirubin is due to known Gilbert syndrome may be enrolled) 13. Severe renal insufficiency (calculated CrCl b30 ml/min) 14. Known positive hepatitis B antigen or hepatitis C antibody before randomization 15. Known positive test for human immunodeficiency virus 16. Hemoglobin b10 g/dl or platelet count b cells/ml or white blood cell count b3000 cells/ml 17. Any other clinically relevant laboratory abnormality as judged by the investigator 18. Preplanned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period 19. Subjects who received any investigational drug or device within 30 d before randomization, or plan to receive such investigational therapy during the study period 20. Subjects previously randomized in a study of edoxaban 21. Women of childbearing potential including: Women with a history of tubal ligation Women b2 y postmenopausal 22. Subjects with the following diagnoses or situations: Active malignancy (diagnosed within 5 y) except for adequately treated nonmelanoma skin cancer or other noninvasive or in situ neoplasm (eg, cervical cancer in situ that has been successfully treated) Treatment with anticancer therapy (drugs, radiation, and/or surgery) within the last 5 y Significant active concurrent medical illness or infection Life expectancy b12 m 23. Subjects who are unlikely to comply with the protocol (eg, uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the investigator to be unlikely to complete the study) 24. Known drug or alcohol dependence within the past 12 m as judged by the investigator 25. Any condition that, in the opinion of the investigator, would place the subject at increased risk of harm if he/she participated in the study ECG, Electrocardiogram; NSAID, nonsteroidal anti-inflammatory drug; ULN, upper limit of normal; MI, myocardial infarction; VKA, vitamin K antagonist; CrCl, creatinine clearance; d, days; m, months; y, years. agent is permitted, although the recommended dose of aspirin is b100 mg. If a patient develops an indication for dual-antiplatelet therapy (eg, after coronary artery stent implantation), both study drugs must be temporarily interrupted; and use of open-label VKA is permitted at the physician's discretion. This recommendation is made because of the higher bleeding rates observed in patients treated with triple therapy (dual-antiplatelet therapy and VKAs). 19 Study end points The primary efficacy end point of the trial is the composite of stroke and SEE (online Appendix A). Key secondary end points include, but are not limited to, the composite outcome of stroke, SEE, and cardiovascular mortality or all-cause mortality, as well as each component separately. The TTR (INR ) will be estimated for each subject randomized to warfarin using the interpolation method of Rosendaal et al. 20 The primary safety end point is a modification (adjusts the fall in hemoglobin if a blood transfusion is required) of the International Society on Thrombosis and Haemostasis definition or major bleeding (online Appendix A). 21 Bleeding will be also analyzed using other bleeding definitions (GUSTO, TIMI) to facilitate comparisons. Other safety end points include major plus clinically relevant nonmajor bleeding and incidence of liver enzyme and bilirubin abnormalities (online Appendix A).

5 American Heart Journal Volume 160, Number 4 Ruff et al 639 Cause of death, stroke, SEE, MI, bleeding, and hepatic events are adjudicated by members of an independent Clinical Events Committee (online Appendix B) blinded to treatment allocation. Statistical considerations This is an event-driven study with a goal of collecting a prespecified number of primary efficacy end points occurring on treatment in the modified intent-to-treat (ITT) analysis set that includes all randomized subjects who receive 1 dose of randomized study drug. Subjects are considered to be at risk for the primary end point only while taking study drug or during the first 3 days after study drug interruption or discontinuation. It is hypothesized that 1 edoxabandoseexposurewill be noninferior to warfarin. To satisfy the noninferiority hypothesis, the upper bound of the 2-sided 97.5% CI for the hazard ratio of the primary end point with edoxaban compared with warfarin must be b1.38. The noninferiority margin of 1.38 was derived to retain 50% of warfarin's effect as determined by a meta-analysis of placebocontrolled trials of warfarin in patients with AF. 22,23 To accrue the target number of primary end points, approximately 20,500 subjects will be enrolled. Sample size and duration of treatment may require adjustment depending upon actual versus anticipated event rates. There is 87% power for confirming noninferiority for at least one of the following comparisons: edoxaban high exposure