Anticoagulation in women with non valvul (1)
Clinical research
European Heart Journal (2006) 27, 1947–1953
doi:10.1093/eurheartj/ehl103
Arrhythmia/electrophysiology
Anticoagulation in women with non-valvular atrial
fibrillation in the stroke prevention using an oral
thrombin inhibitor (SPORTIF) trials
Mardi Gomberg-Maitland1*, Nanette K. Wenger2, Jan Feyzi3, Maria Lengyel4,
Annabelle S. Volgman5, Palle Petersen6, Lars Frison7, and Jonathan L. Halperin8
1
Department of Medicine, Section of Cardiology, University of Chicago Hospitals, University of Chicago, 5841 S Maryland
Avenue, MC2016, Chicago, IL 60637, USA; 2 Emory University School of Medicine, Atlanta, GA, USA; 3 Informatics University of
Wisconsin–Madison, Madison, WI, USA; 4 Hungarian Institute of Cardiology, Budapest, Hungary; 5 Rush University Medical
Center, Chicago, IL, USA; 6 Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
7
¨lndal, Mo
¨lndal, Sweden; and 8 Mount Sinai Medical Center, New York, NY, USA
AstraZeneca R&D Mo
See page 1893 for the editorial comment on this article (doi:10.1093/eurheartj/ehl140)
KEYWORDS
Atrial fibrillation;
Women;
Anticoagulation;
Thromboembolism
Aims The risk of stroke is greater among women with atrial fibrillation (AF) than men. Warfarin protects
against stroke, but treatment-related bleeding occurs more often in women than in men.
Methods and results SPORTIF III (open label, n ¼ 3410) and V (double-blind, n ¼ 3922) included 2257
women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0–3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischaemic/haemorrhagic) and systemic embolic event. Women were older, on average, than men, 73.4 + 8.0
vs. 69.8 + 9.0 years (P , 0.0001). More women were .75-years old and women had more risk factors
than men had (P , 0.0001). The INR on warfarin (mean 2.5 + 0.7) was within target range for 67% of
follow-up regardless of gender. Women more often developed primary events [2.08%/year, 95% confidence interval (CI) 1.60–2.56%/year vs. 1.44%/year, 95% CI 1.18–1.71%/year in men; P ¼ 0.016).
Major bleeding rates were similar (P ¼ 0.766) but women experienced more overall (major/minor)
bleeding (P , 0.001). Warfarin was associated with more overall bleeding in both genders and more
major bleeding in women than in men (P ¼ 0.001).
Conclusion When compared with men with AF, women in these studies were older and had more stroke
risk factors. Women were more prone to anticoagulant-related bleeding; the higher rate of
thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy.
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac
rhythm disorder encountered in clinical practice and an
important risk factor for ischaemic stroke.1,2 Its prevalence
increases with age, affecting women slightly less often than
men.2–6 Stroke rates with AF are higher in women than in
men,3,7–10 and AF is the most common cause of stroke in
elderly women.
Despite the established efficacy of anticoagulation for
prevention of stroke in both men and women with AF, warfarin is prescribed for less than one-third of women with
AF at hospital discharge, a lower rate than for men, and
this under-use is associated with adverse outcomes.11 Few
randomized trials have enrolled a sufficient proportion of
women to specifically evaluate differential efficacy or
safety on the basis of gender,12,13 but data from a
prospective cohort demonstrate that women have a higher
risk than men for AF-related thrombo-embolism and that
warfarin is as effective in women as in men with AF.10
The Stroke Prevention using an Oral Thrombin Inhibitor in
patients with AF(SPORTIF) programme included two clinical
trials that compared the efficacy and safety of ximelagatran
vs. warfarin in patients with AF at risk of ischaemic stroke.
The combined cohort of SPORTIF III and V includes the
largest number of women yet reported with non-valvular
AF followed prospectively on anticoagulation; 50% of the
women enrolled were over 75 years of age. The results
provide information about sex-based and age-based differences in rates of ischaemic events and bleeding among anticoagulated patients with AF and about the relative safety and
efficacy of warfarin and ximelagatran in women and men.
Methods
* Corresponding author. Tel: þ1 773 702 5589; fax: þ1 773 834 1764.
E-mail address: mgomberg@medicine.bsd.uchicago.edu
The design, characteristics of enrolled patients, statistical analysis,
and main results of the SPORTIF III and V trials have been
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 3, 2013
Received 11 November 2005; revised 15 May 2006; accepted 26 May 2006; online publish-ahead-of-print 14 June 2006
1948
reported.14–16 Entry criteria, based on current clinical indications for
antithrombotic therapy,16,17 were identical for the two studies16 and
included persistent or paroxysmal non-valvular AF verified by ECG
within 2 weeks before randomization and at least one of the following
additional risk factors for stroke: hypertension, age 75 years, previous stroke, transient ischaemic attack (TIA) or systemic embolic
event (SEE), left ventricular (LV) dysfunction [LV ejection fraction
(LVEF) ,40% or symptomatic congestive heart failure (CHF)], age
65 years with coronary artery disease (CAD), or age 65 years and
diabetes mellitus. The principal exclusion criteria were: stroke,
TIA, or SEE within 30 days before entry; bleeding disorders; conditions requiring conventional anticoagulant therapy; AF secondary
to reversible disorders (e.g. thyrotoxicosis); hypertension .180/
100 mmHg despite medication; previous disabling stroke with modified Rankin score .3; acute coronary syndrome within 30 days;
planned cardioversion, treatment with platelet-inhibitor drugs
other than aspirin 100 mg/day within 10 days; renal insufficiency
(calculated creatinine clearance ,30 mL/min); active liver disease
or persistent elevation of liver enzymes two or more times the
upper limit of normal (ULN); childbearing potential, pregnancy, or
lactation.
Patients were randomized to treatment with ximelagatran at a fixed
dose of 36 mg twice daily or to warfarin dose adjusted to maintain
the international normalized ratio (INR) between 2.0 and 3.0, based
on blood test monitoring at maximum intervals of 4 weeks.
Allocation was balanced according to aspirin therapy at entry, previous stroke or TIA, and country, using an adaptive allocation algorithm. In SPORTIF III, treatment was administered open label at 259
sites in 23 countries in Europe, Australia, New Zealand, and Asia,
with blinded endpoint event assessment. In SPORTIF V, treatment
was double blind at 409 sites in North America.
Concomitant estrogen replacement therapy
Some women took estrogen replacement therapy (ERT) during the
trial on the advice of their physician. For this analysis, women
were considered to be on ERT when either oral or subcutaneous
estrogen alone or in conjunction with progesterone therapy was
recorded as a concomitant medication at randomization, but
topical therapies and progesterone monotherapy were excluded.
Clinical assessments and endpoints
After randomization, patients were seen at 1, 4, and 6 weeks and
then at 2, 3, 4, 5, 6, 8, 10, and 12 months, and every 3 months
thereafter for detection of stroke or SEE (primary events), TIA,
acute myocardial infarction (MI), or bleeding complications.
Events were also detected by a standard stroke-symptom questionnaire administered by telephone; positive responses prompted
additional evaluation. A study-affiliated neurologist or stroke
specialist blinded to treatment allocation evaluated all possible
primary events and TIA. An independent, central clinical event
adjudication committee also blinded to treatment reviewed clinical
reports of all primary and secondary events. Primary endpoints for
the trial were stroke and SEE. Secondary endpoints were acute MI,
TIA, death, and major and minor bleeding.16
Statistical analysis
The trials were based on establishing non-inferiority within an absolute margin of 2%/year for the difference in primary event rates
between the two treatment groups. The analysis reported here
was planned to compare the efficacy and safety of anticoagulation
in women with that in men enrolled in both trials. Comparisons
were made for age 75 or younger, paroxysmal or persistent AF,
and use of ERT at randomization. In addition, we performed multivariable analysis of the pooled data for trial effect, study treatment
effect, and their interactions within these subgroups. Sensitivity
analyses comparing men and women for the primary endpoint
were performed on the basis of a Cox-regression using study as a
factor in the model and for interaction between study and gender.
