Exposure-response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation.

AIMS: AZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible thrombin inhibitor. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR-H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients. METHODS: Blood samples were obtained from 601 AF patients randomized to one of four doses of AZD0837 (blinded treatment) or dose-adjusted vitamin K antagonists (VKA, open treatment) for 3-9 months. A pharmacodynamic model was developed to describe the time course of the AR-H067637 exposure dependent effects and the effect of VKA on fibrin D-dimer. The thrombin generation measured ex vivo in venous plasma was also investigated. RESULTS: The PK exposure of AR-H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D-dimer levels decreased with more rapid onset than for VKA. The decrease in D-dimer levels correlated with steady-state plasma concentrations (C(ss)) of AR-H067637, with a maximum decrease of baseline D-dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR-H067637. CONCLUSIONS: The effects on thrombin generation and fibrin D-dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well-controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837.

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.

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 randomized, 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 > or =1 additional risk factor for stroke were randomized 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 clinically 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 approximately 10% from baseline and returned to baseline following treatment cessation. The frequency of serum alanine aminotransferase > or =3x 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 ClinicalTrials.gov, number NCT00684307.

Atrial fibrillatory rate and risk of stroke in atrial fibrillation.

AIMS: In atrial fibrillation (AF), a relation between electrocardiogram (ECG) parameters such as fibrillatory wave amplitude and stroke has been sought with conflicting results. In this study, we tested the hypothesis that the atrial fibrillatory rate of surface ECG lead V1 is related to stroke risk and may consequently be helpful for identifying high-risk patients. METHODS AND RESULTS: Atrial fibrillatory rate of 79 consecutive patients with AF and embolic stroke (age 83 +/- 7 years, 41% male) was compared with those of a matched AF population without stroke (n = 79). Atrial fibrillatory rate was determined from the surface ECG using spatiotemporal QRST cancellation and time-frequency analysis of lead V1. There was no significant difference in any clinical or echocardiographic variable in patients with stroke compared with AF controls without stroke. Atrial fibrillatory rate measured 373 +/- 55 fibrillations per minute (fpm; range 235-505 fpm) in the entire population. There was no fibrillatory rate difference between stroke patients (369 +/- 54 fpm, range 256-505 fpm) and AF controls without stroke (378 +/- 56 fpm, range 235-488 fpm). There was an inverse correlation between fibrillatory rate and age (R = -0.219, P = 0.006). Individuals aged >or=85 years had a significantly lower fibrillatory rate (356 +/- 44 fpm) than individuals aged 65-74 years (384 +/- 56 fpm, P = 0.033) and individuals aged 75-84 years (384 +/- 60 fpm, P = 0.016). In those subgroups, fibrillatory rates were, however, also similar in stroke patients and AF controls. CONCLUSION: Atrial fibrillatory rate obtained from surface ECG lead V1 is not a risk marker for stroke in AF.

Interatrial conduction can be accurately determined using standard 12-lead electrocardiography: validation of P-wave morphology using electroanatomic mapping in man.

BACKGROUND: Different P-wave morphologies during sinus rhythm as displayed on standard ECGs have been postulated to correspond to differences in interatrial conduction. OBJECTIVE: The purpose of this study was to evaluate the hypothesis by comparing P-wave morphologies using left atrial activation maps. METHODS: Twenty-eight patients (mean age 49 +/- 9 years) admitted for ablation of paroxysmal atrial fibrillation were studied. Electroanatomic mapping of left atrial activation was performed at baseline during sinus rhythm with simultaneous recording of standard 12-lead ECG. Unfiltered signal-averaged P waves were analyzed to determine orthogonal P-wave morphology. The morphology was subsequently classified into one of three predefined types. All analyses were blinded. RESULTS: The primary left atrial breakthrough site was the fossa ovalis in 8 patients, Bachmann bundle in 18, and coronary sinus in 2. Type 1 P-wave morphology was observed in 9 patients, type 2 in 17, and type 3 in 2. Seven of eight patients with fossa ovalis breakthrough had type 1 P-wave morphology, 16 of 18 patients with Bachmann bundle breakthrough had type 2 morphology, and both patients with coronary sinus breakthrough had type 3 P-wave morphology. Overall, P-wave morphology criteria correctly identified the site of left atrial breakthrough in 25 (89%) of 28 patients. CONCLUSION: In the vast majority of patients, P-wave morphology derived from standard 12-lead ECG can be used to correctly identify the left atrial breakthrough site and the corresponding route of interatrial conduction.

