Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation (2024)

ContextIn patients with nonvalvular atrial fibrillation, warfarin preventsischemic stroke, but dose adjustment, coagulation monitoring, and bleedinglimit its use.

ObjectiveTo compare the efficacy of the oral direct thrombin inhibitor ximelagatranwith warfarin for prevention of stroke and systemic embolism.

Design, Setting, and ParticipantsDouble-blind, randomized, multicenter trial (2000-2001) conducted at409 North American sites, involving 3922 patients with nonvalvular atrialfibrillation and additional stroke risk factors.

InterventionsAdjusted-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 MeasuresThe primary end point was all strokes (ischemic or hemorrhagic) andsystemic embolic events. The primary analysis was based on demonstrating noninferioritywithin an absolute margin of 2.0% per year according to the intention-to-treatmodel.

ResultsDuring 6405 patient-years (mean 20 months) of follow-up, 88 patientsexperienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) waswithin target during 68% of the treatment period. The primary event rate withximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolutedifference, 0.45% per year; 95% confidence interval, −0.13% to 1.03%per year; P<.001 for the predefined noninferiorityhypothesis). When all-cause mortality was included in addition to stroke andsystemic embolic events, the rate difference was 0.10% per year (95% confidenceinterval, −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 aminotransferaselevels rose to greater than 3 times the upper limit of normal in 6.0% of patientstreated with ximelagatran, usually within 6 months and typically declinedwhether or not treatment continued; however, one case of documented fatalliver disease and one other suggestive case occurred.

ConclusionsThe results establish the efficacy of fixed-dose oral ximelagatran withoutcoagulation monitoring compared with well-controlled warfarin for preventionof thromboembolism in patients with atrial fibrillation requiring chronicanticoagulant therapy, but the potential for hepatotoxicity requires furtherinvestigation.

Nonvalvular atrial fibrillation is implicated in nearly 15% of strokes.¹ By meta-analysis of 6 randomized trials, dose-adjustedwarfarin decreases stroke risk by 62%.^2,3 Inpractice, the risk of bleeding limits treatment with warfarin, particularlyamong the elderly. Variability of anticoagulation intensity from interactionswith foods and medication⁴ necessitates frequentmonitoring and dose adjustments yet leaves patients outside the therapeuticrange almost half the time.^5,6 Underuseof warfarin in patients with atrial fibrillation at high risk of bleeding^5,6 calls for safer, more dependable alternatives.^7,8

The direct thrombin inhibitor ximelagatran offers fixed oral dosingwithout need for coagulation monitoring, rapid onset and offset of action,stable pharmaco*kinetics with little potential for drug interactions, and noknown food interactions.^9-12 TheSPORTIF (Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation)program included 2 long-term trials comparing ximelagatran to warfarin forprevention of thromboembolism in patients with atrial fibrillation. The open-labelSPORTIF III study found ximelagatran at least as effective as warfarin.¹³ This report describes SPORTIF V, based on the sameprotocol except that anticoagulation was administered in a double-blindedmanner.

The rationale, design, and patient characteristics of the SPORTIF Vtrial have been previously described.^13,14 Briefly,the trial compared fixed-dose oral ximelagatran with adjusted-dose warfarinfor prevention of stroke and systemic embolism in patients with nonvalvularatrial fibrillation requiring chronic anticoagulant therapy. The executivesteering committee developed the protocol, guided study execution masked totreatment outcomes, and prepared results for publication with unrestrictedaccess to data. The sponsor provided 2 of the 8 voting members.

Written consent was required from each patient according to a protocolapproved by local institutional review boards and compliant with the Declarationof Helsinki. Between August 2, 2000, and December 7, 2001, a total of 3922patients were randomized at 409 sites in the United States and Canada, includingacademic and nonacademic offices and clinics attended by both general practitionersand specialists. Entry criteria were based on current guidelines for anticoagulationand required at least 1 of the following risk factors in addition to persistentor paroxysmal nonvalvular atrial fibrillation: previous stroke, transientischemic 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 diseaseor diabetes mellitus.^15,16 Raceand ethnicity were classified according to self-report.