The intention-to-treat (ITT) analysis for primary events and mortality included all randomized patients until study closure, irrespective of protocol adherence, or continued participation. Remaining
endpoints were recorded during the on-treatment (OT) period
with exposure censored from the 31st consecutive day or 61st
cumulative day off study drug. Events before first dose intake in
randomized patients were included in the analysis. No patient was
counted more than once for a given composite endpoint.
All patients were followed for primary events and mortality until
study closure. Remaining outcomes were recorded during the OT
period. Hence, composite endpoints confined to stroke, SEE, and
death were analyzed according to ITT, whereas assessments of all
other outcomes, composite endpoints and exploratory analyses
used the OT approach.
In addition to analyses of efficacy, the safety profiles of ximelagatran and warfarin were compared between genders. For each treatment group, the proportions of patients experiencing major
bleeding, minor bleeding, or bleeding causing permanent treatment
cessation were calculated, accounting for duration of exposure for
each patient. Other adverse events and laboratory variables are
summarized using descriptive statistics.
The analysis of the difference in primary event rates between the
treatment groups was made under the assumption of exponentially
distributed lifetimes. This is equivalent to assuming a constant
event rate over time and hence the probability of an event over a
year can be estimated from the complete follow-up of all patients.
The variance for the difference in event rates was estimated using
the method described by Cox and Oakes.18 Two-sided P-values for
differences between treatments were obtained by Fisher’s exact
test, using the number of patient-years as analyses units. ERT was
a conceived subgroup analysis prior to completion of the trials.
Because both age .75 and pattern of AF (paroxysmal or persistant)
are perceived risk factors for AF, we performed substudy analyses.
Also, for both SPORTIF III and V comparisons of primary event
rates according to age .75 vs. ,75 was a predefined tertiary
endpoint. Thus the writing group felt that examination in this
cohort was important for substudy analyses.
Cox-regression analyses used the following baseline stroke risk
factors as covariates for multivariable analyses after validation of
the proportional hazards model assumption: gender, baseline systolic blood pressure and diastolic blood pressure (DBP), prior stroke/
TIA, SEE, hypertension, CAD (MI, angioplasty, or angina), diabetes
mellitus, LV dysfunction (LVEF ,40% or symptomatic CHF), age
(both as a continuous and as a categorical variable), smoking (past
or present vs. none), body mass index (,30 vs. 30), alcohol as a
dichotomous variable, trial, and study treatment.
Results
Baseline characteristics
Baseline characteristics of enrolled patients are compared
by gender in Table 1. Of the 7329 subjects enrolled, 2257
(30.8%) were women (30.9% in SPORTIF III and 30.7% in
SPORTIF V). The mean age was 73.4 + 8 years for women
and 69.8 + 9 years for men (P , 0.0001). The mean blood
pressure in women was 138.5 + 18 mmHg systolic and
79.8 + 10 mmHg
diastolic
when
compared
with
134.0 + 18 mmHg (P , 0.0001) and 79.2 + 11 mmHg in
men (P ¼ 0.015). Ninety-three per cent of women and 92%
of men were Caucasian compared to other races
(P , 0.0001). Only 5% of women were occasional or habitual
smokers when compared with 11% of men (P , 0.0001). The
onset of AF was within 1 year in 23% of women vs. 18% of
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Randomized treatment
M. Gomberg-Maitland et al.
Anticoagulation in women with non-valvular AF in the stroke prevention
1949
Table 1 Baseline characteristics
Baseline characteristics
Men (n ¼ 5072)
Women (n ¼ 2257)
P-value
Age (years)
SBP (mmHg)
DBP (mmHg)
Race, n (%)
Caucasian
African-American
Oriental
Other
Smoking, n (%)
Non-smoker
Ex-smoker
Occasional
Habitual
AF, n (%)
Persistent
Paroxysmal
Years since first AF diagnosis, n (%)
,1
1–2
2–5
.5
History of stroke, n (%)
History of TIA, n (%)
History of diabetes, n (%)
History of CAD, n (%)
High-risk factors, n (%)
Hypertension
Age 75 years
Prior stroke/TIA
SEE
LV dysfunction
Age 65 and diabetes
Age 65 and CAD
Number of risk factors, n (%)
0
1
2
3
4
.4
Concomitant medications, n (%)
ASA
b-Blocker
ACE-inhibitor
Statin
ERT
69.8 + 9
134.0 + 18
79.2 + 11
73.4 + 8
138.5 + 18
79.8 + 10
,0.0001
,0.0001
0.015
4658 (92)
75 (2)
323 (6)
16 (0)
2099
53
99
6
(93)
(2)
(4)
(0)
,0.001
1605 (32)
2907 (57)
118 (2)
442 (9)
1496
643
22
96
(66)
(29)
(1)
(4)
,0.0001
4354 (89)
537 (11)
1956 (87)
299 (13)
,0.001
477
245
555
761
286
246
495
864
(23)
(12)
(27)
(38)
(13)
(11)
(22)
(38)
,0.0001
3804 (75)
1670 (33)
1048 (21)
224 (4)
1942 (38)
921 (18)
1985 (39)
1821
1134
491
104
739
419
779
(81)
(50)
(22)
(5)
(33)
(19)
(35)
,0.0001
,0.0001
0.29
0.71
,0.0001
0.68
,0.001
13 (0)
1520 (30)
1636 (32)
1097 (22)
565 (11)
241 (5)
4
531
745
582
275
120
(0)
(24)
(33)
(26)
(12)
(5)
,0.0001
878 (17)
2425 (48)
2621 (52)
1737 (34)
0 (0)
304
1040
945
610
381
(14)
(46)
(42)
(27)
(17)
,0.0001
0.17
,0.0001
,0.0001
,0.0001
0.74
0.56
0.03
,0.0001
ASA, acetylsalicylic acid; SBP, systolic blood pressure; DBP, diastolic blood pressure; TIA, transient ischaemic attack;
SEE, systemic embolic event; LV, left ventricular; CAD, coronary artery disease; ACE, angiotensin converting enzyme.
men (P , 0.0001). A history of hypertension was more
frequent (81% vs. 75%; P , 0.0001), but the prevalence of
diabetes (22% vs. 24%; P ¼ 0.03), coronary heart disease
(38% vs. 48%; P , 0.0001), and LV systolic dysfunction (33%
vs. 38%; P , 0.0001) was lower among women. Women had
a larger number of associated thrombo-embolic risk factors
(43% vs. 38% with three or more risk factors in addition to
AF; P , 0.0001).
Prior to randomization, women were less often treated
with cardiovascular medications such as b-blockers,
angiotensin-converting enzyme (ACE) inhibitors, or statins
but there was no difference in use of vitamin K antagonists
or aspirin. After randomization, the INR was within the
target range (2.0–3.0) 66.6% of the time on treatment and
in the expanded range of 1.8–3.2 for 81.5% of the time
among the 1099 women assigned to warfarin therapy.
Among men on warfarin (n ¼ 2525), INR was between 2.0
and 3.0 for 67.8% and between 1.8 and 3.2 for 82.7% of
the time on treatment.
