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Original Contribution |

Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation:  A Randomized Trial FREE

SPORTIF Executive Steering Committee for the SPORTIF V Investigators
[+] Author Affiliations

Authors/SPORTIF Executive Steering Committee: Stanford Stroke Center, Palo Alto, Calif (Gregory W. Albers, MD); Department of Neurology, University of Essen, Essen, Germany (Hans-Christoph Diener, MD); Department of Biostatistics, AstraZeneca Research and Development Mölndal, Mölndal, Sweden (Lars Frison, PhD); Departments of Clinical Science (Margaretha Grind, MD, PhD), Clinical Project Management (Mark Nevinson, BPharm), and Clinical Development (Stephen Partridge, PhD), AstraZeneca Research and Development Charnwood, Charnwood, England; Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (Jonathan L. Halperin, MD); Department of Clinical Development, AstraZeneca LP, Wilmington, Del (Jay Horrow, MD); Department of Cardiology, University Hospital, Lund, Sweden (S. Bertil Olsson, MD, PhD); Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark (Palle Petersen, MD, DMSc); and Department of Cardiology, Hospital Tenon, Paris, France (Alec Vahanian, MD).

More Author Information
JAMA. 2005;293(6):690-698. doi:10.1001/jama.293.6.690.
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Published online

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.

Figures in this Article

Nonvalvular atrial fibrillation is implicated in nearly 15% of strokes.1 By meta-analysis of 6 randomized trials, dose-adjusted warfarin decreases stroke risk by 62%.2,3 In practice, the risk of bleeding limits treatment with warfarin, particularly among the elderly. Variability of anticoagulation intensity from interactions with foods and medication4 necessitates frequent monitoring and dose adjustments yet leaves patients outside the therapeutic range almost half the time.5,6 Underuse of warfarin in patients with atrial fibrillation at high risk of bleeding5,6 calls for safer, more dependable alternatives.7,8

The direct thrombin inhibitor ximelagatran offers fixed oral dosing without need for coagulation monitoring, rapid onset and offset of action, stable pharmacokinetics with little potential for drug interactions, and no known food interactions.912 The SPORTIF (Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation) program included 2 long-term trials comparing ximelagatran to warfarin for prevention of thromboembolism in patients with atrial fibrillation. The open-label SPORTIF III study found ximelagatran at least as effective as warfarin.13 This report describes SPORTIF V, based on the same protocol except that anticoagulation was administered in a double-blinded manner.

The rationale, design, and patient characteristics of the SPORTIF V trial have been previously described.13,14 Briefly, the trial compared fixed-dose oral ximelagatran with adjusted-dose warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation requiring chronic anticoagulant therapy. The executive steering committee developed the protocol, guided study execution masked to treatment outcomes, and prepared results for publication with unrestricted access to data. The sponsor provided 2 of the 8 voting members.

Patients

Written consent was required from each patient according to a protocol approved by local institutional review boards and compliant with the Declaration of Helsinki. Between August 2, 2000, and December 7, 2001, a total of 3922 patients were randomized at 409 sites in the United States and Canada, including academic and nonacademic offices and clinics attended by both general practitioners and specialists. Entry criteria were based on current guidelines for anticoagulation and required at least 1 of the following risk factors in addition to persistent or paroxysmal nonvalvular atrial fibrillation: previous stroke, transient ischemic attack, or systemic embolism, hypertension, left ventricular dysfunction (ejection fraction <40% or symptomatic systolic or diastolic heart failure), aged 75 years or older, or aged 65 years or older with known coronary disease or diabetes mellitus.15,16 Race and ethnicity were classified according to self-report.

Treatment Allocation

Treatment was randomized to either adjusted-dose warfarin, target international normalized ratio (INR) 2.0 to 3.0, or fixed-dose ximelagatran, 36 mg twice daily, according to a centralized adaptive allocation algorithm that balanced groups according to concurrent aspirin use at entry and previous thromboembolism.17 Using a double-dummy design to maintain blinding, all patients received both assigned anticoagulant and placebo and underwent blood sampling at intervals of 31 days or fewer. Most INR measurements (86%) were made by finger-stick sampling using uniform point-of-care devices (ProTime, Microcoagulation System, International Technidyne Corp, Edison, NJ). Another 14% were performed at a commercial laboratory (Quest Diagnostics Inc, Van Nuys, Calif); fewer than 1% involved local laboratories, with results reported to unblinded personnel not engaged in patient management or assessment. Warfarin dose was based on actual INR results, with adherence estimated by linear interpolation as proportion of time in the therapeutic range.18,19 For patients assigned to ximelagatran, sham INR values were generated to mimic variations on warfarin; compliance was estimated by tablet counts. Aspirin was permitted16 in doses up to 100 mg daily, but nonsteroidal anti-inflammatory medication was limited to 7 days or fewer per month. Other antithrombotic medications were prohibited.

End Points and Assessments

The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events (Box). After randomization, patients were seen at weeks 1, 4, and 6; months 2, 3, 4, 5, 6, 8, 10, and 12; and every 3 months thereafter. Primary events were evaluated as early as feasible based on clinical findings and brain imaging. Detection was enhanced by administering a stroke-symptom questionnaire every 6 months. Positive responses prompted evaluation by study-affiliated neurologists who were blinded to treatment. An independent, blinded, central event adjudication committee reviewed the reports. Stroke severity was assessed 3 months after an event, according to the modified Rankin20 and Barthel indices.21

Box. Adjudicated Events and End Point Definitions

Events

Stroke: Abrupt onset of a focal neurological deficit in the distribution of a brain artery persisting more than 24 hours or due to intracerebral hemorrhage.

Death

Transient ischemic attack: Abrupt onset of a focal neurological deficit in the distribution of a brain artery persisting less than 24 hours.

Systemic embolic event (SEE): Abrupt vascular insufficiency associated with clinical and radiological evidence of arterial occlusion in the absence of another likely mechanism.