versus warfarin or edoxaban low exposure versus warfarin. The primary analysis will test that 1 edoxaban treatment exposure is noninferior to warfarin using a pairwise comparison (modified ITT). The time to first event will be analyzed using the Cox proportional hazards model including treatments with stratification by CHADS 2 risk score and anticipated drug exposure (normal or increased). Further sensitivity analyses will be performed using the ITT cohort including all events occurring while in study and the on-treatment analytic approach based on the per protocol principle (subjects who receive 1 dose of randomized study drug and do not have any major protocol violations). If noninferiority is first established for the edoxaban high-exposure strategy, hierarchical testing for superiority will be carried out in the ITT cohort. Key specified proper subgroups include (but are not limited to) warfarin experience status at randomization, TTR of the INR, CHADS 2 risk score categories, CrCl, and geographic region. An independent DMC (online Appendix B) is responsible for monitoring safety during the study. This committee is unblinded to treatment assignment. The DMC Chairperson receives safety reports every 1,000 subjects enrolled; and the full DMC reviews safety data when 5,000 subjects have been randomized and when 25%, 50%, and 75% of primary end points are reported. All Table II. Additional scientific investigations Name Pharmacokinetics/ pharmacodynamics Health economics/quality of life Pharmacogenetics Biomarker Continuous and static electrocardiography Echocardiography Objective Characterize the relationship between exposure and response to edoxaban Cost-effectiveness of edoxaban therapy Identify genetic polymorphisms that identify patients at higher risk for recurrent AF, thromboembolism, and bleeding Correlate concentrations of biomarkers of thrombosis, inflammation, necrosis and hemodynamic status with efficacy and safety profiles of anticoagulant therapy Determine the varying risk associated with different burdens of AF Determine if left atrial size predicts thromboembolic risk 4 interim reviews will evaluate the safety of the high- and low-exposure groups of edoxaban versus warfarin for lifethreatening bleeding, intracranial hemorrhage, and mortality. The third interim analyses (50% of events reported) will evaluate inferiority of any of the edoxaban exposure groups to warfarin (1-sided P b.001 with regard to the primary efficacy end point). There are no stopping rules for superior efficacy of edoxaban. Additional scientific investigations Several additional scientific investigations (Table II) are aimed at improving our understanding of the pathophysiology of AF, providing more accurate predictions of thromboembolic and bleeding risks, and enhancing the assessment of the efficacy of oral anticoagulant therapy in greater detail. Study organization The Study Oversight Committee, composed of representatives from the TIMI Study Group, Quintiles (contract research organization), and the sponsor (Daiichi Sankyo Inc), jointly manages all aspects of the trial (online Appendix B). The Steering Committee provides guidance on protocol development, study implementation, conduct of the study, and interpretation of results. An independent data safety monitoring committee is responsible for independent assessment of the study and periodic reviews of accumulating safety data from the trial. The study was designed by the TIMI Study Group in conjunction with the Steering Committee and the trial sponsor. Data analysis will be conducted as per the final statistical analysis plan agreed with the regulatory agencies for the New Drug Application (NDA) submission. The TIMI Study Group will also have free and complete access to the raw data for the purpose of submitting the results for publication in a peer-reviewed journal. The trial registration number is NCT

6 640 Ruff et al American Heart Journal October 2010 Table III shows the baseline characteristics of the first 15,000 randomized patients. Discussion There are several promising oral anticoagulants in latestage clinical development that could replace warfarin for the prevention of stroke in AF. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE- LY) trial (N = 18,113) used a prospective, randomized, open-label, blinded-end point design to compare 2 dose strategies of the direct thrombin inhibitor dabigatran (110 and 150 mg twice daily) with open-label warfarin. 