Endpoint events
By ITT analysis, more women than men developed primary
events (stroke or SEE), with 72 women experiencing events
during 3465 patient-years [2.08%/year, 95% confidence
interval (CI) 1.60–2.56%/year] vs. 112 men during 7759
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850 (18)
561 (12)
1249 (27)
1986 (43)
631 (12)
530 (10)
1230 (24)
2415 (48)
1950
M. Gomberg-Maitland et al.
Table 2 Event rates: women vs. men and women aged 75 years vs. women aged ,75 years
Events, n
Event rate, % per year
P-value
72
112
45
27
3465
7759
1724
1742
2.08
1.44
2.61
1.55
95
301
67
28
3507
7831
1746
1760
2.71
3.84
3.84
1.59
,0.001
49
101
3037
6960
1.61
1.45
0.53
22
78
3038
6949
0.72
1.12
0.08
68
149
41
27
3022
6924
1474
1548
2.25
2.15
2.78
1.74
889
1776
467
422
2153
5237
1044
1109
41.29
33.91
44.73
38.05
patient-years (1.44%/year, 95% CI 1.18–1.71%/year;
P ¼ 0.016; Table 2). However, this difference was limited
to the ximelagatran group (2.17%/year, 95% CI 1.48–2.87%/
year vs. 1.38%/year, 95% CI 1.00–1.75%/year; P ¼ 0.03).
There was no significant difference in primary event rates
based on gender in the warfarin group (Figure 1).
Comparing women in the ximelagatran and warfarin
groups, 38 patients experienced primary events during
1748 patient-years with ximelagatran (2.17%/year) vs. 34
during 1717 patient-years for warfarin (1.98%/year;
P ¼ 0.722). Among men, during 3854 patient-years, 53
developed primary events in the ximelagatran group
(1.38%/year) when compared with 59 in the warfarin
group during 3905 patient-years (1.51%/year; P ¼ 0.635).
In contrast to their more favourable outcome with respect
to the primary events, men suffered higher all-cause mortality than women, with 301 male deaths over 7831 patientyears (3.84%/year, 95% CI 3.41–4.28%/year) when compared
with 93 deaths among women over 3507 patient-years
(2.71%/year, 95% CI 2.16–3.25%/year; P ¼ 0.002).
Furthermore, the difference in primary event rates
between women and men was not apparent when assessed
by OT analysis (1.61%/year in women, 95% CI 1.16–2.07%/
year vs. 1.45%/year in men, 95% CI 1.17–1.73%/year;
P ¼ 0.53). The mean number of stroke risk factors other
than AF among women who discontinued anticoagulation
during the trial was 2.54 (95% CI 2.47–2.61) when compared
with a mean of 2.21 (95% CI 2.17–2.24), among those who
were able to sustain anticoagulation (P , 0.0001). Primary
events included haemorrhagic stroke in four women (three
fatal), ischaemic stroke in 40 (seven fatal), and SEE in five
(one fatal). Ten men developed haemorrhagic stroke of
0.016
0.032
0.002
0.766
0.065
,0.001
0.002
which five were fatal, 86 ischaemic stroke (eight fatal),
and six SEE (one fatal), using a 30-day rule.
Bleeding complications
There was no difference in major bleeding complications
between women and men overall (2.25% vs. 2.15%/year;
P ¼ 0.765) or in either of the treatment groups (0.57%/
year on ximelagatran, P ¼ 0.208, and 20.35%/year on warfarin, P ¼ 0.491). Among women, there was no difference in
major bleeding in the ximelagatran vs. warfarin groups.
More men developed major bleeding on warfarin (91
events; 2.57%/year) when compared with those on ximelagatran (58 events, 1.71%/year; P ¼ 0.016). Combined rates
of both major and minor bleeding were greater among
women than men (41.29%/year vs. 33.91%/year;
P , 0.001) that carried across both treatment groups (a
difference in rates of 5.37%/year between women and
men on ximelagatran, P ¼ 0.001, and a difference of
8.56%/year on warfarin, P , 0.0001). Comparing the two
treatments, bleeding was less frequent among women in
the ximelagatran group (35.48%/year) than in the warfarin
group (44.82%/year, P , 0.001). The same was true among
men (30.85%/year in the ximelagatran group vs. 37.01%/
year in the warfarin group; P , 0.001).
Liver function abnormalities
Women in the ximelagatran group developed serum levels of
S-alanine aminotransferase (ALT) beyond three times the
ULN more often than men (8.4% vs. 5.1%; P , 0.001;
Table 3). Incidences in the warfarin group were 1.0%
among women and 0.7% among men. Incidences of ALT
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Stroke and SEE (ITT analysis)
Women
Men
Women aged 75 years
Women aged ,75 years
Mortality
Women
Men
Women aged 75 years
Women aged ,75 years
Stroke and SEE (OT analysis)
Women
Men
MI
Women
Men
Major bleeding
Women
Men
Women aged 75 years
Women aged ,75 years
Major and minor bleeding
Women
Men
Women aged 75 years
Women aged ,75 years
Patient-years
Anticoagulation in women with non-valvular AF in the stroke prevention
Primary event rates over time: women vs. men on ximelagatran and women vs. men on warfarin.
Table 3 Liver function tests: number of patients by gender
maximal S-ALT multiple of ULN during study (ITT population)
ULN
Women, n (%)
ALT . ULN 1
ALT . ULN 2
ALT . ULN 3
ALT . ULN 5
ALT . ULN 10
Men, n (%)
ALT . ULN 1
ALT . ULN 2
ALT . ULN 3
ALT . ULN 5
ALT . ULN 10
Ximelagatran
Warfarin
Total
338 (29.6)
152 (13.3)
96 (8.4)
51 (4.5)
9 (0.8)
104 (9.3)
21 (1.9)
11 (1.0)
5 (0.4)
1 (0.0)
442 (20.0)
173 (8.0)
107 (5.0)
56 (2.0)
9 (0.0)
591 (23.4)
218 (8.6)
128 (5.1)
65 (2.6)
22 (0.9)
326 (12.8)
51 (2.0)
18 (0.7)
7 (0.3)
1 (0.0)
917 (18.0)
269 (5.0)
146 (3.0)
72 (1.0)
23 (0.0)
beyond five times the ULN occurred more often in women
than in men (4.5% vs. 2.6%) on ximelagatran but with little
difference on warfarin (0.4% vs. 0.3%).
Differences based on age
Compared with younger women, those aged 75 years were
more often Caucasian (96 vs. 90%), non-smokers (68 vs.
65%), with higher systolic blood pressure (139.8 vs.
137.2 mmHg), taking aspirin (15 vs. 12%), with persistent
AF (89 vs. 85%) and a history of TIA (12 vs. 10%). Elderly
women had more risk factors for stroke (three or more in
63 vs. 23%) but less often had a history of hypertension (77
vs. 84%) and had a lower DBP (79.0 vs. 80.7 mmHg) or
diabetes (18 vs. 36%). Older women more often had CAD
than younger women (40 vs. 29%).
More women over the age of 75 years developed
primary events (2.61 vs. 1.55%/year; P ¼ 0.032; ITT
analysis). Older women also displayed greater all-cause
mortality (P , 0.001;). Rates of major bleeding were not
significantly different between older and younger women
(2.78 vs. 1.74%; P ¼ 0.065), but the elder group developed
more overall (major and minor) bleeding events (44.73
vs. 38.05%/year; P ¼ 0.002). There were no differences
in major bleeding based on treatment group assignment among either older women (2.97%/year in the ximelagatran group vs. 2.60%/year in the warfarin group;
P ¼ 0.752) or younger women (1.66%/year in the
ximelagatran group vs. 1.83%/year in the warfarin group;
P ¼ 0.848).