Acute myocardial infarction: At least 2 of the following: (1) typical chest pain for at least 20 minutes; (2) electrocardiogram showing changes of acute myocardial infarction; and (3) cardiac enzyme elevation more than twice the upper limit of normal.

Major bleeding: Bleeding that was fatal or clinically overt and associated with either transfusion of 2 units or more of blood or a 20-g/L or more decrease in hemoglobin or bleeding that was intracranial, retroperitoneal, spinal, ocular, pericardial, or atraumatic articular. (Intracranial bleeding excludes intracerebral hemorrhages, which were counted as primary events.)

End Points

Primary: Stroke (ischemic or hemorrhagic) and SEE.

Secondary

  1. Stroke, SEE, death, acute myocardial infarction

  2. Ischemic stroke, transient ischemic attack, SEE*

  3. Major bleeding

  4. Major and bleeding†

*The central event adjudication committee categorized strokes as ischemic or hemorrhagic.
†Reported by local investigators but did not satisfy criteria for major bleeding.

Because in an earlier study22 4.3% of patients taking ximelagatran developed serum alanine aminotransferase (ALT) concentrations higher than 3 times the upper limit of normal (ULN), liver function (ALT, aspartate aminotransferase, alkaline phosphatase, and total bilirubin) was tested at least monthly for 6 months, then bimonthly for the first year, and then quarterly. Weekly testing was required if any value exceeded 3 times the ULN, and drug discontinuation was required if a value exceeded 3 times the ULN for 4 weeks or 7 times the ULN at any time or clinical hepatotoxicity developed. In October 2001, limits were modified to twice the ULN for weekly testing and 5 times the ULN for drug discontinuation.

Statistical Analyses

The primary analysis compared treatment efficacy for first occurrence of a primary event among all randomized patients according to the intention-to-treat (ITT) principle, assuming a constant event rate over time. The objective was to establish whether ximelagatran was noninferior23 to warfarin within an absolute margin of 2.0% per year for the difference in rates of primary events.14,24 This margin was based on the expected rate during warfarin therapy and a prespecified judgment about clinically meaningful difference. The criteria required that the upper bound of the 1-sided 97.5% confidence interval (CI) for the difference in event rates not exceed 2.0% per year. The P value for noninferiority is the probability of incorrectly rejecting the prespecified null hypothesis that the true difference between event rates (ximelagatran-warfarin) exceeds 2% per year.

The ITT analysis included all patients, regardless of adherence, with exposure truncated at last contact. Confirmatory sensitivity analyses included all-cause mortality in addition to the primary end point and on-treatment analysis of the primary end point excluding events beyond 30 consecutive or 60 cumulative days off randomized treatment. Accumulation of primary events and deaths continued until study closure, even if assigned treatment was stopped, whereas other events were recorded during the period on treatment. Unless otherwise stated, analyses of end points composed of only stroke, systemic embolism, or death were based on ITT; other analyses used the on-treatment approach. All analyses were performed using SAS version 8.2 software (SAS Institute, Cary, NC) and are reported as the number of patients experiencing each event or composite.

The protocol stipulated exposure of at least 12 months per patient, at least 4000 patient-years of aggregate follow-up, and at least 80 patients with verified primary events. This provided 90% power to demonstrate noninferiority for aggregate primary event rates of 4.0% per year or less, based on 1-sided α = 0.025. The data and safety monitoring board conducted interim analyses at approximately 12.5%, 25%, 50%, and 75% of total exposure. The Lan-DeMets quadratic α spending function guided safety monitoring.25 This group sequential stopping rule was applied only for negative trends along safety parameters prespecified before accessing unblinded data. Interim analyses for the primary end point were guided by the Haybittle-Peto group sequential boundaries, requiring no adjustments to the final analysis.26,27 Based on analysis of the event rate after 50% of exposure elapsed, the data safety monitoring board recommended extension of accrual to accumulate the requisite number of events.

Patients and Follow-up

The study included 3922 patients randomly assigned, including 3 of 1960 without qualifying risk factors in the ximelagatran group and 4 of 1962 in the warfarin group (Figure 1). This resulted in a net exposure of 6405 patient-years for the primary outcome. Nine patients assigned to receive warfarin and 6 to receive ximelagatran did not take either study drug. Although none developed end point events, all were included in ITT analyses. Ninety-six percent of patients were white; 69%, men; 2193 (56%), previous smokers; and 2314 (59%) denied regular alcohol use. The mean (SD) age was 72 (9.1) years; weight averaged 90 (22) kg: 95 (20) kg for men and 78 (20) kg for women. Of the total study population, 1658 patients (42%) were aged at least 75 years, 3307 (84%) had atrial fibrillation for at least a year, and 3367 (86%) had persistent atrial fibrillation. In addition to atrial fibrillation, 2916 patients (74%) had 2 or more stroke risk factors. Before entry, 3278 patients (84%) were taking a vitamin K antagonist (usually warfarin); 719 (18%), acetylsalicylic acid; 1909 (49%), a β-adrenergic antagonist; 1875 (48%), an angiotensin-converting enzyme inhibitor; 1442 (37%), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin); and 177 (4.5%), amiodarone. During the study, patients took a median of 12 other prescribed medications. Clinical characteristics were balanced between treatment groups (Table 1) and were similar to cohorts in earlier trials demonstrating superiority of warfarin over placebo for prevention of atrial fibrillation–related stroke.13,14

Table Graphic Jump LocationTable 1. Characteristics of Randomized Patients According to Randomized Treatment Assignment*

In patients assigned to receive warfarin, the mean (SD) INR across all measurements was 2.4 (0.8). Values fell within target range (2.0-3.0) for 68% of the time on treatment, below 2.0 for 20%, above 3.0 for 12%, and between 1.8 and 3.2 for 83%. Anticoagulation intensity was within target range at least half the time on treatment in 1667 patients (85%) assigned to receive warfarin. For 1389 patients (71%) receiving ximelagatran, compliance was 90% or higher, and sham INR values averaged a mean (SD) of 2.4 (0.6) over more than 38 000 measurements.