24 Dabigatran 150 mg twice daily was superior to warfarin in reducing stroke and systemic embolism, and dabigatran 110 mg twice daily was noninferior to warfarin. The rate of myocardial infarction was significantly higher in the dabigatran 150-mg group compared with warfarin. The risk of major bleeding was similar in the dabigatran 150-mg and warfarin groups and significantly lower in the dabigatran 110-mg group. There was a significantly higher rate of discontinuation with both dabigatran doses compared with warfarin, with dyspepsia reported as the most frequent adverse event. Inhibiting FXa has some potential advantages over thrombin inhibition. There are several other oral agents (rivaroxaban and apixaban) that are being investigated in large phase 3 trials. 25,26 Factor Xa inhibition may be more potent than inhibiting thrombin that is located at the terminus of the coagulation cascade because of amplification: one molecule of FXa can catalyze the formation of N1,000 molecules of thrombin. 27 Another potential disadvantage of thrombin inhibition is rebound hypercoagulability. 28 Experimental evidence suggests that direct thrombin inhibitors allow for increased thrombin generation compared with FXa inhibitors, which may explain the clinical observation of higher rates of myocardial infarction seen in several studies. 24,28-30 ENGAGE AF TIMI 48 is a phase 3, randomized, doubleblind, double-dummy trial comparing the efficacy and safety of 2 exposure strategies of edoxaban (high and low) to warfarin. It is challenging to maintain a double blind with a drug such as warfarin as the comparator because frequent monitoring of the level of anticoagulation is required. However, we felt that blinding was critical to limit bias in the reporting and adjudication of events. This trial not only uses 2 dose levels of edoxaban but permits dynamic dose adjustment during the trial for conditions that would lead to increased drug exposure and risk of bleeding (low body weight, moderate renal dysfunction, concomitant verapamil or quinidine). A 2-dose strategy has several potential advantages. The higher dose could have superior efficacy with similar bleeding, and the lower dose may have similar efficacy and less bleeding. A practicing clinician could choose the best strategy depending on an individual patient's risk Table III. Baseline characteristics for subjects Demographics Age (y) 72 (64-77) Age 75 y 39 Female 38 CHADS Warfarin naïve 39 Category of AF Paroxysmal 26 Persistent 23 Permanent 52 Any reason for dose adjustment 25 Weight 60 kg 10 CrCl 50 ml/min 19 Concomitant verapamil or quinidine 4 Data are shown as percentage for dichotomous variables and median (25th-75th percentile) for continuous variables. Subjects may have N1 reason for dose adjustment; thus, the total of the individual reasons is N25%. profile. It is also not uncommon for there to be a wide variation in body weight, renal function, and medication use in a heterogeneous population of patients with AF that will result in large differences in drug exposure. Dose adjustment may allow clinicians to protect patients from the risk of thromboembolism while reducing bleeding. The once-daily dosing of edoxaban was based upon analysis of pharmacokinetic and safety data from phase 2 trials and may facilitate patient compliance. There are several additional scientific investigations that may further improve our understanding of the pathogenesis of AF and help identify patients at increased risk of thromboembolic complications. References 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. 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8 American Heart Journal Volume 160, Number 4 Ruff et al 641.e1 Appendix A. End point definitions Stroke A stroke is defined as an abrupt onset, over minutes to hours, of a focal neurologic deficit that is generally in the distribution of a single brain artery (including the retinal artery) and that is not due to an identifiable nonvascular cause (ie, brain tumor or trauma). The deficit must either be associated with symptoms lasting N24 hours or result in death within 24 hours of symptom onset. Because strokes may have variable clinical presentations (eg, a large hemorrhagic stroke presenting with sudden syncope, embolic stroke with multiple deficits in N1 vascular territory), supplementary information such as brain imaging may be used by the Clinical Events Committee to determine if a stroke has occurred. Systemic embolic event A systemic embolic event is defined as an abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms (eg, atherosclerosis, instrumentation). Arterial embolic events involving the central nervous system (including the eye), coronary, and pulmonary arterial circulation are not considered SEEs, but will be classified, respectively, as stroke/transient ischemic attack, myocardial infarction, and pulmonary embolism. In the presence of atherosclerotic peripheral vascular disease, diagnosis of embolism to the lower extremities requires arteriographic