Differences based on ERT
In both trials combined, 381 women (17%) took ERT at randomization and for more than half the follow-up period,
and 413 (18%) used ERT at some point during the trial. Of
those taking ERT at entry, 14 developed ischaemic stroke,
SEE, or TIA and 27 had ischaemic stroke, SEE, TIA, MI, or
death. The small number of women using ERT and the infrequency of events left the results of univariate and multivariable analyses inconclusive.
Differences based on pattern of AF
Most women (87%) had persistent AF. There were no
differences in baseline demographics between those with
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Figure 1
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1952
persistent vs. paroxysmal AF except for age (42% with
paroxysmal AF were 75 years vs. 52% with persistent
AF; P ¼ 0.002) and LV dysfunction (25% with paroxysmal
AF vs. 34% with persistent AF; P ¼ 0.0025). Women with
persistent AF had more stroke risk factors (45 vs. 35%
with more than three risk factors in addition to AF;
P , 0.0001).
Multivariable analyses
Discussion
This cohort of 2257 women with AF on anticoagulation is the
largest described to date; even so, as only 31% of randomized patients were women, statistical power of conclusions
specifically involving women remains limited. Compared
with men in these trials, women were typically older than
75 years, had a history of hypertension, and had more risk
factors for stroke though they were less often diabetic and
had normal LV function. By ITT analysis, women had a
higher rate of primary events while there was no difference
by OT analysis. Although one interpretation is that the
higher rate of thrombo-embolism among women with AF
might have been related to interruption of anticoagulant
therapy, it was not possible to verify whether the number
of primary events following drug interruption differed
between genders. The data do, however, support the conclusion that those who discontinued therapy were at
higher intrinsic risk, similar to the recent report from the
ATRIA investigators.10
Although the SPORTIF III trial was conducted open label
and SPORTIF V was double blind, we consider it valid to
combine data from both because of the measures taken to
minimize bias. The ‘hard’ primary endpoints (all strokes
and SEE) and multiple levels of blinded adjudication were
the same for both trials. A specific symptom questionnaire
was uniformly employed to ensure the detection of relatively minor events, and all suspected endpoint events
(including TIA) were assessed at each study centre by an
independent neurologist or stroke physician unaware of randomized treatment assignment and adjudicated by a single,
independent, clinical events adjudication committee, also
blinded to treatment. Major haemorrhage and MI were similarly adjudicated. Other potential sources of bias included
differences in concomitant medication or choice of stroke
prevention strategy upon cessation of study medication,
but these were relatively minor.
Half the female cohort was 75 years of age, a larger proportion than men, and these older women had a higher
primary event rate than younger women. Although the
results of this subgroup analysis should be interpreted cautiously, they are consistent with reports emerging from
other prospectively followed cohorts of patients of both
genders with AF. Despite a lower prevalence of diagnosed
hypertension, these elderly women had higher systolic
blood pressure than men of comparable age, consistent
with previous reports.19 Although elderly women had more
stroke risk factors, there were only small differences in
the incidence of prior thrombo-embolism. Despite comparable or greater comorbidities, women were less likely to
have taken antithrombotic medication prior to entry,
perhaps reflecting fear of anticoagulant-related bleeding
among elderly women.20,21 In addition, fewer women than
men received such concurrent medications as b-blockers,
ACE-inhibitors, or lipid-lowering agents at entry or during
the course of the studies, yet the all-cause mortality rate
during follow-up was higher among men than women.
Some of the discrepancy might reflect the less frequent
diagnosis of coronary heart disease among women.22
Women had a slightly higher rate of major and minor
bleeding than men, but gender did not influence rates of
major bleeding and this argues in favour of anticoagulation
for women with AF. Compared with younger women, the
elderly had similar rates of major bleeding but slightly
more overall bleeding than younger women, arguing for
anticoagulation of all age groups. The quality of warfarin
control was as good among women as in men, with INR
values within the INR range of 2–3 about two-thirds of the
time on treatment. Warfarin-naı¨ve patients may have
more events than patients who had taken warfarin previously, as reported in another prospective trial of anticoagulation in patients with AF.23 The safety and efficacy we
observed during warfarin anticoagulation reflect highquality management in patients of both genders, and the
higher bleeding rates in elderly women cannot be explained
by lax INR control.
Few women took ERT during the study periods, possibly
because of the reported risks of MI and death in women
with CAD taking hormonal therapy,24 although more North
American women than those in other countries were using
ERT. The limited use of ERT among enrolled women makes
it difficult to evaluate its impact on the risk of stroke, but
we observed no difference in event rates.
The higher primary event rates among women than men
were independent of treatment assignment. When examined separately on the basis of ITT, both women and men
responded as well to ximelagatran as to well-controlled warfarin for prevention of thrombo-embolism. The efficacy of
ximelagatran was also consistent across genders when evaluated by OT analysis. Men had lower rates of major bleeding
on ximelagatran than on warfarin, but there were no significant differences in rates of intracerebral haemorrhage,
which was infrequent in both genders and in both treatment
groups.
Elevations of serum transaminase enzymes occurred more
often in women, but rates in both men and women fell
within the range reported in other trials involving patients
with venous thrombo-embolism and acute coronary syndromes treated with ximelagatran. The mechanism of this
reaction is not known, but concerns about potential hepatotoxicity led to withdrawal of ximelagatran from the
marketplace.25
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 3, 2013
There were no significant interactions between gender and
either trial or treatment; hence, data were pooled over
trial and treatment for all gender-based analyses. When
included as the only variable in the model, gender was significantly related to the primary event rate [hazard ratio
(HR) 1.44; 95% CI 1.07–1.93; P ¼ 0.0161). After adjusting
for the covariates above, however, this difference was no
longer significant (HR 1.27; 95% CI 0.91–1.76; P ¼ 0.16).
On the basis of Cox-regression analyses, the P-value for
the gender comparison for the primary endpoint remained
unchanged with (P ¼ 0.016) or without (P ¼ 0.016) study
present as a factor in the model. There was no interaction
between study and gender (P ¼ 0.92).
M. Gomberg-Maitland et al.
Anticoagulation in women with non-valvular AF in the stroke prevention
The SPORTIF trials represent the largest randomized
cohort of women with AF on anticoagulation yet reported,
with a high representation of elderly women. As a group,
women in the SPORTIF studies were older and had greater
comorbidity than in earlier trials of anticoagulation and
thus contributed more ischaemic and fatal events for analysis. Although less total bleeding occurred in women on ximelagatran when compared with warfarin, the elevation of
liver enzymes offset this benefit. Their clinical features
may reflect practice patterns at the time the studies were
carried out, yet the differences they exhibited compared
with men with AF appear robust across time.
Acknowledgements
Conflict of interest: The SPORTIF studies were sponsored by AstraZeneca, Mo
¨lndal, Sweden. Drs Gomberg-Maitland, Wenger, Volgmar,
and Halperin and Ms Fenzi have received grant support from AstraZeneca; Drs Petersen and Halperin have served as consultants for
AstraZeneca as members of the Executive Steering Committee;
and Dr Frison is a full time employee of AstraZeneca. Dr Lengyel
has no financial disclosure.
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The SPORTIF studies were sponsored by AstraZeneca, Mo
¨lndal,
Sweden. Drs G.-M., N.K.W., A.S.V., J.L.H., and Ms Fenzi have
received grant support from AstraZeneca; Drs P.P. and J.L.H. have
served as consultants for AstraZeneca; and Dr L.F. is a full-time
employee of AstraZeneca. Dr M.L. has no financial disclosure.