Fibrillatory rate response to candesartan in persistent atrial fibrillation.

INTRODUCTION: Angiotensin-receptor blockers may exert favourable anti-arrhythmic effects in atrial fibrillation (AF), but their mechanisms are not fully understood. In this study, we tested the hypotheses that (i) candesartan reduces atrial fibrillatory rate and (ii) fibrillatory rate and its response to candesartan are related with the outcome of cardioversion. For this purpose, a post hoc subanalysis of the randomized, placebo-controlled CAPRAF (Candesartan in the Prevention of Relapsing Atrial Fibrillation) trial was performed. METHODS AND RESULTS: Patients with AF undergoing electrical cardioversion were randomized to receive candesartan 8 mg once daily (n = 58) or matching placebo (n = 66) and no additional class I or III anti-arrhythmic drugs. Fibrillatory rate was determined from ECG lead V1 at baseline and at the day of cardioversion using spatiotemporal QRST cancellation and time-frequency analysis. The median time on treatment was 29 days. Candesartan reduced fibrillatory rate [399 +/- 48 vs. 388 +/- 49 fibrillations/min (fpm), P = 0.04], but not placebo (402 +/- 58 vs. 402 +/- 61 fpm, P = 0.986). Candesartan effects were only observed if the baseline fibrillatory rate was high [>420 fpm: 445 +/- 21 vs. 415 +/- 49 fpm, P = 0.006 vs. intermediate (360-420 fpm): 397 +/- 19 vs. 391 +/- 37 fpm, P = 0.351 vs. low (<360 fpm): 326 +/- 26 vs. 338 +/- 29 fpm, P = 0.179]. Cardioversion success was 100% in patients with an on-treatment rate <360 fpm vs. 83% in patients with higher rates (P = 0.02). Risk for AF recurrence was similar in patients with low (64%), intermediate (75%), or high on-treatment rates (63%, P = 0.446) and was also independent of candesartan effects on the fibrillatory rate. CONCLUSION: In patients with persistent AF, candesartan decreases the fibrillatory rate, but this effect is restricted to patients with high baseline fibrillatory rates and is not associated with improved cardioversion outcome. Fibrillatory rates <360 fpm are associated with successful cardioversion, but not with AF recurrence.

Permanent atrial fibrillation in patients without structural heart disease is not associated with signs of infection by Chlamydia pneumoniae and Helicobacter pylori.

OBJECTIVE: The objective of this study was to explore the role of Chlamydia pneumoniae and Helicobacter pylori infections in patients with idiopathic permanent atrial fibrillation. METHODS AND RESULTS: Sera from 72 patients with permanent atrial fibrillation without structural heart disease (mean age 69.6 years, 23 women) were analysed for IgG antibodies against Chlamydia pneumoniae and Helicobacter pylori and compared in a I:I age- and sex-matched case:control manner with those pooled from a healthy reference population of 72 individuals from the same geographical area. After excluding patients with other possible or definite factors known either to cause atrial fibrillation or to affect the prevalence of seropositivity to these agents, the frequency of seropositivity due to one or both of the infectious agents was compared. Serum C-reactive protein (CRP) level was assessed using immunoturbidimetry technique. Both agents were equally common in men and women. Neither seropositivity to Chlamydia pneumoniae (76% vs. 83%, patients vs. control subjects, ns) nor to Helicobacter pylori (57% contra 55%, patients vs. controls, ns) alone reached significance in the comparisons between patients with atrial fibrillation and control subjects. Serum CRP was higher in patients with AF (5.3 mg/L vs. 2.8 mg/L, P < 0.001). CONCLUSIONS: Though presence of permanent AF is associated with elevated CRP levels, this elevation is not the result of earlier infections with Chlamydia pneumoniae or Helicobacter pylori or their combination.

Direct thrombin inhibition and stroke prevention in elderly patients with atrial fibrillation: experience from the SPORTIF III and V Trials.