Mean (SD) follow-up was 20 (5.1) months in both treatment groups (overall median, 20; range, 0-31 months), yielding 3212 patient-years at risk in the warfarin group and 3193 in the ximelagatran group. Thirty-five percent of patients prematurely stopped treatment, 640 (33%) assigned to receive warfarin and 718 (37%) assigned to receive ximelagatran (P = .01). At the end of the trial, special efforts to ascertain the vital status of 226 patients (6%) who interrupted follow-up disclosed no additional cases of stroke and 8 deaths in 104 of 119 patients assigned to receive ximelagatran (status remained unknown for 15) and none with stroke and 7 deaths in 99 of 107 such patients in the warfarin group (8 unknown). A total of 137 patients (7.0%) in the warfarin group and 130 (6.6%) in the ximelagatran group stopped assigned treatment when end points occurred. In the warfarin group, 205 (10.6%) chose to stop treatment and 175 (8.9%) stopped because of adverse events compared with 197 (10.0%) and 238 (12.1%), respectively, with ximelagatran, the latter due mainly to elevation of serum transaminase enzymes.

Treatment Outcomes

Primary End Points. The central event adjudication committee confirmed primary events in 37 patients assigned to receive warfarin and 51 patients assigned to receive ximelagatran, corresponding to incidence rates of 1.16% and 1.61% per year, respectively (P = .13 for a difference between treatments). The P value for noninferiority, that is, the probability of incorrectly rejecting the prespecified null hypothesis that the true difference between event rates (ximelagatran-warfarin) exceeds 2% per year was lower than .001. The upper bound of the 95% confidence interval (CI) surrounding the difference of 0.45% per year was 1.03, well below the specified margin of 2.0% per year (Figure 2). Of primary events among patients assigned to warfarin, 37 were ischemic strokes, 2 were hemorrhagic strokes, and 1 was systemic embolism; 3 patients had multiple events. In the patients assigned to receive ximelagatran, there were 49 ischemic strokes, 2 hemorrhagic strokes, and 6 systemic embolic events; 6 patients experienced multiple events (Table 2).

Figure 2. Kaplan-Meier Analysis of Primary Outcomes
Graphic Jump Location
Table Graphic Jump LocationTable 2. Rates of Primary and Secondary Events According to Assigned Treatment*

The secondary on-treatment analysis discounted events occurring after treatment cessation in 9 patients assigned to receive warfarin and 10 assigned to receive ximelagatran, rates of 1.02% and 1.57% per year, respectively, difference 0.55% per year (95% CI, −0.06% to 1.2% per year). Results were similar using a shorter 10-day period off-treatment (event rate difference, 0.44% per year; 95% CI, −0.14% to 1.01% per year). Among those taking warfarin, all 28 primary events were ischemic strokes; one patient also developed hemorrhagic stroke. In the 23 patients with values available within 30 days of ischemic stroke, INR was no more than 2.0 in 9 (39%). Among 41 patients developing primary events while taking ximelagatran, there were 35 ischemic strokes, 1 hemorrhagic stroke, and 6 systemic embolic events (1 patient had multiple events).

Secondary End Points. Fifty-two patients taking warfarin experienced ischemic stroke, transient ischemic attack, or systemic embolism (1.9% per year) compared with 67 given ximelagatran (2.6% per year; P = .12; on-treatment analysis; Table 2). There were 123 deaths (3 fatal strokes) in the warfarin group and 116 (10 fatal strokes) in the ximelagatran group (ITT analysis). Nonfatal disabling stroke (modified Rankin score ≥3 or Barthel index <60) occurred in 7 patients in the warfarin group and 6 in the ximelagatran group. Composite rates for all-cause mortality plus primary events were 4.7% and 4.8% per year, respectively. The composite end point of stroke, systemic embolism, myocardial infarction, or death occurred in 119 patients taking warfarin (4.3% per year) and 110 taking ximelagatran (4.2% per year; P = .84).

Hemorrhage. Hemorrhagic strokes (included as primary events) occurred in 2 patients in each group (0.06% per year; Table 3). Seven patients in the warfarin group and 5 in the ximelagatran group developed subdural hematoma. Major extracerebral bleeding occurred in 84 patients assigned to the warfarin group (3.1% per year) and in 63 assigned to the ximelagatran group (2.4% per year), a reduction of 0.66% per year (95% CI, –1.55% to 0.23% per year). Of confirmed major hemorrhages, bleeding was fatal in 1 patient assigned to the warfarin and 2 assigned to the ximelagatran groups. Decreased hemoglobin accounted for 41% and transfusion for 5% of major bleeding; proportions were similar in both treatment groups. Among the 84 patients in the warfarin group with major bleeding, INR exceeded 3.0 in 20 cases. Considering minor plus major hemorrhages, there was significantly more bleeding among patients receiving warfarin (903 patients, 47% per year) than ximelagatran (737 patients, 37% per year; relative risk reduction 21%; 95% CI, –14 to –6.0% per year; for the difference, P<.001). The 571 patients (15%) who took aspirin (≤100 mg/d) along with the anticoagulant at any time during the trial had higher overall (major and minor) bleeding rates (41% per year with ximelagatran, 69% per year with warfarin) than those not taking aspirin (37% per year with ximelagatran, 44% per year with warfarin).

Other Adverse Events. Adverse events other than bleeding occurred with equal frequency in both groups (Table 3). In 117 patients (6.0%) taking ximelagatran, serum ALT levels rose to higher than 3 times ULN compared with 15 patients taking warfarin (0.8%; P<.001). Elevations typically occurred between 2 and 6 months after initiating treatment and returned toward baseline without clinical sequelae either spontaneously (45 patients) or after treatment cessation (68 patients). Alanine aminotransferase levels returned to below the ULN in all but 5 patients, including 1 who died 3 days after repair of an iliac artery aneurysm, 1 whose serum ALT level of 165 U/L and bilirubin level was normal 2 weeks before death from ischemic heart disease, and 1 for whom no follow-up information could be obtained. The other cases are discussed below.