1953
European Heart Journal (2006) 27, 1947–1953
doi:10.1093/eurheartj/ehl103
Arrhythmia/electrophysiology
Anticoagulation in women with non-valvular atrial
fibrillation in the stroke prevention using an oral
thrombin inhibitor (SPORTIF) trials
Mardi Gomberg-Maitland1*, Nanette K. Wenger2, Jan Feyzi3, Maria Lengyel4,
Annabelle S. Volgman5, Palle Petersen6, Lars Frison7, and Jonathan L. Halperin8
1
Department of Medicine, Section of Cardiology, University of Chicago Hospitals, University of Chicago, 5841 S Maryland
Avenue, MC2016, Chicago, IL 60637, USA; 2 Emory University School of Medicine, Atlanta, GA, USA; 3 Informatics University of
Wisconsin–Madison, Madison, WI, USA; 4 Hungarian Institute of Cardiology, Budapest, Hungary; 5 Rush University Medical
Center, Chicago, IL, USA; 6 Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
7
¨lndal, Mo
¨lndal, Sweden; and 8 Mount Sinai Medical Center, New York, NY, USA
AstraZeneca R&D Mo
See page 1893 for the editorial comment on this article (doi:10.1093/eurheartj/ehl140)
KEYWORDS
Atrial fibrillation;
Women;
Anticoagulation;
Thromboembolism
Aims The risk of stroke is greater among women with atrial fibrillation (AF) than men. Warfarin protects
against stroke, but treatment-related bleeding occurs more often in women than in men.
Methods and results SPORTIF III (open label, n ¼ 3410) and V (double-blind, n ¼ 3922) included 2257
women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0–3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischaemic/haemorrhagic) and systemic embolic event. Women were older, on average, than men, 73.4 + 8.0
vs. 69.8 + 9.0 years (P , 0.0001). More women were .75-years old and women had more risk factors
than men had (P , 0.0001). The INR on warfarin (mean 2.5 + 0.7) was within target range for 67% of
follow-up regardless of gender. Women more often developed primary events [2.08%/year, 95% confidence interval (CI) 1.60–2.56%/year vs. 1.44%/year, 95% CI 1.18–1.71%/year in men; P ¼ 0.016).
Major bleeding rates were similar (P ¼ 0.766) but women experienced more overall (major/minor)
bleeding (P , 0.001). Warfarin was associated with more overall bleeding in both genders and more
major bleeding in women than in men (P ¼ 0.001).
Conclusion When compared with men with AF, women in these studies were older and had more stroke
risk factors. Women were more prone to anticoagulant-related bleeding; the higher rate of
thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy.
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac
rhythm disorder encountered in clinical practice and an
important risk factor for ischaemic stroke.1,2 Its prevalence
increases with age, affecting women slightly less often than
men.2–6 Stroke rates with AF are higher in women than in
men,3,7–10 and AF is the most common cause of stroke in
elderly women.
Despite the established efficacy of anticoagulation for
prevention of stroke in both men and women with AF, warfarin is prescribed for less than one-third of women with
AF at hospital discharge, a lower rate than for men, and
this under-use is associated with adverse outcomes.11 Few
randomized trials have enrolled a sufficient proportion of
women to specifically evaluate differential efficacy or
safety on the basis of gender,12,13 but data from a
prospective cohort demonstrate that women have a higher
risk than men for AF-related thrombo-embolism and that
warfarin is as effective in women as in men with AF.10
The Stroke Prevention using an Oral Thrombin Inhibitor in
patients with AF(SPORTIF) programme included two clinical
trials that compared the efficacy and safety of ximelagatran
vs. warfarin in patients with AF at risk of ischaemic stroke.
The combined cohort of SPORTIF III and V includes the
largest number of women yet reported with non-valvular
AF followed prospectively on anticoagulation; 50% of the
women enrolled were over 75 years of age. The results
provide information about sex-based and age-based differences in rates of ischaemic events and bleeding among anticoagulated patients with AF and about the relative safety and
efficacy of warfarin and ximelagatran in women and men.
Methods
* Corresponding author. Tel: þ1 773 702 5589; fax: þ1 773 834 1764.
E-mail address: mgomberg@medicine.bsd.uchicago.edu
The design, characteristics of enrolled patients, statistical analysis,
and main results of the SPORTIF III and V trials have been
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 3, 2013
Received 11 November 2005; revised 15 May 2006; accepted 26 May 2006; online publish-ahead-of-print 14 June 2006
1948
reported.14–16 Entry criteria, based on current clinical indications for
antithrombotic therapy,16,17 were identical for the two studies16 and
included persistent or paroxysmal non-valvular AF verified by ECG
within 2 weeks before randomization and at least one of the following
additional risk factors for stroke: hypertension, age 75 years, previous stroke, transient ischaemic attack (TIA) or systemic embolic
event (SEE), left ventricular (LV) dysfunction [LV ejection fraction
(LVEF) ,40% or symptomatic congestive heart failure (CHF)], age
65 years with coronary artery disease (CAD), or age 65 years and
diabetes mellitus. The principal exclusion criteria were: stroke,
TIA, or SEE within 30 days before entry; bleeding disorders; conditions requiring conventional anticoagulant therapy; AF secondary
to reversible disorders (e.g. thyrotoxicosis); hypertension .180/
100 mmHg despite medication; previous disabling stroke with modified Rankin score .3; acute coronary syndrome within 30 days;
planned cardioversion, treatment with platelet-inhibitor drugs
other than aspirin 100 mg/day within 10 days; renal insufficiency
(calculated creatinine clearance ,30 mL/min); active liver disease
or persistent elevation of liver enzymes two or more times the
upper limit of normal (ULN); childbearing potential, pregnancy, or
lactation.
Patients were randomized to treatment with ximelagatran at a fixed
dose of 36 mg twice daily or to warfarin dose adjusted to maintain
the international normalized ratio (INR) between 2.0 and 3.0, based
on blood test monitoring at maximum intervals of 4 weeks.
Allocation was balanced according to aspirin therapy at entry, previous stroke or TIA, and country, using an adaptive allocation algorithm. In SPORTIF III, treatment was administered open label at 259
sites in 23 countries in Europe, Australia, New Zealand, and Asia,
with blinded endpoint event assessment. In SPORTIF V, treatment
was double blind at 409 sites in North America.
Concomitant estrogen replacement therapy
Some women took estrogen replacement therapy (ERT) during the
trial on the advice of their physician. For this analysis, women
were considered to be on ERT when either oral or subcutaneous
estrogen alone or in conjunction with progesterone therapy was
recorded as a concomitant medication at randomization, but
topical therapies and progesterone monotherapy were excluded.
Clinical assessments and endpoints
After randomization, patients were seen at 1, 4, and 6 weeks and
then at 2, 3, 4, 5, 6, 8, 10, and 12 months, and every 3 months
thereafter for detection of stroke or SEE (primary events), TIA,
acute myocardial infarction (MI), or bleeding complications.
Events were also detected by a standard stroke-symptom questionnaire administered by telephone; positive responses prompted
additional evaluation. A study-affiliated neurologist or stroke
specialist blinded to treatment allocation evaluated all possible
primary events and TIA. An independent, central clinical event
adjudication committee also blinded to treatment reviewed clinical
reports of all primary and secondary events. Primary endpoints for
the trial were stroke and SEE. Secondary endpoints were acute MI,
TIA, death, and major and minor bleeding.16
Statistical analysis
The trials were based on establishing non-inferiority within an absolute margin of 2%/year for the difference in primary event rates
between the two treatment groups. The analysis reported here
was planned to compare the efficacy and safety of anticoagulation
in women with that in men enrolled in both trials. Comparisons
were made for age 75 or younger, paroxysmal or persistent AF,
and use of ERT at randomization. In addition, we performed multivariable analysis of the pooled data for trial effect, study treatment
effect, and their interactions within these subgroups. Sensitivity
analyses comparing men and women for the primary endpoint
were performed on the basis of a Cox-regression using study as a
factor in the model and for interaction between study and gender.