BACKGROUND AND PURPOSE: Warfarin prevents stroke in atrial fibrillation (AF); however, concerns regarding international normalized ratio control and hemorrhage limit its use in the elderly. The oral direct thrombin inhibitors (DTIs) are potential alternatives to warfarin, offering fixed dosing without drug and dietary interactions and the need for international normalized ratio monitoring. Although ximelagatran, a DTI studied in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation trials, has been withdrawn, development of other DTIs continues. We report our experience in elderly high-risk AF patients on ximelagatran compared with warfarin therapy. METHODS: Data from patients with AF and stroke risk factors randomized in Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials to ximelagatran or warfarin were analyzed for stroke/systemic emboli, bleeding, and raised alanine aminotransferase levels in those >or=75 (n=2804) and <75 (n=4525) years. RESULTS: Ximelagatran was as effective as warfarin in reducing stroke/systemic emboli in the elderly (2.23%/y with ximelagatran vs 2.27%/y with warfarin) as in younger patients (1.25%/y vs 1.28%/y). Total bleeds were significantly lower with ximelagatran compared with warfarin in elderly (40% vs 45%, P=0.01) and younger (27% vs 35%, P<0.001) patients. Raised alanine aminotransferase values (>3-fold elevation) among ximelagatran patients were more common in older (7.5% old vs 5.3% young) patients, particularly women (9.5% elderly women vs 6.1% elderly men). CONCLUSIONS: In high-risk elderly AF patients, ximelagatran is as effective as warfarin with less bleeding, but alanine aminotransferase elevations are common, particularly in elderly women. Oral DTIs for stroke prevention show promise in elderly patients.

Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. The Euro Heart Survey on Atrial Fibrillation.

BACKGROUND: The Euro Heart Survey showed that antithrombotic treatment in patients with atrial fibrillation (AF) was moderately tailored to the 2001 American College of Cardiology, American Heart Association, and European Society of Cardiology (ACC/AHA/ESC) guidelines for the management of AF. What consequences does guideline-deviant antithrombotic treatment have in daily practice? METHODS: In the Euro Heart Survey on AF (2003-2004), an observational study on AF care in European cardiology practices, information was available on baseline stroke risk profile and antithrombotic drug treatment and on cardiovascular events during 1-year follow-up. Antithrombotic guideline adherence is assessed according to the 2001 ACC/AHA/ESC guidelines. Multivariable logistic regression was performed to assess the association of guideline deviance with adverse outcome. RESULTS: The effect of antithrombotic guideline deviance was analyzed exclusively in 3634 high-risk patients with AF because these composed the majority (89%) and because few cardiovascular events occurred in low-risk patients. Among high-risk patients, antithrombotic treatment was in agreement with the guidelines in 61% of patients, whereas 28% were undertreated and 11% overtreated. Compared to guideline adherence, undertreatment was associated with a higher chance of thromboembolism (odds ratio [OR], 1.97; 95% CI, 1.29-3.01; P = .004) and the combined end point of cardiovascular death, thromboembolism, or major bleeding (OR, 1.54; 95% CI, 1.14-2.10; P = .024). This increased risk was nonsignificant for the end point of stroke alone (OR, 1.42; 95% CI, 0.82-2.46; P = .170). Overtreatment was nonsignificantly associated with a higher risk for major bleeding (OR, 1.52; 95% CI, 0.76-3.02; P = .405). CONCLUSIONS: Antithrombotic undertreatment of high-risk patients with AF was associated with a worse cardiovascular prognosis during 1 year, whereas overtreatment was not associated with a higher chance for major bleeding.

Prolonged P wave duration in adults with secundum atrial septal defect: a marker of delayed conduction rather than increased atrial size?