Within 30 days of ALT concentration elevation higher than 3 times the ULN, total serum bilirubin concentration rose above twice the ULN in 9 patients taking ximelagatran and 1 taking warfarin. One patient with serum ALT higher than 3 times ULN 85 days after beginning ximelagatran treatment displayed hepatic necrosis on liver biopsy result 20 days after stopping the drug. This patient died 145 days after random assignment following corticosteroid treatment; autopsy revealed resolving hepatitis (nodular islands of regenerating hepatocytes without active inflammation) and hemorrhagic perforation of a duodenal ulcer. Another patient whose serum ALT concentrations reached 11 times the ULN with ximelagatran (total serum bilirubin, 1.6 mg/dL (27.4 μmol/L), 1.45 times the ULN) developed fatal gastrointestinal hemorrhage.

In this double-blind trial involving relatively high-risk patients with nonvalvular atrial fibrillation, the direct thrombin inhibitor ximelagatran was noninferior to well-controlled warfarin within the prespecified margin of 2.0% per year for prevention of stroke and systemic embolism. The difference in primary event rates between treatments was 0.45% per year in the ITT model, and the upper bound of the 95% CI surrounding this difference was 1.03% per year. Hence, the probability of rejecting noninferiority was <.001 for the specified margin (2.0% per year) and 0.06 for a margin of 1.0% per year. Although the warfarin dose was regulated to maintain anticoagulation within a narrow range while ximelagatran was administered in fixed dose without anticoagulation monitoring, there was no increase in bleeding (indeed, less minor bleeding) with ximelagatran.

Thrombin plays a pivotal role in fibrin formation and activation of platelets and other coagulation factors in a variety of cardiovascular diseases. Although anticoagulants such as warfarin and heparin inhibit thrombin indirectly, ximelagatran, rapidly converted to melagatran after oral administration, inhibits soluble and fibrin-bound thrombin directly.28,29 In previous studies, ximelagatran compared favorably with warfarin or low-molecular-weight heparin for prevention and treatment of venous thromboembolism3033 and in combination with aspirin was superior to aspirin alone for prevention of ischemic events in patients with acute coronary syndromes.34

The well-established and accepted efficacy of warfarin for prevention of thromboembolism in high-risk patients with nonvalvular atrial fibrillation made a placebo-controlled study unethical; hence, the protocol was based on noninferiority analysis using an active control.14,24 The primary analysis demonstrating comparable efficacy was sustained when all-cause mortality was included or primary events were evaluated by on-treatment analyses. Although there were fewer events in the warfarin group, the absolute difference of <0.5% per year was not statistically significant. There was a lower rate of total bleeding with ximelagatran but no significant difference in major hemorrhage rates.

Secondary efficacy analyses mirror the primary analysis. The composite of all stroke, systemic embolism, death, and myocardial infarction occurred with similar frequency in both groups, as did a composite limited to ischemic events. Consistency in both primary and secondary end points strengthens confidence in the noninferiority assessment.

Enrolled patients represented those typical in clinical practice, bearing considerable cardiovascular comorbidity as reflected in their advanced age, stroke risk profiles, and concurrent medications. Even so, rates of thromboembolism were low, 1.4% per year overall. Among high-risk cohorts in previous trials, thromboembolism rates were more than 7% per year without anticoagulation35 and 2.4% per year with warfarin (range, 0.6%-3.1% per year).2 The quality of anticoagulation control with warfarin was better in our trial than in previous studies and seldom achieved in practice but comparable with SPORTIF III.13 The low warfarin event rate2,14 may reflect better dose regulation, control of hypertension or hyperlipidemia, other differences in patient characteristics or management, or chance.

Rates of intracerebral hemorrhage during treatment were exceptionally low, but extracerebral hemorrhage was more frequent than in other randomized trials. This reflects the criterion of declining hemoglobin of 2 g/dL or higher, without which major bleeding was 2.1% per year in the warfarin group, comparable with previous studies,2 and 1.6% per year in the ximelagatran group (P = .22). Liberal reporting criteria for minor bleeding may have captured some episodes of little clinical importance.

The combination of low rates of stroke and cerebral hemorrhage might be explained by control of hypertension. Mean systolic blood pressure was 133 mm Hg even though 80% of patients had a history of hypertension at entry. In a recent trial involving patients with atrial fibrillation, lowering systolic blood pressure by 9 mm Hg reduced ischemic stroke by nearly 30% and halved the rate of intracerebral hemorrhage.36 Control of hypertension seems to be a critically important adjunct to antithrombotic therapy to avoid adverse neurological outcomes in patients with atrial fibrillation.

The incidence of serum ALT concentration elevations higher than 3 times the ULN (6.0%) was similar to that in previous clinical trials of ximelagatran.13,22,33,34 This reaction typically occurred 1 to 6 months after initiation and then normalized, whether or not treatment continued. In at least 1 case, however, severe hepatitis developed with fatal gastrointestinal hemorrhage. Despite extensive investigation, the mechanism of ALT elevation remains unknown, though numerous types of reactions known to cause hepatotoxicity have been excluded.37,38 Surveillance of serum enzymes prior to and during therapy is necessary to exclude patients with elevated levels and minimize the risk of hepatotoxicity.

Ximelagatran is eliminated mainly through renal clearance, and patients with a creatinine clearance lower than 30 mL/min (0.501 mL/s) were excluded. The relative safety and efficacy of ximelagatran and warfarin should not be extrapolated to patients with valvular heart disease, pregnancy, or severe renal insufficiency or to those undergoing cardioversion of atrial fibrillation without additional experience in these clinical situations.

