SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial FibrillationA Randomized Trial. JAMA. 2005;293(6):690–698. doi:10.1001/jama.293.6.690
Authors/SPORTIF Executive Steering Committee:
Stanford Stroke Center, Palo Alto, Calif
(Gregory W.AlbersMD); Department
of Neurology, University of Essen, Essen, Germany
Department of Biostatistics, AstraZeneca Research and Development Mölndal,
(LarsFrisonPhD); Departments of Clinical Science
Clinical Project Management
(MarkNevinsonBPharm), and Clinical Development
(StephenPartridgePhD), AstraZeneca Research and Development Charnwood,
Charnwood, England; Cardiovascular Institute, Mount Sinai Medical Center,
New York, NY
(Jonathan L.HalperinMD); Department of Clinical Development, AstraZeneca
LP, Wilmington, Del
Department of Cardiology, University Hospital,
(S. BertilOlssonMD, PhD); Department of Neurology, Copenhagen University
Hospital, Copenhagen, Denmark
(PallePetersenMD, DMSc); and Department
of Cardiology, Hospital Tenon, Paris, France
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
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
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.9- 12 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
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.
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 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.
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
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.
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
Primary: Stroke (ischemic or hemorrhagic) and
Stroke, SEE, death, acute myocardial infarction
Ischemic stroke, transient ischemic attack, SEE*
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.
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.
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
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.
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).
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
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
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)
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 thromboembolism30- 33 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
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
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
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
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,
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,
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,
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
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.
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