Treatment was randomized to either adjusted-dose warfarin, target internationalnormalized ratio (INR) 2.0 to 3.0, or fixed-dose ximelagatran, 36 mg twicedaily, according to a centralized adaptive allocation algorithm that balancedgroups 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 underwentblood 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). Another14% were performed at a commercial laboratory (Quest Diagnostics Inc, VanNuys, Calif); fewer than 1% involved local laboratories, with results reportedto unblinded personnel not engaged in patient management or assessment. Warfarindose was based on actual INR results, with adherence estimated by linear interpolationas proportion of time in the therapeutic range.^18,19 Forpatients assigned to ximelagatran, sham INR values were generated to mimicvariations on warfarin; compliance was estimated by tablet counts. Aspirinwas permitted¹⁶ in doses up to 100 mg daily,but nonsteroidal anti-inflammatory medication was limited to 7 days or fewerper month. Other antithrombotic medications were prohibited.

The primary end point was all strokes (ischemic or hemorrhagic) andsystemic 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 wereevaluated as early as feasible based on clinical findings and brain imaging.Detection was enhanced by administering a stroke-symptom questionnaire every6 months. Positive responses prompted evaluation by study-affiliated neurologistswho were blinded to treatment. An independent, blinded, central event adjudicationcommittee reviewed the reports. Stroke severity was assessed 3 months afteran event, according to the modified Rankin²⁰ andBarthel indices.²¹

Events

Stroke: Abrupt onset of a focal neurologicaldeficit in the distribution of a brain artery persisting more than 24 hoursor due to intracerebral hemorrhage.

Death

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

Systemic embolic event (SEE): Abrupt vascularinsufficiency associated with clinical and radiological evidence of arterialocclusion in the absence of another likely mechanism.

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

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

End Points

Primary: Stroke (ischemic or hemorrhagic) andSEE.

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 ischemicor hemorrhagic.
†Reported by local investigators but did not satisfycriteria for major bleeding.

Because in an earlier study²² 4.3% ofpatients taking ximelagatran developed serum alanine aminotransferase (ALT)concentrations higher than 3 times the upper limit of normal (ULN), liverfunction (ALT, aspartate aminotransferase, alkaline phosphatase, and totalbilirubin) was tested at least monthly for 6 months, then bimonthly for thefirst year, and then quarterly. Weekly testing was required if any value exceeded3 times the ULN, and drug discontinuation was required if a value exceeded3 times the ULN for 4 weeks or 7 times the ULN at any time or clinical hepatotoxicitydeveloped. In October 2001, limits were modified to twice the ULN for weeklytesting and 5 times the ULN for drug discontinuation.

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

The ITT analysis included all patients, regardless of adherence, withexposure truncated at last contact. Confirmatory sensitivity analyses includedall-cause mortality in addition to the primary end point and on-treatmentanalysis of the primary end point excluding events beyond 30 consecutive or60 cumulative days off randomized treatment. Accumulation of primary eventsand deaths continued until study closure, even if assigned treatment was stopped,whereas other events were recorded during the period on treatment. Unlessotherwise stated, analyses of end points composed of only stroke, systemicembolism, or death were based on ITT; other analyses used the on-treatmentapproach. All analyses were performed using SAS version 8.2 software (SASInstitute, Cary, NC) and are reported as the number of patients experiencingeach 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 patientswith verified primary events. This provided 90% power to demonstrate noninferiorityfor 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 atapproximately 12.5%, 25%, 50%, and 75% of total exposure. The Lan-DeMets quadratic αspending function guided safety monitoring.²⁵ Thisgroup sequential stopping rule was applied only for negative trends alongsafety parameters prespecified before accessing unblinded data. Interim analysesfor the primary end point were guided by the Haybittle-Peto group sequentialboundaries, requiring no adjustments to the final analysis.^26,27 Basedon analysis of the event rate after 50% of exposure elapsed, the data safetymonitoring board recommended extension of accrual to accumulate the requisitenumber of events.