The SPORTIF V trial is the largest yet reported trial involving patients with atrial fibrillation for prevention of stroke and systemic embolism. Low rates of thromboembolism and bleeding occurred when ximelagatran was given in a fixed dose without anticoagulation monitoring. Further investigation is needed to clarify the risk of serious hepatic reactions and identify predictive features to select appropriate patients for treatment with ximelagatran. In the balance are a large number of potentially preventable fatal or disabling strokes that accumulate as a consequence of the limitations and underutilization of warfarin.

Corresponding Author: Jonathan L. Halperin, MD, The Zena and Michael A. Wiener Cardiovascular Institute and The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10024 (Jonathan.Halperin@msnyuhealth.org).

Author Contributions: Dr Halperin, as a principal investigator of this trial, had complete access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analyses.

An independent data and safety monitoring board (DSMB) that included academic statisticians and no employees of the sponsor oversaw patient safety, had access to all data, and independently confirmed the results at an independent statistical center at the University of Wisconsin under the direction of David DeMets, PhD.

Study concept and design: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Acquisition of data: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Analysis and interpretation of data: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Drafting of the manuscript: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Critical revision of the manuscript: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Statistical analysis: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Obtained funding: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Administrative, technical, or material support: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Study supervision: Albers, Diener, Frison, Grind, Halperin, Horrow, Nevinson, Olsson, Partridge, Petersen, Vahanian.

Financial Disclosures: Drs Diener, Halperin, Olsson, Petersen, and Vahanian have served as consultants to and have been paid lecture fees by AstraZeneca. Dr Albers has served as a consultant to and has been paid lecture fees by AstraZeneca and Boehringer Ingelheim and has received grant support from the National Institutes of Health, Warner-Lambert, Parke-Davis, AstraZeneca, Fujisawa USA, Boehringer Ingelheim, Aventis, Ono, and NMT Medical. Drs Frison, Grind, Horrow, and Partridge and Mr Nevinson are employees of AstraZeneca.

SPORTIF Executive Steering Committee:Voting members: Drs Albers, Diener, Grind, Halperin, co-chairman, Horrow, Olsson, co-chairman, Petersen, and Vahanian. Nonvoting members: Drs Frison and Partridge and Mr Nevinson.

SPORTIF V Steering Committee: Canada: J. Andrews, S. Connolly, and J. Teitelbaum; England: M. Grind and M. Nevinson; Sweden: A. Vieira; and United States: J. L. Halperin, co-chairman, G. Albers, co-chairman, J. Blackshear, R. Ekeland, G. Flaker, J. Ghali, and J. Horrow.

Data and Safety Monitoring Board: Denmark: G. Boysen; England: D. Julian; and United States: R. Hart and D. DeMets.

Data and Safety Monitoring Board Statistical Center: United States: D. DeMets, J. Feyzi, and R. Bechhofer.

Central Event Adjudication Committee:Germany: R. von Kummer, D. Mucha, G. Gahn, A. Schmeisser, A. Müller, H. Reichmann, T. Schwarz, and O. Wunderlich.

SPORTIF V Data Center: Wilmington, Del: D. Cerro, G. Chen, G. Cunningham, R. Ekeland, V. Evans, R. Fountas, T. Garacani, J. McElhattan, D. Peterson, J. Sugg, A. Travalent, C. Xu, S. Yuan.