AIMS: Although atrial fibrillation is a frequent complication of an atrial septal defect (ASD) of the secundum type, the underlying mechanisms are poorly understood. Atrial conduction disturbances, manifested as a prolonged P-wave duration, have been suggested as a substrate for arrhythmia. Prolongation of the P-wave in unrepaired ASD has been demonstrated by means of the conventional ECG, but not by more sophisticated methods. The aim of the study was to analyse P-wave duration and morphology by high-resolution P-wave signal-averaged ECG (PSA-ECG) and to investigate potential atrial mechano-electrical interactions in adults with an unrepaired ASD. METHODS AND RESULTS: P-wave signal-averaged-ECG was obtained in 35 adult patients (age 53 +/- 15 years) with ASD and compared with an equal number of sex- and age-matched healthy controls. Right and left atrial sizes were assessed by echocardiography in the ASD group. P wave duration was significantly longer in the ASD group than in control subjects (148 +/- 16 vs. 128 +/- 15 ms, P < 0.0001). P-wave morphology did not differ significantly between patients and controls. There was no clear relation between P-wave duration and atrial size. CONCLUSION: Atrial septal defect in the adult is characterized by a prolonged P-wave duration, indicating delayed atrial conduction, which is not related to the enlargement of the atria but rather to conduction delay. The nature and potential reversibility of this warrant further investigation.

Low-energy ultrasound exposure of the streptokinase molecule may enhance but also attenuate its fibrinolytic properties.

INTRODUCTION: This study explores the mechanisms of ultrasound-enhanced fibrinolysis by investigating the effects of pre-exposure to pulsed high-frequency, low-energy ultrasound on the fibrinolytic properties of streptokinase. MATERIALS AND METHODS: Fibrinolytic activity was measured as haemoglobin release from blood clots. The fibrinolytic effects of streptokinase and ultrasound separately and in combination were studied by evaluating cumulative percentages of haemoglobin release following 1 h of exposure using two clots, one for intervention and the other concomitantly as control. In particular, the effects of exposure to ultrasound on clot-free streptokinase solution were compared to those of concomitant exposures of streptokinase solution with clot. The exposures were made at a frequency of 1 MHz (10% duty cycle) and at three intensity levels (0.5, 1.0 and 4.0 W/cm2 intensity I(SATA)). RESULTS: Increased fibrinolysis (31.2%, P=0.028) was observed after concomitant ultrasound exposure of clot and streptokinase solution at 0.5 W/cm2 intensity. Compared to unexposed streptokinase solution, the lytic effect following exposure of streptokinase solution to ultrasound was significantly increased (32.7%, P=0.002). This enhancement effect disappeared at intensity 1 W/cm2, whilst further increase to 4.0 W/cm2 inhibited the lytic effect of streptokinase, both during concomitant exposure (-25.2%, P=0.028) and after pre-exposure of streptokinase solution to ultrasound (-25.4%, P=0.002). CONCLUSION: The fibrinolytic property of streptokinase is modulated by exposure to pulsed ultrasound of frequency 1 MHz, being enhanced at low intensity and inhibited at high intensity.

Direct action on the molecule is one of several mechanisms by which ultrasound enhances the fibrinolytic effects of reteplase.

Enhanced fibrinolytic reperfusion therapy may improve the outcome in embolic stroke, where ultrasound exposure has been shown to be one option. We recently verified that the fibrinolytic properties of streptokinase were modulated following ultrasound exposure of the molecule. We have now explored this possibility following ultrasound exposure of the reteplase molecule. The effects on clot lysis of reteplase and ultrasound both separately and in combination were studied by evaluating cumulated release of haemoglobin from whole blood clots following 1 h of exposure. Specifically, we investigated how clot lysis was modulated following pulsed 1 MHz ultrasound pre-exposure of the reteplase solution at intensities ranging between 0.125 and 4 W/cm2 spatial-average temporal-average intensity (SATA) and the effects of reteplase following 1 h of pre-exposure of clots to ultrasound at high intensity (4 W/cm2SATA). Significant enhancement of clot lysis during concomitant reteplase and pulsed ultrasound exposure were observed in two intensity ranges: 0.125-0.25 and 2-4 W/cm2SATA. Pre-exposing reteplase solution to ultrasound significantly increased clot lysis only in the lower intensity range. At high ranges, pre-exposure of clots to ultrasound was followed by an increased fibrinolytic action of reteplase. Pre-exposing reteplase solution to low-intensity ultrasound induced changes in the reteplase molecule that enhanced its fibrinolytic effects. Although this effect disappeared at moderately higher ultrasound intensity, the pre-exposure of clots to ultrasound of higher intensity induced increased fibrinolytic effects of reteplase solution.