The intention-to-treat (ITT) analysis for primary events and mortality included all randomized patients until study closure, irrespective of protocol adherence, or continued participation. Remaining
endpoints were recorded during the on-treatment (OT) period
with exposure censored from the 31st consecutive day or 61st
cumulative day off study drug. Events before first dose intake in
randomized patients were included in the analysis. No patient was
counted more than once for a given composite endpoint.
All patients were followed for primary events and mortality until
study closure. Remaining outcomes were recorded during the OT
period. Hence, composite endpoints confined to stroke, SEE, and
death were analyzed according to ITT, whereas assessments of all
other outcomes, composite endpoints and exploratory analyses
used the OT approach.
In addition to analyses of efficacy, the safety profiles of ximelagatran and warfarin were compared between genders. For each treatment group, the proportions of patients experiencing major
bleeding, minor bleeding, or bleeding causing permanent treatment
cessation were calculated, accounting for duration of exposure for
each patient. Other adverse events and laboratory variables are
summarized using descriptive statistics.
The analysis of the difference in primary event rates between the
treatment groups was made under the assumption of exponentially
distributed lifetimes. This is equivalent to assuming a constant
event rate over time and hence the probability of an event over a
year can be estimated from the complete follow-up of all patients.
The variance for the difference in event rates was estimated using
the method described by Cox and Oakes.18 Two-sided P-values for
differences between treatments were obtained by Fisher’s exact
test, using the number of patient-years as analyses units. ERT was
a conceived subgroup analysis prior to completion of the trials.
Because both age .75 and pattern of AF (paroxysmal or persistant)
are perceived risk factors for AF, we performed substudy analyses.
Also, for both SPORTIF III and V comparisons of primary event
rates according to age .75 vs. ,75 was a predefined tertiary
endpoint. Thus the writing group felt that examination in this
cohort was important for substudy analyses.
Cox-regression analyses used the following baseline stroke risk
factors as covariates for multivariable analyses after validation of
the proportional hazards model assumption: gender, baseline systolic blood pressure and diastolic blood pressure (DBP), prior stroke/
TIA, SEE, hypertension, CAD (MI, angioplasty, or angina), diabetes
mellitus, LV dysfunction (LVEF ,40% or symptomatic CHF), age
(both as a continuous and as a categorical variable), smoking (past
or present vs. none), body mass index (,30 vs. 30), alcohol as a
dichotomous variable, trial, and study treatment.
Results
Baseline characteristics
Baseline characteristics of enrolled patients are compared
by gender in Table 1. Of the 7329 subjects enrolled, 2257
(30.8%) were women (30.9% in SPORTIF III and 30.7% in
SPORTIF V). The mean age was 73.4 + 8 years for women
and 69.8 + 9 years for men (P , 0.0001). The mean blood
pressure in women was 138.5 + 18 mmHg systolic and
79.8 + 10 mmHg
diastolic
when
compared
with
134.0 + 18 mmHg (P , 0.0001) and 79.2 + 11 mmHg in
men (P ¼ 0.015). Ninety-three per cent of women and 92%
of men were Caucasian compared to other races
(P , 0.0001). Only 5% of women were occasional or habitual
smokers when compared with 11% of men (P , 0.0001). The
onset of AF was within 1 year in 23% of women vs. 18% of
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 3, 2013
Randomized treatment
M. Gomberg-Maitland et al.
Anticoagulation in women with non-valvular AF in the stroke prevention
1949
Table 1 Baseline characteristics
Baseline characteristics
Men (n ¼ 5072)
Women (n ¼ 2257)
P-value
Age (years)
SBP (mmHg)
DBP (mmHg)
Race, n (%)
Caucasian
African-American
Oriental
Other
Smoking, n (%)
Non-smoker
Ex-smoker
Occasional
Habitual
AF, n (%)
Persistent
Paroxysmal
Years since first AF diagnosis, n (%)
,1
1–2
2–5
.5
History of stroke, n (%)
History of TIA, n (%)
History of diabetes, n (%)
History of CAD, n (%)
High-risk factors, n (%)
Hypertension
Age 75 years
Prior stroke/TIA
SEE
LV dysfunction
Age 65 and diabetes
Age 65 and CAD
Number of risk factors, n (%)
0
1
2
3
4
.4
Concomitant medications, n (%)
ASA
b-Blocker
ACE-inhibitor
Statin
ERT
69.8 + 9
134.0 + 18
79.2 + 11
73.4 + 8
138.5 + 18
79.8 + 10
,0.0001
,0.0001
0.015
4658 (92)
75 (2)
323 (6)
16 (0)
2099
53
99
6
(93)
(2)
(4)
(0)
,0.001
1605 (32)
2907 (57)
118 (2)
442 (9)
1496
643
22
96
(66)
(29)
(1)
(4)
,0.0001
4354 (89)
537 (11)
1956 (87)
299 (13)
,0.001
477
245
555
761
286
246
495
864
(23)
(12)
(27)
(38)
(13)
(11)
(22)
(38)
,0.0001
3804 (75)
1670 (33)
1048 (21)
224 (4)
1942 (38)
921 (18)
1985 (39)
1821
1134
491
104
739
419
779
(81)
(50)
(22)
(5)
(33)
(19)
(35)
,0.0001
,0.0001
0.29
0.71
,0.0001
0.68
,0.001
13 (0)
1520 (30)
1636 (32)
1097 (22)
565 (11)
241 (5)
4
531
745
582
275
120
(0)
(24)
(33)
(26)
(12)
(5)
,0.0001
878 (17)
2425 (48)
2621 (52)
1737 (34)
0 (0)
304
1040
945
610
381
(14)
(46)
(42)
(27)
(17)
,0.0001
0.17
,0.0001
,0.0001
,0.0001
0.74
0.56
0.03
,0.0001
ASA, acetylsalicylic acid; SBP, systolic blood pressure; DBP, diastolic blood pressure; TIA, transient ischaemic attack;
SEE, systemic embolic event; LV, left ventricular; CAD, coronary artery disease; ACE, angiotensin converting enzyme.
men (P , 0.0001). A history of hypertension was more
frequent (81% vs. 75%; P , 0.0001), but the prevalence of
diabetes (22% vs. 24%; P ¼ 0.03), coronary heart disease
(38% vs. 48%; P , 0.0001), and LV systolic dysfunction (33%
vs. 38%; P , 0.0001) was lower among women. Women had
a larger number of associated thrombo-embolic risk factors
(43% vs. 38% with three or more risk factors in addition to
AF; P , 0.0001).
Prior to randomization, women were less often treated
with cardiovascular medications such as b-blockers,
angiotensin-converting enzyme (ACE) inhibitors, or statins
but there was no difference in use of vitamin K antagonists
or aspirin. After randomization, the INR was within the
target range (2.0–3.0) 66.6% of the time on treatment and
in the expanded range of 1.8–3.2 for 81.5% of the time
among the 1099 women assigned to warfarin therapy.
Among men on warfarin (n ¼ 2525), INR was between 2.0
and 3.0 for 67.8% and between 1.8 and 3.2 for 82.7% of
the time on treatment.