Contributing Centers’ Principal Investigators: Canada:Alberta: P. Ma and T. Winder; British Columbia: K. G. Gin, C. Kerr, D. Novak, and W. Shtybel; Manitoba: A. Morris and N. Shaikh; New Brunswick: P. Bailey; Newfoundland: B. Rose; Nova Scotia: D. Anderson; Ontario: J. C. Berlingieri, T. Bhesania, P. Bolli, D. Borts, Y. K. Chan, L. J. Charles, S. J. Connolly, R. Davies, P. De Young, M. del Campo, H. B. Desai, K. J. C. Finnie, A. Glanz, F. Halperin, K. Kwok, R. Leader, G. Moddel, G. Moe, T. Monchesky, D. Newman, J. M. Niznick, J. W. Norris, A. Panju, E. Raimondo, D. Selchen, M. Sharma, P. Tanser, R. Vexler, and G. Wisenberg; Quebec: J. Bedard, L. Berger, J. Champagne, C. Constance, L. Desjardins, C. Fortin, A. F. Gagnon, F. Grondin, P. LeBouthillier, L. H. Lebrun, J. Lenis, J. Minuk, D. Savard, D. Simard, M. Talajic, J. Teitelbaum, and C. Van Kieu; and Saskatchewan: N. Habib and A. Rajput; United States: Alabama: W. H. Haught and M. B. Williams; Arkansas: G. S. Greer, J. L. Hargrove, R. F. Hundley, and E. Smith; Arizona: R. Ashar, B. M. Coull, J. L. Evans, P. E. Fenster, J. L. Frey, M. C. Goldberg, S. Goldman, R.E. Halligan, Jr, R. R. Heuser, A. J. Kaplan, R. Patel, B. D. Peart, G. Pennock, R. M. Siegel, and G. K. Watson; California: P. Akins, G. W. Albers, P. Applegate, M. K. Ariani, W. F. Baker, Jr, S. B. Baron, D. Blanchard, K. W. Carr, C. Chen, B. B. Cleeremans, A. P. Corr, P. C. Deedwania, G. W. Dennish, M. A. Drehobl, B. Elias, G. Emlein, C. Feind, D. M. Gallik, R. J. Grossman, R. E. Gwynn, J. M. Hagar, S. W. Halpern, J. Hambleton, J. M. Hawkins, Jr, D. Hill, G. Hilliard, A. G. Israel, B. K. Jackson, A. K. Jacobson, A. D. Johnson, B. Joshi, K. Jutzy, R. A. Kaplan, P. E. Linz, P. R. Mahrer, R. H. Miller, P. M. Moloney, M. Nathan, G. O'Neill, W. D. O'Riordan, G. Pauls, K. Rapeport, D. E. Rediker, S. G. Rockson, H. R. Shah, S. Shapiro, T. L. Shook; R. A. Shubin, J. Sklar, L. W. Sprinkle, D. M. Stieber, M. Sullivan, M. J. Tonkon, B. A. Volpi, R. White, and L. G. Yellen; Colorado: P. Coleman, E. P. Havranek, R. Levy, B. L. Molk, N. Vijay, and W. Voyles; Connecticut: P. E. Barwick, W. Gorgan, C. Landau, B. D. Pollack, A. M. Rashkow, A. Roselli, J. Rosen, D. I. Silverman, and E. F. Smith; Delaware: R. W. Powell and H. Weiner; Florida: R. Abadier, K. Adams, M. Amin, M. Basnight, R. Betzu, J. L. Blackshear, A. J. Bradley, S. S. Brady, J. F. Butler, N. R. Cho, C. W. Crandall, D. de Guia, M. El Shahawy, H. Feldman, R. L. Feldman, T. Feldman, J. A. Fialkow, R. A. Filart, M. Frey, V. R. Geer, C. A. Hamburg, K. J. Kaplan, S. G. Keim, D. M. Kenton, E. M. Kolettis, M. Koren, G. A. Lamas, R. M. Luceri, M. Mollod, A. L. Niederman, D. M. Normandin, J. P. O'Bryan, B. Pierpont, R. Powell, K. Ranadive, C. P. Riley, E. W. Rogers, Jr, M. Rubin, R. M. Schneider, R. C. Sheppard, V. N. Singh, J. O. Smith, C. M. Sotolongo, R. Tobar, G. Vitiello, R. Vitullo, W. R. Wainwright, J. L. Walker, W. H. Willis, and R. G. Zoble; Georgia: R. Ahmed, S. Beer, D. M. Clark, T. F. Deering, N. Dhruva, M. I. Harris, J. Liss, T. Monitz, P. M. Murray, V. Robinson, and N. K. Wenger, Idaho: S. Fonken; Illinois: M. H. Davidson, D. W. Dixon, J. J. Giardina, R. Kinn, J. G. Shanes, and A. S. Volgman; Indiana: D. M. Denny, C. R. Gest, J. H. Hall, E. N. Prystowsky, amd W. W. Wilson; Kansas: E. L. Franks, T. C. Klein, L. M. Reusser, and D. Vine; Kentucky: G. Fuchs, L. C. Pettigrew, J. L. Smith, and M. F. Stoddard, Louisiana: F. M. Abi-Samra, D. H. Banish, V. K. Bethala, B. G. Denys, R. H. Fei, J. K. Ghali, M. A. Gomez, U. A. Patel, P. C. Reddy, W. B. Smith, and E. Wong; Massachusetts: M. Baig, S. Bilazarian, J. Ellis, R. H. Falk, S. Z. Goldhaber, T. C. Hack, D. Hirsch, M. Katcher, D. E. Loew, M. E. Motta, amd F. Scheel; Maryland: D. E. Bush, R. L. Desmarais, R. J. Feldman, S. O. Gottlieb, S. E. Hearne, J. Porterfield, J. L. Raffetto, K. W. Sullivan, and J. W. Zebley; Maine: R. J. Weiss; Michigan: S. M. A. Jafri, S. Kaatz, R. Kothari, T. B. Levine, J. McCord, and J. R. Schairer; Minnesota: S. W. Adler II, I. M. Altafullah, J. Chambers, J. M. Haugland, S. A. Kuross, and W. K. Shen; Missouri: G. Flaker, M. Gleva, A. J. Labovitz, L. V. Lee, M. E. Lucas, T. M. Siler, and P. N. Tadros; Montana: D. Dietrich; NorthCarolina: G. Arnold, T. E. Borresen, R. DonDiego, W. Ferrell, P. Goodfield, W. T. Maddox, Jr, S. Mediratta, R. M. Rothbart, J. Rubino, P. S. Vrooman, Jr; A. L. Wellford, and J. D. Williamson; Nebraska: A. Arouni and J. T. Haas; New Hampshire: E. J. Funk and B. Gerling; New Jersey: M. Biehl, K. Chandrasekaran, L. J. Gessman, J. Kramer, K. A. Levin, D. Shindler, N. G. Tullo, M. Williams, and H. K. C. Yu; New Mexico: C. H. Karian and N. Shadoff, Nevada: J. Christensen, I. L. Goldsmith, S. H. Miller, and A. D. Steljes; New York: L. Baruch, A. J. Binder, D. Bloomfield, R. Carhart, J. L. Halperin, E. N. Heller, K. Marzo, R. Mendelson, D. L. Roberts, J. D. Sacco, J. S. Steinberg, R. H. Steingart, and G. Turitto; Ohio: G. J. Fishbein, T. Isakov, D. Katula, A. Klein, W. R. Lewis, S. L. Moore, and N. H. Smiley; Oklahoma: J. L. Anderson, D. L. Brewer, T. F. McGarry, Jr, and T. L. Whitsett; Oregon: D. L. Dawley, S. J. Lewis, J. H. McAnulty, Jr, and S. D. Promisloff, Pennsylvania: B. L. Alpert, A. D. Belber, M. Cohen, J. Doherty, G. S. Garibian, M. J. Geller, J. M. George, D. B. Goldner, A. M. Greenspan, P. Grena, D. Karalis, J. D. Krantzler, E. W. LaPorta, P. Lavine, M. R. Modi, V. K. Nadar, D. Santram, R. S. Small, J. Spandorfer, S. L. Zelenkofse, and G. M. Ziady; Rhode Island: A. R. Hordes and J. H. Klie; South Carolina: W. H. Collins III, B. T. McLaurin, B. R. Reeves, Jr; and G. San; South Dakota: L. M. Gutnik; Tennessee: J. Cox, Jr, C. L. Gruver, E. C. Madu, and D. M. Salerno; Texas: M. R. Berk, R. K. Bhalla, G. A. Buser, L. Campos, P. W. Dlabal; M. A. Franco, W. G. Friesen, D. A. Hector, A. Jain, D. J. Kessler, B. D. Loftus, R. Lyons, S. T. Minor, P. A. Overlie, W. C. L. Wu, and M. Zabalgoitia; Utah: M. Plainse and D. A. Rawling; Virginia: A. Caruso, J. S. Golden, A. K. Gupta, N. F. Jarmukli, D. K. Kotlaba, P. F. A. Magee, L. A. Miller, J. Onufer, A. J. Rosenblatt, and C. M. Valentine; Washington: J. King, L. W. Kirkegaard, M. R. Mitchell, and M. J. Wilson; Washington,DC: S. K. Bennett, S. W. Lee, and P. Narayan, Wisconsin: J. C. Bartlett, W. G. Friesen, F. W. Kilpatrick, R. Z. Paster, Y. Shalev, and S. H. Yale.