The study included 3922 patients randomly assigned, including 3 of 1960without qualifying risk factors in the ximelagatran group and 4 of 1962 inthe warfarin group (Figure 1). Thisresulted in a net exposure of 6405 patient-years for the primary outcome.Nine patients assigned to receive warfarin and 6 to receive ximelagatran didnot take either study drug. Although none developed end point events, allwere included in ITT analyses. Ninety-six percent of patients were white;69%, men; 2193 (56%), previous smokers; and 2314 (59%) denied regular alcoholuse. 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, 1658patients (42%) were aged at least 75 years, 3307 (84%) had atrial fibrillationfor at least a year, and 3367 (86%) had persistent atrial fibrillation. Inaddition to atrial fibrillation, 2916 patients (74%) had 2 or more strokerisk factors. Before entry, 3278 patients (84%) were taking a vitamin K antagonist(usually warfarin); 719 (18%), acetylsalicylic acid; 1909 (49%), a β-adrenergicantagonist; 1875 (48%), an angiotensin-converting enzyme inhibitor; 1442 (37%),a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin); and177 (4.5%), amiodarone. During the study, patients took a median of 12 otherprescribed medications. Clinical characteristics were balanced between treatmentgroups (Table 1) and were similar tocohorts in earlier trials demonstrating superiority of warfarin over placebofor prevention of atrial fibrillation–related stroke.^13,14

In patients assigned to receive warfarin, the mean (SD) INR across allmeasurements was 2.4 (0.8). Values fell within target range (2.0-3.0) for68% of the time on treatment, below 2.0 for 20%, above 3.0 for 12%, and between1.8 and 3.2 for 83%. Anticoagulation intensity was within target range atleast half the time on treatment in 1667 patients (85%) assigned to receivewarfarin. 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 morethan 38 000 measurements.

Mean (SD) follow-up was 20 (5.1) months in both treatment groups (overallmedian, 20; range, 0-31 months), yielding 3212 patient-years at risk in thewarfarin group and 3193 in the ximelagatran group. Thirty-five percent ofpatients prematurely stopped treatment, 640 (33%) assigned to receive warfarinand 718 (37%) assigned to receive ximelagatran (P=.01).At the end of the trial, special efforts to ascertain the vital status of226 patients (6%) who interrupted follow-up disclosed no additional casesof 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 of107 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 stoppedassigned 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 comparedwith 197 (10.0%) and 238 (12.1%), respectively, with ximelagatran, the latterdue mainly to elevation of serum transaminase enzymes.

Primary End Points. The central event adjudicationcommittee confirmed primary events in 37 patients assigned to receive warfarinand 51 patients assigned to receive ximelagatran, corresponding to incidencerates of 1.16% and 1.61% per year, respectively (P=.13for a difference between treatments). The P valuefor noninferiority, that is, the probability of incorrectly rejecting theprespecified null hypothesis that the true difference between event rates(ximelagatran-warfarin) exceeds 2% per year was lower than .001. The upperbound 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 assignedto warfarin, 37 were ischemic strokes, 2 were hemorrhagic strokes, and 1 wassystemic embolism; 3 patients had multiple events. In the patients assignedto receive ximelagatran, there were 49 ischemic strokes, 2 hemorrhagic strokes,and 6 systemic embolic events; 6 patients experienced multiple events (Table 2).

The secondary on-treatment analysis discounted events occurring aftertreatment cessation in 9 patients assigned to receive warfarin and 10 assignedto 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). Resultswere 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 takingwarfarin, all 28 primary events were ischemic strokes; one patient also developedhemorrhagic stroke. In the 23 patients with values available within 30 daysof ischemic stroke, INR was no more than 2.0 in 9 (39%). Among 41 patientsdeveloping primary events while taking ximelagatran, there were 35 ischemicstrokes, 1 hemorrhagic stroke, and 6 systemic embolic events (1 patient hadmultiple events).