Prediction of sinus rhythm maintenance following DC-cardioversion of persistent atrial fibrillation - the role of atrial cycle length.

BACKGROUND: Atrial electrical remodeling has been shown to influence the outcome the outcome following cardioversion of atrial fibrillation (AF) in experimental studies. The aim of the present study was to find out whether a non-invasively measured atrial fibrillatory cycle length, alone or in combination with other non-invasive parameters, could predict sinus rhythm maintenance after cardioversion of AF. METHODS: Dominant atrial cycle length (DACL), a previously validated non-invasive index of atrial refractoriness, was measured from lead V1 and a unipolar oesophageal lead prior to cardioversion in 37 patients with persistent AF undergoing their first cardioversion. RESULTS: 32 patients were successfully cardioverted to sinus rhythm. The mean DACL in the 22 patients who suffered recurrence of AF within 6 weeks was 152 +/- 15 ms (V1) and 147 +/- 14 ms (oesophagus) compared to 155 +/- 17 ms (V1) and 151 +/- 18 ms (oesophagus) in those maintaining sinus rhythm (NS). Left atrial diameter was 48 +/- 4 mm and 44 +/- 7 mm respectively (NS). The optimal parameter predicting maintenance of sinus rhythm after 6 weeks appeared to be the ratio of the lowest dominant atrial cycle length (oesophageal lead or V1) to left atrial diameter. This ratio was significantly higher in patients remaining in sinus rhythm (3.4 +/- 0.6 vs. 3.1 +/- 0.4 ms/mm respectively, p = 0.04). CONCLUSION: In this study neither an index of atrial refractory period nor left atrial diameter alone were predictors of AF recurrence within the 6 weeks of follow-up. The ratio of the two (combining electrophysiological and anatomical measurements) only slightly improve the identification of patients at high risk of recurrence of persistent AF. Consequently, other ways to asses electrical remodeling and / or other variables besides electrical remodeling are involved in determining the outcome following cardioversion.

Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.

BACKGROUND: Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but dose adjustment, coagulation monitoring, and bleeding risk limit its use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative. We aimed to establish whether ximelagatran is non-inferior to warfarin, within a margin of 2% per year, for prevention of stroke and systemic embolism. METHODS: We randomised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin (adjusted-dose, international normalised ratio [INR] 2.0-3.0) or ximelagatran (fixed-dose, 36 mg twice daily); patients were recruited from 259 hospitals, doctor's offices, or health-care clinics. Primary analysis was based on masked event assessment and was by intention to treat. Primary endpoint was stroke or systemic embolism. FINDINGS: During 4941 patient-years of exposure (mean 17.4 months, SD 4.1), 96 patients had primary events (56 in the warfarin group vs 40 in the ximelagatran group). The primary event rate by intention to treat was 2.3% per year with warfarin and 1.6% per year with ximelagatran (absolute risk reduction 0.7% [95% CI -0.1 to 1.4], p=0.10; relative risk reduction 29% [95% CI -6.5 to 52]). Rates of disabling or fatal stroke, mortality, and major bleeding were similar between groups, but combined minor and major haemorrhages were lower with ximelagatran than with warfarin (29.8% vs 25.8% per year; relative risk reduction 14% [4 to 22]; p=0.007). Raised serum alanine aminotransferase was more common with ximelagatran. INTERPRETATION: In high-risk patients with atrial fibrillation, fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism.

Time-frequency analysis of the surface electrocardiogram for monitoring antiarrhythmic drug effects in atrial fibrillation.

This study explored time-frequency analysis of surface electrocardiograms in patients with persistent atrial fibrillation for monitoring atrial drug action. Drug loading over 3 days with oral flecainide (n = 13) or amiodarone (n = 17) organized the fibrillatory process expressed by decreased atrial fibrillatory rate, increased rate stability, and decreased exponential decay. Effects were more pronounced with flecainide than with amiodarone.

Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.

CONTEXT: In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use. OBJECTIVE: To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors. INTERVENTIONS: Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. MAIN OUTCOME MEASURES: The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model. RESULTS: During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, -0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, -0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, -14% to -6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred. CONCLUSIONS: The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.