Endpoint events
By ITT analysis, more women than men developed primary
events (stroke or SEE), with 72 women experiencing events
during 3465 patient-years [2.08%/year, 95% confidence
interval (CI) 1.60–2.56%/year] vs. 112 men during 7759
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 3, 2013
850 (18)
561 (12)
1249 (27)
1986 (43)
631 (12)
530 (10)
1230 (24)
2415 (48)
1950
M. Gomberg-Maitland et al.
Table 2 Event rates: women vs. men and women aged 75 years vs. women aged ,75 years
Events, n
Event rate, % per year
P-value
72
112
45
27
3465
7759
1724
1742
2.08
1.44
2.61
1.55
95
301
67
28
3507
7831
1746
1760
2.71
3.84
3.84
1.59
,0.001
49
101
3037
6960
1.61
1.45
0.53
22
78
3038
6949
0.72
1.12
0.08
68
149
41
27
3022
6924
1474
1548
2.25
2.15
2.78
1.74
889
1776
467
422
2153
5237
1044
1109
41.29
33.91
44.73
38.05
patient-years (1.44%/year, 95% CI 1.18–1.71%/year;
P ¼ 0.016; Table 2). However, this difference was limited
to the ximelagatran group (2.17%/year, 95% CI 1.48–2.87%/
year vs. 1.38%/year, 95% CI 1.00–1.75%/year; P ¼ 0.03).
There was no significant difference in primary event rates
based on gender in the warfarin group (Figure 1).
Comparing women in the ximelagatran and warfarin
groups, 38 patients experienced primary events during
1748 patient-years with ximelagatran (2.17%/year) vs. 34
during 1717 patient-years for warfarin (1.98%/year;
P ¼ 0.722). Among men, during 3854 patient-years, 53
developed primary events in the ximelagatran group
(1.38%/year) when compared with 59 in the warfarin
group during 3905 patient-years (1.51%/year; P ¼ 0.635).
In contrast to their more favourable outcome with respect
to the primary events, men suffered higher all-cause mortality than women, with 301 male deaths over 7831 patientyears (3.84%/year, 95% CI 3.41–4.28%/year) when compared
with 93 deaths among women over 3507 patient-years
(2.71%/year, 95% CI 2.16–3.25%/year; P ¼ 0.002).
Furthermore, the difference in primary event rates
between women and men was not apparent when assessed
by OT analysis (1.61%/year in women, 95% CI 1.16–2.07%/
year vs. 1.45%/year in men, 95% CI 1.17–1.73%/year;
P ¼ 0.53). The mean number of stroke risk factors other
than AF among women who discontinued anticoagulation
during the trial was 2.54 (95% CI 2.47–2.61) when compared
with a mean of 2.21 (95% CI 2.17–2.24), among those who
were able to sustain anticoagulation (P , 0.0001). Primary
events included haemorrhagic stroke in four women (three
fatal), ischaemic stroke in 40 (seven fatal), and SEE in five
(one fatal). Ten men developed haemorrhagic stroke of
0.016
0.032
0.002
0.766
0.065
,0.001
0.002
which five were fatal, 86 ischaemic stroke (eight fatal),
and six SEE (one fatal), using a 30-day rule.
Bleeding complications
There was no difference in major bleeding complications
between women and men overall (2.25% vs. 2.15%/year;
P ¼ 0.765) or in either of the treatment groups (0.57%/
year on ximelagatran, P ¼ 0.208, and 20.35%/year on warfarin, P ¼ 0.491). Among women, there was no difference in
major bleeding in the ximelagatran vs. warfarin groups.
More men developed major bleeding on warfarin (91
events; 2.57%/year) when compared with those on ximelagatran (58 events, 1.71%/year; P ¼ 0.016). Combined rates
of both major and minor bleeding were greater among
women than men (41.29%/year vs. 33.91%/year;
P , 0.001) that carried across both treatment groups (a
difference in rates of 5.37%/year between women and
men on ximelagatran, P ¼ 0.001, and a difference of
8.56%/year on warfarin, P , 0.0001). Comparing the two
treatments, bleeding was less frequent among women in
the ximelagatran group (35.48%/year) than in the warfarin
group (44.82%/year, P , 0.001). The same was true among
men (30.85%/year in the ximelagatran group vs. 37.01%/
year in the warfarin group; P , 0.001).
Liver function abnormalities
Women in the ximelagatran group developed serum levels of
S-alanine aminotransferase (ALT) beyond three times the
ULN more often than men (8.4% vs. 5.1%; P , 0.001;
Table 3). Incidences in the warfarin group were 1.0%
among women and 0.7% among men. Incidences of ALT
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Stroke and SEE (ITT analysis)
Women
Men
Women aged 75 years
Women aged ,75 years
Mortality
Women
Men
Women aged 75 years
Women aged ,75 years
Stroke and SEE (OT analysis)
Women
Men
MI
Women
Men
Major bleeding
Women
Men
Women aged 75 years
Women aged ,75 years
Major and minor bleeding
Women
Men
Women aged 75 years
Women aged ,75 years
Patient-years
Anticoagulation in women with non-valvular AF in the stroke prevention
Primary event rates over time: women vs. men on ximelagatran and women vs. men on warfarin.
Table 3 Liver function tests: number of patients by gender
maximal S-ALT multiple of ULN during study (ITT population)
ULN
Women, n (%)
ALT . ULN 1
ALT . ULN 2
ALT . ULN 3
ALT . ULN 5
ALT . ULN 10
Men, n (%)
ALT . ULN 1
ALT . ULN 2
ALT . ULN 3
ALT . ULN 5
ALT . ULN 10
Ximelagatran
Warfarin
Total
338 (29.6)
152 (13.3)
96 (8.4)
51 (4.5)
9 (0.8)
104 (9.3)
21 (1.9)
11 (1.0)
5 (0.4)
1 (0.0)
442 (20.0)
173 (8.0)
107 (5.0)
56 (2.0)
9 (0.0)
591 (23.4)
218 (8.6)
128 (5.1)
65 (2.6)
22 (0.9)
326 (12.8)
51 (2.0)
18 (0.7)
7 (0.3)
1 (0.0)
917 (18.0)
269 (5.0)
146 (3.0)
72 (1.0)
23 (0.0)
beyond five times the ULN occurred more often in women
than in men (4.5% vs. 2.6%) on ximelagatran but with little
difference on warfarin (0.4% vs. 0.3%).
Differences based on age
Compared with younger women, those aged 75 years were
more often Caucasian (96 vs. 90%), non-smokers (68 vs.
65%), with higher systolic blood pressure (139.8 vs.
137.2 mmHg), taking aspirin (15 vs. 12%), with persistent
AF (89 vs. 85%) and a history of TIA (12 vs. 10%). Elderly
women had more risk factors for stroke (three or more in
63 vs. 23%) but less often had a history of hypertension (77
vs. 84%) and had a lower DBP (79.0 vs. 80.7 mmHg) or
diabetes (18 vs. 36%). Older women more often had CAD
than younger women (40 vs. 29%).
More women over the age of 75 years developed
primary events (2.61 vs. 1.55%/year; P ¼ 0.032; ITT
analysis). Older women also displayed greater all-cause
mortality (P , 0.001;). Rates of major bleeding were not
significantly different between older and younger women
(2.78 vs. 1.74%; P ¼ 0.065), but the elder group developed
more overall (major and minor) bleeding events (44.73
vs. 38.05%/year; P ¼ 0.002). There were no differences
in major bleeding based on treatment group assignment among either older women (2.97%/year in the ximelagatran group vs. 2.60%/year in the warfarin group;
P ¼ 0.752) or younger women (1.66%/year in the
ximelagatran group vs. 1.83%/year in the warfarin group;
P ¼ 0.848).