Secondary End Points. Fifty-two patients takingwarfarin experienced ischemic stroke, transient ischemic attack, or systemicembolism (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 warfaringroup 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% and4.8% 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 asprimary events) occurred in 2 patients in each group (0.06% per year; Table 3). Seven patients in the warfarin groupand 5 in the ximelagatran group developed subdural hematoma. Major extracerebralbleeding occurred in 84 patients assigned to the warfarin group (3.1% peryear) and in 63 assigned to the ximelagatran group (2.4% per year), a reductionof 0.66% per year (95% CI, –1.55% to 0.23% per year). Of confirmed majorhemorrhages, bleeding was fatal in 1 patient assigned to the warfarin and2 assigned to the ximelagatran groups. Decreased hemoglobin accounted for41% and transfusion for 5% of major bleeding; proportions were similar inboth treatment groups. Among the 84 patients in the warfarin group with majorbleeding, INR exceeded 3.0 in 20 cases. Considering minor plus major hemorrhages,there was significantly more bleeding among patients receiving warfarin (903patients, 47% per year) than ximelagatran (737 patients, 37% per year; relativerisk reduction 21%; 95% CI, –14 to –6.0% per year; for the difference, P<.001). The 571 patients (15%) who took aspirin (≤100mg/d) along with the anticoagulant at any time during the trial had higheroverall (major and minor) bleeding rates (41% per year with ximelagatran,69% per year with warfarin) than those not taking aspirin (37% per year withximelagatran, 44% per year with warfarin).

Other Adverse Events. Adverse events otherthan bleeding occurred with equal frequency in both groups (Table 3). In 117 patients (6.0%) taking ximelagatran, serum ALTlevels rose to higher than 3 times ULN compared with 15 patients taking warfarin(0.8%; P<.001). Elevations typically occurredbetween 2 and 6 months after initiating treatment and returned toward baselinewithout clinical sequelae either spontaneously (45 patients) or after treatmentcessation (68 patients). Alanine aminotransferase levels returned to belowthe ULN in all but 5 patients, including 1 who died 3 days after repair ofan iliac artery aneurysm, 1 whose serum ALT level of 165 U/L and bilirubinlevel was normal 2 weeks before death from ischemic heart disease, and 1 forwhom no follow-up information could be obtained. The other cases are discussedbelow.

Within 30 days of ALT concentration elevation higher than 3 times theULN, total serum bilirubin concentration rose above twice the ULN in 9 patientstaking ximelagatran and 1 taking warfarin. One patient with serum ALT higherthan 3 times ULN 85 days after beginning ximelagatran treatment displayedhepatic necrosis on liver biopsy result 20 days after stopping the drug. Thispatient died 145 days after random assignment following corticosteroid treatment;autopsy revealed resolving hepatitis (nodular islands of regenerating hepatocyteswithout active inflammation) and hemorrhagic perforation of a duodenal ulcer.Another patient whose serum ALT concentrations reached 11 times the ULN withximelagatran (total serum bilirubin, 1.6 mg/dL (27.4 μmol/L), 1.45 timesthe ULN) developed fatal gastrointestinal hemorrhage.

In this double-blind trial involving relatively high-risk patients withnonvalvular atrial fibrillation, the direct thrombin inhibitor ximelagatranwas noninferior to well-controlled warfarin within the prespecified marginof 2.0% per year for prevention of stroke and systemic embolism. The differencein 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% peryear. Hence, the probability of rejecting noninferiority was <.001 forthe 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 withina narrow range while ximelagatran was administered in fixed dose without anticoagulationmonitoring, there was no increase in bleeding (indeed, less minor bleeding)with ximelagatran.