Funding/Support: This study was funded by AstraZeneca.

Role of the Sponsor: The sponsor, AstraZeneca, participated in the design and conduct of the study. The sponsor collected and managed the data; the sponsor and the data and safety monitoring board performed the analysis of the data, and the executive steering committee interpreted the data. The executive steering committee prepared, reviewed, and approved the manuscript.

Cerebral Embolism Task Force.  Cardiogenic brain embolism: the second report of the Cerebral Embolism Task Force.  Arch Neurol. 1989;46:727-743
PubMed   |  Link to Article
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.  Ann Intern Med. 1999;131:492-501
PubMed   |  Link to Article
Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions.  Arch Intern Med. 1994;154:1443-1448
PubMed   |  Link to Article
Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food.  Ann Intern Med. 1994;121:676-683
PubMed   |  Link to Article
Samsa GP, Matchar DB, Goldstein LB.  et al.  Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.  Arch Intern Med. 2000;160:967-973
PubMed   |  Link to Article
Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.  Ann Intern Med. 1999;131:927-934
PubMed   |  Link to Article
Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin?  Arch Intern Med. 2000;160:41-46
PubMed   |  Link to Article
Frykman V, Beerman B, Ryden L, Rosenqvist M. Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications.  Eur Heart J. 2001;22:1954-1959
PubMed   |  Link to Article
Eriksson UG, Bredberg U, Gislén K.  et al.  Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects.  Eur J Clin Pharmacol. 2003;59:35-43
PubMed
Johansson LC, Frison L, Logren U, Fager G, Gustafsson D, Eriksson UG. The influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;42:381-392
PubMed   |  Link to Article
Sarich TC, Teng R, Peters GR.  et al.  No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor, ximelagatran.  Clin Pharmacokinet. 2003;42:485-492
PubMed   |  Link to Article
Bredberg E, Andersson TB, Frison L.  et al.  Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions.  Clin Pharmacokinet. 2003;42:765-777
PubMed   |  Link to Article
Executive Steering Committee on behalf of the SPORTIF III Investigators.  Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): a randomized trial.  Lancet. 2003;362:1691-1698
PubMed   |  Link to Article
Halperin JL.The Executive Steering Committee on behalf of the SPORTIF III and V Study Investigators.  Ximelagatran compared with warfarin for the prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives and design of a pair of clinical trials and baseline patient characteristics (SPORTIF III and V).  Am Heart J. 2003;146:431-438
PubMed   |  Link to Article
Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial fibrillation.  Chest. 2001;119:(suppl 1)  194S-206S
PubMed   |  Link to Article
Fuster V, Rydén LE, Asinger RW.  et al.  ACC/AHA/ESC 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 and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation).  J Am Coll Cardiol. 2001;38:1231-1266
PubMed   |  Link to Article
Pocock S, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.  Biometrics. 1975;31:103-115
PubMed   |  Link to Article
Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy.  Thromb Haemost. 1993;69:236-239
PubMed
Gadisseur AP, Breukink-Engbers WG, van der Meer FJ, van den Besselaar AM, Sturk A, Rosendaal FR. Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized anticoagulation clinics in the Netherlands: a randomized clinical trial.  Arch Intern Med. 2003;163:2639-2646
PubMed   |  Link to Article
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients.  Stroke. 1988;19:604-607
PubMed   |  Link to Article
Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: a reliability study.  Int Disabil Stud. 1988;10:61-63
PubMed   |  Link to Article
Petersen P, Grind M, Adler J.for the SPORTIF II Investigators.  Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study.  J Am Coll Cardiol. 2003;41:1445-1451
PubMed   |  Link to Article
Ebbutt AF, Frith L. Practical issues in equivalence trials.  Stat Med. 1998;17:1691-1701
PubMed   |  Link to Article
Gomberg-Maitland M, Frison L, Halperin JL. Active-control clinical trials to establish equivalence or noninferiority: methodological and statistical concepts linked to quality.  Am Heart J. 2003;146:398-403
PubMed   |  Link to Article
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika. 1983;70:659-663
Link to Article
Haybittle JL. Repeated assessment of results in clinical trials.  Br J Radiol. 1971;44:793-797
PubMed   |  Link to Article
Peto R. Design and analysis of randomized clinical trials.  Br J Cancer. 1976;34:585-612
PubMed   |  Link to Article
Klement P, Carlsson S, Rak J.  et al.  The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.  J Thromb Haemost. 2003;1:587-594
PubMed   |  Link to Article
Lebrazi J, Elalami I, Samama MM. Inhibitory effect of melagatran and hirudin on clot-bound thrombin.  Throm Res. 2003;110:249-252
PubMed   |  Link to Article
Eriksson BI, Bergqvist D, Kälebo P.  et al.  Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial.  Lancet. 2002;360:1441-1447
PubMed   |  Link to Article
Francis CW, Berkowitz SD, Comp PC.  et al.  Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.  N Engl J Med. 2003;349:1703-1712
PubMed   |  Link to Article
Eriksson BI, Agnelli G, Cohen AT.  et al.  Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.  Thromb Haemost. 2003;89:288-296
PubMed
Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H.THRIVE III Investigators.  Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.  N Engl J Med. 2003;349:1713-1721
PubMed   |  Link to Article
Wallentin L, Wilcox RG, Weaver WD.  et al.  Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.  Lancet. 2003;362:789-797
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.  Lancet. 1996;348:633-638
PubMed   |  Link to Article
Chapman N, Huxley R, Anderson C.  et al.  Effects of a perindopril-based blood pressure–lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS trial.  Stroke. 2004;35:116-121
PubMed   |  Link to Article
Andersson TB, Anderson S, Li X, Johansson I, Carlsson S, Ingelman-Sundberg M. Reduction of the amidoximes: preliminary characterization of the enzyme system reducing the hydroxyamidine function in ximelagatran [abstract].  Drug Metab Rev. 2004;36:(suppl 1)  101
Andersson TB, Hoffman KJ, Bredberg U, Casatagnoli N. Lack of reactive metabolite formation during bioactivation of ximelagatran [abstract].  Drug Metab Rev. 2004;36:(suppl 1)  198

