Anticoagulation in women with non valvul (1)

(1)

Arrhythmia

/

electrophysiology

Anticoagulation in women with non-valvular atrial

fibrillation in the stroke prevention using an oral

thrombin inhibitor (SPORTIF) trials

Mardi Gomberg-Maitland

1

*, Nanette K. Wenger

2

_{, Jan Feyzi}

3

_{, Maria Lengyel}

4

_,

Annabelle S. Volgman

5

, Palle Petersen

6

, Lars Frison

7

, and Jonathan L. Halperin

8

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

AstraZeneca R&D Mo

¨lndal, Mo

¨lndal, Sweden; and

8

Mount Sinai Medical Center, New York, NY, USA

Received 11 November 2005; revised 15 May 2006; accepted 26 May 2006; online publish-ahead-of-print 14 June 2006

See page 1893 for the editorial comment on this article (doi:10.1093/eurheartj/ehl140)

AimsThe 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 resultsSPORTIF III (open label,n¼3410) and V (double-blind,n¼3922) included 2257 women with AF and one or more stroke risk factors randomized to warfarin [target international normal-ized ratio (INR) 2.0–3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischae-mic/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% confi-dence interval (CI) 1.60–2.56%/year vs. 1.44%/year, 95% CI 1.18–1.71%/year in men; P¼0.016). Major bleeding rates were similar (P¼0.766) 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 (P¼0.001).

ConclusionWhen 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.

KEYWORDS

Atrial fibrillation; Women; Anticoagulation; Thromboembolism

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,

war-farin 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

differ-ences in rates of ischaemic events and bleeding among

antic-oagulated patients with AF and about the relative safety and

efficacy of warfarin and ximelagatran in women and men.

Methods

The design, characteristics of enrolled patients, statistical analysis, and main results of the SPORTIF III and V trials have been

&

*

Corresponding author. Tel:þ1 773 702 5589; fax:þ1 773 834 1764.

E-mail address: mgomberg@medicine.bsd.uchicago.edu doi:10.1093/eurheartj/ehl103

by guest on June 3, 2013

http://eurheartj.oxfordjournals.org/

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reported.14–16_{Entry criteria, based on current clinical indications for} antithrombotic therapy,16,17_{were identical for the two studies}16_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, age75 years, pre-vious 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 age65 years and diabetes mellitus. The principal exclusion criteria were: stroke, TIA, or SEE within 30 days before entry; bleeding disorders; con-ditions requiring conventional anticoagulant therapy; AF secondary to reversible disorders (e.g. thyrotoxicosis); hypertension .180/ 100 mmHg despite medication; previous disabling stroke with modi-ﬁed Rankin score .3; acute coronary syndrome within 30 days; planned cardioversion, treatment with platelet-inhibitor drugs other than aspirin100 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.

Randomized treatment

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, pre-vious stroke or TIA, and country, using an adaptive allocation algor-ithm. 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 question-naire 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 absol-ute 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 multi-variable 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 mor-tality included all randomized patients until study closure, irrespec-tive 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 ximelaga-tran and warfarin were compared between genders. For each treat-ment 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.18Two-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 systo-lic blood pressure and diastosysto-lic 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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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

Table 1 Baseline characteristics

Baseline characteristics Men (n¼5072) Women (n¼2257) P-value

Age (years) 69.8+9 73.4+8 ,0.0001

SBP (mmHg) 134.0+18 138.5+18 ,0.0001

DBP (mmHg) 79.2+11 79.8+10 0.015

Race,n(%)

Caucasian 4658 (92) 2099 (93) ,0.001

African-American 75 (2) 53 (2)

Oriental 323 (6) 99 (4)

Other 16 (0) 6 (0)

Smoking,n(%)

Non-smoker 1605 (32) 1496 (66) ,0.0001

Ex-smoker 2907 (57) 643 (29)

Occasional 118 (2) 22 (1)

Habitual 442 (9) 96 (4)

AF,n(%)

Persistent 4354 (89) 1956 (87) ,0.001

Paroxysmal 537 (11) 299 (13)

Years since first AF diagnosis,_n(%)

,1 850 (18) 477 (23) ,0.0001

1–2 561 (12) 245 (12)

2–5 1249 (27) 555 (27)

.5 1986 (43) 761 (38)

History of stroke,n(%) 631 (12) 286 (13) 0.74

History of TIA,n(%) 530 (10) 246 (11) 0.56

History of diabetes,n(%) 1230 (24) 495 (22) 0.03

History of CAD,n(%) 2415 (48) 864 (38) ,0.0001

High-risk factors,n(%)

Hypertension 3804 (75) 1821 (81) ,0.0001

Age75 years 1670 (33) 1134 (50) ,0.0001

Prior stroke/TIA 1048 (21) 491 (22) 0.29

SEE 224 (4) 104 (5) 0.71

LV dysfunction 1942 (38) 739 (33) ,0.0001

Age65 and diabetes 921 (18) 419 (19) 0.68

Age65 and CAD 1985 (39) 779 (35) ,0.001

Number of risk factors,_n(%)

0 13 (0) 4 (0) ,0.0001

1 1520 (30) 531 (24)

2 1636 (32) 745 (33)

3 1097 (22) 582 (26)

4 565 (11) 275 (12)

.4 241 (5) 120 (5)

Concomitant medications,n(%)

ASA 878 (17) 304 (14) ,0.0001

b-Blocker 2425 (48) 1040 (46) 0.17

ACE-inhibitor 2621 (52) 945 (42) ,0.0001

Statin 1737 (34) 610 (27) ,0.0001

ERT 0 (0) 381 (17) ,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.