Thrombin plays a pivotal role in fibrin formation and activation ofplatelets 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, inhibitssoluble and fibrin-bound thrombin directly.^28,29 Inprevious studies, ximelagatran compared favorably with warfarin or low-molecular-weightheparin for prevention and treatment of venous thromboembolism^30-33 andin combination with aspirin was superior to aspirin alone for prevention ofischemic events in patients with acute coronary syndromes.³⁴

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

Secondary efficacy analyses mirror the primary analysis. The compositeof all stroke, systemic embolism, death, and myocardial infarction occurredwith similar frequency in both groups, as did a composite limited to ischemicevents. Consistency in both primary and secondary end points strengthens confidencein the noninferiority assessment.

Enrolled patients represented those typical in clinical practice, bearingconsiderable cardiovascular comorbidity as reflected in their advanced age,stroke risk profiles, and concurrent medications. Even so, rates of thromboembolismwere 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 anticoagulationcontrol with warfarin was better in our trial than in previous studies andseldom achieved in practice but comparable with SPORTIF III.¹³ Thelow warfarin event rate^2,14 mayreflect better dose regulation, control of hypertension or hyperlipidemia,other differences in patient characteristics or management, or chance.

Rates of intracerebral hemorrhage during treatment were exceptionallylow, but extracerebral hemorrhage was more frequent than in other randomizedtrials. 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, comparablewith previous studies,² and 1.6% per year inthe ximelagatran group (P=.22). Liberalreporting criteria for minor bleeding may have captured some episodes of littleclinical importance.

The combination of low rates of stroke and cerebral hemorrhage mightbe explained by control of hypertension. Mean systolic blood pressure was133 mm Hg even though 80% of patients had a history of hypertension at entry.In a recent trial involving patients with atrial fibrillation, lowering systolicblood pressure by 9 mm Hg reduced ischemic stroke by nearly 30% and halvedthe rate of intracerebral hemorrhage.³⁶ Controlof hypertension seems to be a critically important adjunct to antithrombotictherapy to avoid adverse neurological outcomes in patients with atrial fibrillation.

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

Ximelagatran is eliminated mainly through renal clearance, and patientswith 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 beextrapolated to patients with valvular heart disease, pregnancy, or severerenal insufficiency or to those undergoing cardioversion of atrial fibrillationwithout additional experience in these clinical situations.

The SPORTIF V trial is the largest yet reported trial involving patientswith atrial fibrillation for prevention of stroke and systemic embolism. Lowrates of thromboembolism and bleeding occurred when ximelagatran was givenin a fixed dose without anticoagulation monitoring. Further investigationis needed to clarify the risk of serious hepatic reactions and identify predictivefeatures to select appropriate patients for treatment with ximelagatran. Inthe balance are a large number of potentially preventable fatal or disablingstrokes that accumulate as a consequence of the limitations and underutilizationof warfarin.

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

Author Contributions: Dr Halperin, as a principalinvestigator of this trial, had complete access to all of the data and takesresponsibility for the integrity of the data and the accuracy of the dataanalyses.

An independent data and safety monitoring board (DSMB) that includedacademic statisticians and no employees of the sponsor oversaw patient safety,had access to all data, and independently confirmed the results at an independentstatistical center at the University of Wisconsin under the direction of DavidDeMets, 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 beenpaid lecture fees by AstraZeneca. Dr Albers has served as a consultant toand has been paid lecture fees by AstraZeneca and Boehringer Ingelheim andhas 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 Nevinsonare employees of AstraZeneca.

SPORTIF Executive Steering Committee:Voting members: Drs Albers, Diener, Grind, Halperin, co-chairman,Horrow, Olsson, co-chairman, Petersen, and Vahanian. Nonvotingmembers: 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, andJ. 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. Morrisand 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. delCampo, 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, andE. 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; SouthCarolina: W. H. Collins III, B. T. McLaurin, B. R. Reeves, Jr; andG. 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, andC. 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 collectedand managed the data; the sponsor and the data and safety monitoring boardperformed the analysis of the data, and the executive steering committee interpretedthe data. The executive steering committee prepared, reviewed, and approvedthe manuscript.