demonstration of abrupt arterial occlusion. Bleeding events (modified International Society on Thrombosis and Haemostasis definition) A major bleeding event is defined as clinically overt bleeding event (ie, bleeding that is visualized by examination or radiologic imaging) that meets 1 of the following: 1. Fatal bleeding 2. Symptomatic bleeding in a critical area or organ such as: Retroperitoneal Intracranial Intraocular Intraspinal Intraarticular Pericardial Intramuscular with compartment syndrome 3. A clinically overt bleeding event that causes a fall in hemoglobin level of 2.0 g/dl (1.24 mmol/l), adjusted for transfusions. Each 1 unit of packed red blood cell or whole blood is counted as a 1.0-g/dL decrease in hemoglobin. In the case of surgical procedural-related bleeding, the bleeding must be in excess of that normally associated with the surgery/procedure. In the absence of hemoglobin data, a fall of hematocrit of 6.0%, adjusted for transfusion, will satisfy the criteria for a major bleeding event. Major bleeding events will also be further subclassified as life threatening or non life threatening. A lifethreatening major bleed is defined as a bleeding event that either is intracranial or is associated with hemodynamic compromise requiring intervention. Clinically relevant nonmajor bleeding events A clinically relevant nonmajor bleeding event is defined as clinically overt bleeding event that requires medical attention. Examples of bleeding requiring medical attention include, but are not limited to, bleeding events that result in the following diagnostic or therapeutic measures: Requires or prolongs hospitalization Laboratory evaluation Imaging studies Endoscopy, colonoscopy, cystoscopy, or bronchoscopy Nasal packing Compression Ultrasound-guided closure of an aneurysm Coil embolization Inotropic support Surgery Interruption or stopping study medication at the advice of a health care provider Changing concomitant therapies (eg, reducing the dose of or discontinuing aspirin) at the advice of a health care provider Note: An outpatient visit without any of the above or similar diagnostic/therapeutic measures does not satisfy the criteria for requiring medical attention. Minor (not clinically relevant) bleeding events Other overt bleeding events that do not fulfill the criteria of a major bleeding event or a clinically relevant nonmajor bleeding event (eg, epistaxis that does not require medical attention) will be classified as a minor bleeding event. Note: All other events (eg, decline in hemoglobin with no overt bleeding event) will be classified as no bleeding event. Appendix B. Study Oversight Committee TIMI Study Group, Brigham and Women's Hospital, Boston, MA E. Braunwald (Study Chairman), C. McCabe (Director), E. Antman (Principal Investigator), R. Giugliano (Co- Principal Investigator), C. Ruff (Co-Investigator), S. Crugnale, L. Grip (Project Managers), J. Durgin (Assistant Project Manager). Daiichi Sankyo Inc, Parsippany, NJ (sponsor) Clinical Development: T. Bocanegra, M. Mercuri, I. Patel, A. Duggal, J. Hanyok, R. van Kranen, S. Whitaker, J.

9 641.e2 Ruff et al American Heart Journal October 2010 Dave. Regulatory Affairs: D. Morgan. Clinical Pharmacology: J. Mendell-Harary. Risk Management: Y. Choi. Biostatistics: M. Shi. Project Management: W. Maxwell, A. Inoguchi. Data Coordinating Center, Randomization and Site Management: Quintiles Incorporated, Research Triangle, NC (CRO) Global Operations: C. Giordano (Global Operations Head). Project Management: J. Norris (Senior Project Director), S. Patel (Project Manager). Biostatistics: J. Betcher (Project Statistician), G. Selicato (Functional Lead Statistician), M. Ennis (Independent Unblinded Statistician). Steering Committee D. Alexopoulos, D. Atar, P. Aylward, N. Babilonia, M. Bergovec, J. J. Blanc, R. Botero, J. Camm, S. A. Chen, N. Chung, S. Connolly, R. Corbalan, A. Dalby, R. DeCaterina, M. Dorobantu, T. Duris, M. R. Essop, M. Ezekowitz, A. Garcia-Castillo, A. Goudev, P. Grande, J. Halperin, C. Hassager, H. Heidbuchel, M. Horna, H. Huikuri, S. Juul- Möller, R. Kiss, Y. Koretsune, J. Y. LeHeuzey, B. Lewis, P. Merlini, M. Metra, V. Mitrovic, T. Moccetti, J. Morais, J. C. Nicolau, M. Nieminen, M. Ostojic, A. Oto, T. Oude Ophuis, E. Paolasso, A. Parkhomenko, T. Pedersen, D. Roy, M. Ruda, W. Ruzyllo, R. Senior, B. SomaRaju, G. Sotomora, J. Spinar, P. Sritara, J. Voitk, A. Waldo, J. Weitz, H. White, T. Yamashita, Y. Yang, J. L. Zamorano Data Monitoring Committee F. Verheugt (Chair), J. Anderson, K. Bauer, J. D. Easton, S. Goto, A. Skene Clinical Events Committee S.Wiviott(Chair),E.Awtry,C.Berger,A.Desai,E.Gelfand, C.Ho,D.Leeman,M.Link,F.Ruberg,J.Vita,N.Rost, S. Silverman, W. Goessling, N. Greenberger, W. Maddrey