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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

mor-tality than women, with 301 male deaths over 7831

patient-years (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

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

2 0.35%/year on

war-farin,

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

ximela-gatran (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

Table 2 Event rates: women vs. men and women aged75 years vs. women aged,75 years

Events,n Patient-years Event rate, % per year P-value

Stroke and SEE (ITT analysis)

Women 72 3465 2.08

Men 112 7759 1.44 0.016

Women aged75 years 45 1724 2.61

Women aged,75 years 27 1742 1.55 0.032

Mortality

Women 95 3507 2.71

Men 301 7831 3.84 0.002

Women aged,75 years 28 1760 1.59 ,0.001

Stroke and SEE (OT analysis)

Women 49 3037 1.61

Men 101 6960 1.45 0.53

MI

Women 22 3038 0.72

Men 78 6949 1.12 0.08

Major bleeding

Women 68 3022 2.25

Men 149 6924 2.15 0.766

Women aged,75 years 27 1548 1.74 0.065

Major and minor bleeding

Women 889 2153 41.29

Men 1776 5237 33.91 ,0.001

Women aged,75 years 422 1109 38.05 0.002

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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

assign-ment among either older women (2.97%/year in the

ximela-gatran 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

ran-domization 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

infre-quency of events left the results of univariate and

multivari-able analyses inconclusive.

Differences based on pattern of AF

Most women (87%) had persistent AF. There were no

differences in baseline demographics between those with

Table 3 Liver function tests: number of patients by gender

maximalS-ALT multiple of ULN during study (ITT population)

ULN Ximelagatran Warfarin Total

Women,n(%)

ALT.ULN1 338 (29.6) 104 (9.3) 442 (20.0) ALT.ULN2 152 (13.3) 21 (1.9) 173 (8.0) ALT.ULN3 96 (8.4) 11 (1.0) 107 (5.0) ALT.ULN5 51 (4.5) 5 (0.4) 56 (2.0) ALT.ULN10 9 (0.8) 1 (0.0) 9 (0.0) Men,n(%)

ALT.ULN1 591 (23.4) 326 (12.8) 917 (18.0) ALT.ULN2 218 (8.6) 51 (2.0) 269 (5.0) ALT.ULN3 128 (5.1) 18 (0.7) 146 (3.0) ALT.ULN5 65 (2.6) 7 (0.3) 72 (1.0) ALT.ULN10 22 (0.9) 1 (0.0) 23 (0.0)

Figure 1 Primary event rates over time: women vs. men on ximelagatran and women vs. men on warfarin.

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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

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

sig-niﬁcantly 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).

Discussion

This cohort of 2257 women with AF on anticoagulation is the

largest described to date; even so, as only 31% of

random-ized 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

con-clusion 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

rela-tively minor events, and all suspected endpoint events

(including TIA) were assessed at each study centre by an

independent neurologist or stroke physician unaware of

ran-domized treatment assignment and adjudicated by a single,

independent, clinical events adjudication committee, also

blinded to treatment. Major haemorrhage and MI were

simi-larly 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

pro-portion 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

cau-tiously, 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

compar-able 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

pre-viously, as reported in another prospective trial of

anticoa-gulation in patients with AF.

23

The safety and efﬁcacy we

observed during warfarin anticoagulation reﬂect

high-quality 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

exam-ined separately on the basis of ITT, both women and men

responded as well to ximelagatran as to well-controlled

war-farin for prevention of thrombo-embolism. The efﬁcacy of

ximelagatran was also consistent across genders when

eval-uated by OT analysis. Men had lower rates of major bleeding

on ximelagatran than on warfarin, but there were no

signiﬁ-cant 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

syn-dromes treated with ximelagatran. The mechanism of this

reaction is not known, but concerns about potential

hepato-toxicity led to withdrawal of ximelagatran from the

marketplace.

25

(7)

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

analy-sis. Although less total bleeding occurred in women on

xime-lagatran 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

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.

Conflict of interest: The SPORTIF studies were sponsored by Astra-Zeneca, Mo¨lndal, Sweden. Drs Gomberg-Maitland, Wenger, Volgmar, and Halperin and Ms Fenzi have received grant support from Astra-Zeneca; 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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