Differences based on ERT
In both trials combined, 381 women (17%) took ERT at randomization and for more than half the follow-up period,
and 413 (18%) used ERT at some point during the trial. Of
those taking ERT at entry, 14 developed ischaemic stroke,
SEE, or TIA and 27 had ischaemic stroke, SEE, TIA, MI, or
death. The small number of women using ERT and the infrequency of events left the results of univariate and multivariable analyses inconclusive.
Differences based on pattern of AF
Most women (87%) had persistent AF. There were no
differences in baseline demographics between those with
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Figure 1
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1952
persistent vs. paroxysmal AF except for age (42% with
paroxysmal AF were 75 years vs. 52% with persistent
AF; P ¼ 0.002) and LV dysfunction (25% with paroxysmal
AF vs. 34% with persistent AF; P ¼ 0.0025). Women with
persistent AF had more stroke risk factors (45 vs. 35%
with more than three risk factors in addition to AF;
P , 0.0001).
Multivariable analyses
Discussion
This cohort of 2257 women with AF on anticoagulation is the
largest described to date; even so, as only 31% of randomized patients were women, statistical power of conclusions
specifically involving women remains limited. Compared
with men in these trials, women were typically older than
75 years, had a history of hypertension, and had more risk
factors for stroke though they were less often diabetic and
had normal LV function. By ITT analysis, women had a
higher rate of primary events while there was no difference
by OT analysis. Although one interpretation is that the
higher rate of thrombo-embolism among women with AF
might have been related to interruption of anticoagulant
therapy, it was not possible to verify whether the number
of primary events following drug interruption differed
between genders. The data do, however, support the conclusion that those who discontinued therapy were at
higher intrinsic risk, similar to the recent report from the
ATRIA investigators.10
Although the SPORTIF III trial was conducted open label
and SPORTIF V was double blind, we consider it valid to
combine data from both because of the measures taken to
minimize bias. The ‘hard’ primary endpoints (all strokes
and SEE) and multiple levels of blinded adjudication were
the same for both trials. A specific symptom questionnaire
was uniformly employed to ensure the detection of relatively minor events, and all suspected endpoint events
(including TIA) were assessed at each study centre by an
independent neurologist or stroke physician unaware of randomized treatment assignment and adjudicated by a single,
independent, clinical events adjudication committee, also
blinded to treatment. Major haemorrhage and MI were similarly adjudicated. Other potential sources of bias included
differences in concomitant medication or choice of stroke
prevention strategy upon cessation of study medication,
but these were relatively minor.
Half the female cohort was 75 years of age, a larger proportion than men, and these older women had a higher
primary event rate than younger women. Although the
results of this subgroup analysis should be interpreted cautiously, they are consistent with reports emerging from
other prospectively followed cohorts of patients of both
genders with AF. Despite a lower prevalence of diagnosed
hypertension, these elderly women had higher systolic
blood pressure than men of comparable age, consistent
with previous reports.19 Although elderly women had more
stroke risk factors, there were only small differences in
the incidence of prior thrombo-embolism. Despite comparable or greater comorbidities, women were less likely to
have taken antithrombotic medication prior to entry,
perhaps reflecting fear of anticoagulant-related bleeding
among elderly women.20,21 In addition, fewer women than
men received such concurrent medications as b-blockers,
ACE-inhibitors, or lipid-lowering agents at entry or during
the course of the studies, yet the all-cause mortality rate
during follow-up was higher among men than women.
Some of the discrepancy might reflect the less frequent
diagnosis of coronary heart disease among women.22
Women had a slightly higher rate of major and minor
bleeding than men, but gender did not influence rates of
major bleeding and this argues in favour of anticoagulation
for women with AF. Compared with younger women, the
elderly had similar rates of major bleeding but slightly
more overall bleeding than younger women, arguing for
anticoagulation of all age groups. The quality of warfarin
control was as good among women as in men, with INR
values within the INR range of 2–3 about two-thirds of the
time on treatment. Warfarin-naı¨ve patients may have
more events than patients who had taken warfarin previously, as reported in another prospective trial of anticoagulation in patients with AF.23 The safety and efficacy we
observed during warfarin anticoagulation reflect highquality management in patients of both genders, and the
higher bleeding rates in elderly women cannot be explained
by lax INR control.
Few women took ERT during the study periods, possibly
because of the reported risks of MI and death in women
with CAD taking hormonal therapy,24 although more North
American women than those in other countries were using
ERT. The limited use of ERT among enrolled women makes
it difficult to evaluate its impact on the risk of stroke, but
we observed no difference in event rates.
The higher primary event rates among women than men
were independent of treatment assignment. When examined separately on the basis of ITT, both women and men
responded as well to ximelagatran as to well-controlled warfarin for prevention of thrombo-embolism. The efficacy of
ximelagatran was also consistent across genders when evaluated by OT analysis. Men had lower rates of major bleeding
on ximelagatran than on warfarin, but there were no significant differences in rates of intracerebral haemorrhage,
which was infrequent in both genders and in both treatment
groups.
Elevations of serum transaminase enzymes occurred more
often in women, but rates in both men and women fell
within the range reported in other trials involving patients
with venous thrombo-embolism and acute coronary syndromes treated with ximelagatran. The mechanism of this
reaction is not known, but concerns about potential hepatotoxicity led to withdrawal of ximelagatran from the
marketplace.25
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There were no significant interactions between gender and
either trial or treatment; hence, data were pooled over
trial and treatment for all gender-based analyses. When
included as the only variable in the model, gender was significantly related to the primary event rate [hazard ratio
(HR) 1.44; 95% CI 1.07–1.93; P ¼ 0.0161). After adjusting
for the covariates above, however, this difference was no
longer significant (HR 1.27; 95% CI 0.91–1.76; P ¼ 0.16).
On the basis of Cox-regression analyses, the P-value for
the gender comparison for the primary endpoint remained
unchanged with (P ¼ 0.016) or without (P ¼ 0.016) study
present as a factor in the model. There was no interaction
between study and gender (P ¼ 0.92).
M. Gomberg-Maitland et al.
Anticoagulation in women with non-valvular AF in the stroke prevention
The SPORTIF trials represent the largest randomized
cohort of women with AF on anticoagulation yet reported,
with a high representation of elderly women. As a group,
women in the SPORTIF studies were older and had greater
comorbidity than in earlier trials of anticoagulation and
thus contributed more ischaemic and fatal events for analysis. Although less total bleeding occurred in women on ximelagatran when compared with warfarin, the elevation of
liver enzymes offset this benefit. Their clinical features
may reflect practice patterns at the time the studies were
carried out, yet the differences they exhibited compared
with men with AF appear robust across time.
Acknowledgements
Conflict of interest: The SPORTIF studies were sponsored by AstraZeneca, Mo
¨lndal, Sweden. Drs Gomberg-Maitland, Wenger, Volgmar,
and Halperin and Ms Fenzi have received grant support from AstraZeneca; Drs Petersen and Halperin have served as consultants for
AstraZeneca as members of the Executive Steering Committee;
and Dr Frison is a full time employee of AstraZeneca. Dr Lengyel
has no financial disclosure.
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The SPORTIF studies were sponsored by AstraZeneca, Mo
¨lndal,
Sweden. Drs G.-M., N.K.W., A.S.V., J.L.H., and Ms Fenzi have
received grant support from AstraZeneca; Drs P.P. and J.L.H. have
served as consultants for AstraZeneca; and Dr L.F. is a full-time
employee of AstraZeneca. Dr M.L. has no financial disclosure.
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