Figures

Figure 2. Kaplan-Meier Analysis of Primary Outcomes
Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of Randomized Patients According to Randomized Treatment Assignment*
Table Graphic Jump LocationTable 2. Rates of Primary and Secondary Events According to Assigned Treatment*

References

Cerebral Embolism Task Force.  Cardiogenic brain embolism: the second report of the Cerebral Embolism Task Force.  Arch Neurol. 1989;46:727-743
PubMed   |  Link to Article
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.  Ann Intern Med. 1999;131:492-501
PubMed   |  Link to Article
Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions.  Arch Intern Med. 1994;154:1443-1448
PubMed   |  Link to Article
Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food.  Ann Intern Med. 1994;121:676-683
PubMed   |  Link to Article
Samsa GP, Matchar DB, Goldstein LB.  et al.  Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities.  Arch Intern Med. 2000;160:967-973
PubMed   |  Link to Article
Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.  Ann Intern Med. 1999;131:927-934
PubMed   |  Link to Article
Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin?  Arch Intern Med. 2000;160:41-46
PubMed   |  Link to Article
Frykman V, Beerman B, Ryden L, Rosenqvist M. Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications.  Eur Heart J. 2001;22:1954-1959
PubMed   |  Link to Article
Eriksson UG, Bredberg U, Gislén K.  et al.  Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects.  Eur J Clin Pharmacol. 2003;59:35-43
PubMed
Johansson LC, Frison L, Logren U, Fager G, Gustafsson D, Eriksson UG. The influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;42:381-392
PubMed   |  Link to Article
Sarich TC, Teng R, Peters GR.  et al.  No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor, ximelagatran.  Clin Pharmacokinet. 2003;42:485-492
PubMed   |  Link to Article
Bredberg E, Andersson TB, Frison L.  et al.  Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions.  Clin Pharmacokinet. 2003;42:765-777
PubMed   |  Link to Article
Executive Steering Committee on behalf of the SPORTIF III Investigators.  Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): a randomized trial.  Lancet. 2003;362:1691-1698
PubMed   |  Link to Article
Halperin JL.The Executive Steering Committee on behalf of the SPORTIF III and V Study Investigators.  Ximelagatran compared with warfarin for the prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives and design of a pair of clinical trials and baseline patient characteristics (SPORTIF III and V).  Am Heart J. 2003;146:431-438
PubMed   |  Link to Article
Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrombotic therapy in atrial fibrillation.  Chest. 2001;119:(suppl 1)  194S-206S
PubMed   |  Link to Article
Fuster V, Rydén LE, Asinger RW.  et al.  ACC/AHA/ESC 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 and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation).  J Am Coll Cardiol. 2001;38:1231-1266
PubMed   |  Link to Article
Pocock S, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.  Biometrics. 1975;31:103-115
PubMed   |  Link to Article
Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy.  Thromb Haemost. 1993;69:236-239
PubMed
Gadisseur AP, Breukink-Engbers WG, van der Meer FJ, van den Besselaar AM, Sturk A, Rosendaal FR. Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized anticoagulation clinics in the Netherlands: a randomized clinical trial.  Arch Intern Med. 2003;163:2639-2646
PubMed   |  Link to Article
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients.  Stroke. 1988;19:604-607
PubMed   |  Link to Article
Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: a reliability study.  Int Disabil Stud. 1988;10:61-63
PubMed   |  Link to Article
Petersen P, Grind M, Adler J.for the SPORTIF II Investigators.  Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study.  J Am Coll Cardiol. 2003;41:1445-1451
PubMed   |  Link to Article
Ebbutt AF, Frith L. Practical issues in equivalence trials.  Stat Med. 1998;17:1691-1701
PubMed   |  Link to Article
Gomberg-Maitland M, Frison L, Halperin JL. Active-control clinical trials to establish equivalence or noninferiority: methodological and statistical concepts linked to quality.  Am Heart J. 2003;146:398-403
PubMed   |  Link to Article
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika. 1983;70:659-663
Link to Article
Haybittle JL. Repeated assessment of results in clinical trials.  Br J Radiol. 1971;44:793-797
PubMed   |  Link to Article
Peto R. Design and analysis of randomized clinical trials.  Br J Cancer. 1976;34:585-612
PubMed   |  Link to Article
Klement P, Carlsson S, Rak J.  et al.  The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model.  J Thromb Haemost. 2003;1:587-594
PubMed   |  Link to Article
Lebrazi J, Elalami I, Samama MM. Inhibitory effect of melagatran and hirudin on clot-bound thrombin.  Throm Res. 2003;110:249-252
PubMed   |  Link to Article
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