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Abstract

There is emerging evidence that women with atrial fibrillation, particularly those aged over 75 years, are more prone to strokes than men. It is also generally believed that older women are more vulnerable than men to warfarin-associated hemorrhage, leading to reluctance among physicians to anticoagulate women with atrial fibrillation. In the SPORTIF trials, the largest randomized cohort of women with atrial fibrillation on anticoagulation, including those aged over 75 years, women developed stroke (either ischemic or hemorrhagic) and systemic embolic events more often than men. In population-based studies such as the ATRIA study, female gender increased the relative risk of stroke significantly (incremental relative risk: 20–90%). Both types of studies demonstrated that maintaining the international normalized ratio within the therapeutic range of 2.0–3.0 was associated with similar rates of major bleeding in older women, younger women and men. Better validated predictors of bleeding than gender should be considered when selecting antithrombotic therapy. New oral anticoagulants are under development to reduce the burden and risk of warfarin-associated anticoagulation.

Keywords

anticoagulants atrial fibrillation stroke prevention warfarin women

There is growing evidence that women with atrial fibrillation (AF), particularly those who are elderly, are more likely to suffer stroke than their male counterparts [1 –5]. More than half of all strokes associated with AF occur in individuals aged over 75 years, making AF the most important risk factor for stroke in elderly women. Warfarin is effective in reducing the risk of stroke in patients with AF [2], but women are less likely to receive anticoagulation therapy for AF than men. One reason is that women may have a higher risk of bleeding complications during anticoagulation [6 –8], and older patients represent a particular challenge with respect to anticoagulation [9].

The Stroke Prevention in Atrial Fibrillation (SPAF) trials were the first to demonstrate an increased risk of stroke among women with non-valvular AF [2]. These three multicenter studies assessed antithrombotic therapies for stroke prevention. In the SPAF I trial, patients eligible for anticoagulation were randomly assigned to open-label warfarin (approximate international normalized ratio [INR]: 2.0–4.5), aspirin (325 mg daily) or placebo; warfarin-ineligible patients were randomized to aspirin or placebo [10]. Both aspirin and warfarin reduced the risk of stroke, although patients aged over 75 years were excluded because of a presumed increased risk of bleeding. In the SPAF II trial, the placebo arm was eliminated and age no longer excluded anticoagulation [11]. Enrolled patients aged over 75 years were mostly women who displayed a high risk of stroke during therapy with aspirin; however, the absolute benefit of warfarin (mean INR: ~2.7) over aspirin (325 mg daily) was overshadowed by a high rate of intracranial hemorrhage. In the SPAF III trial, women aged over 75 years had high rates of cardioembolic stroke; the rate of ischemic stroke and systemic embolism with warfarin (INR: 2.0–3.0; 2.6%/year) was lower than with a combination of low-intensity warfarin (INR: 1.2–1.5) plus aspirin (325 mg daily; 11.5%/year; p < 0.01), with similar rates of major bleeding [Pearce, L. Pers. Comm.].

In a multivariable analysis of patients with AF from the SPAF I–III trials who received aspirin alone or in combination with an inefficacious low dose of warfarin, female gender was a strong predictor of stroke (relative risk [RR]: 1.6; p = 0.01) and disabling or fatal stroke in those with no prior stroke or transient ischemic attack (RR: 1.8; p = 0.03). Female gender was a particularly powerful predictor of first stroke in patients aged over 75 years with AF (9.7 vs 3.2%/year in males) [2]. Female gender was also an independent, statistically significant predictor of stroke in several other cohorts (RR: up to 1.9) [1,5], but not in all [12,13]. In the SPAF aspirin cohort [4], women aged over 75 years were at particularly high risk, but an age/sex interaction was not confirmed in another larger study [8]. This discrepancy regarding female gender as a risk factor for thromboembolism in AF was one factor leading to classification of female gender as a “less validated or weaker risk factor” in the American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for management of patients with AF [9].

The benefit of anticoagulation must be weighed against the risk of bleeding, which has been less well studied in community cohorts than in clinical trials. In general, bleeding is more frequent during anticoagulation of women than men and increases with age [6]. An analysis of nearly 13,559 patients in a large integrated healthcare delivery system in Northern California (USA) from the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) cohort study found warfarin at least as effective in women as in men, with similar rates of major hemorrhage ( Table 1 ) [1].

Table 1.

Summary of stroke risk in women in clinical cohorts with atrial fibrillation.

Study	Population	n	Female (%)	Mean age (years)	Multivariate RR stroke (95% CI)	Ref.
EuroHeart	Multinational survey of patients with valvular and nonvalvular AF	5333	42	70	1.8(1.1–3.0)	[17]
SPORTIF	Clinical trial cohort	7329	30.8	73	2.6 vs 1.6%/year in women aged ≥75 years old	[14]
Wang et al.	Framingham Study cohort	705	48	75	1.9(1.2–3.1)	[5]
Fang et al.	HMO outpatients	6222	45	72	1.6(1.3–1.9)	[1]
SPAF	Pooled analysis of three trials	2012	28	69	1.6	[2]
AFI 1994	Meta-analysis of untreated patients from five trials	1593	27	69	1.2 (0.8–1.8) not significant in multivariate models	[12]

AF: Atrial fibrillation; CI: Confidence interval; HMO: Health Maintenance Organization; RR: Relative risk.

Gender-based differences in rates of thromboembolism and bleeding in randomized trials

In the Stroke Prevention using an Oral Thrombin Inhibitor in Patients with Atrial Fibrillation (SPORTIF) trials, gender- and age-specific safety and efficacy outcomes of patients with nonvalvular AF randomized to anticoagulation with warfarin or an investigational oral direct thrombin inhibitor provide additional insights into the relative risks and benefits of anticoagulation in women compared with men [14]. The multicenter SPORTIF trials incorporated a large, randomized cohort of women with AF on anticoagulation, including a high proportion of women aged over 75 years. SPORTIF-III, an open-label trial, included 3407 patients with nonvalvular AF who had one additional risk factor for stroke. The primary outcome was the rate of all stroke (ischemic and hemorrhagic) and systemic embolic events. SPORTIF-V followed the same protocol, except that therapy was administered in a double-blind manner [15]. These studies yielded valuable information regarding gender differences in the risk of stroke and the safety of anticoagulation in patients with AF.

Compared with earlier studies, the 2257 women enrolled in the SPORTIF trials (30.8% of randomized patients) were older and had more comorbidities [14]. Half were aged over 75 years, representing the largest prospectively studied cohort with nonvalvular AF on anticoagulation. Prior to randomization, women were less likely to receive antithrombotic medication than men, although women had a higher rate of stroke and systemic embolic events. Among patients assigned to the warfarin group, including 1099 women, there was no significant difference in rates of primary events (stroke and systemic embolism) based upon gender, although older women were more likely than younger women to sustain stroke or embolism. Women were more prone to anticoagulation-related bleeding than their male counterparts, despite a similar percentage achieving therapeutic anticoagulation intensity. This increased rate of bleeding was mainly attributed to higher rates of minor bleeding in women. Minor bleeding was more common in older women than younger women, and rates of major bleeding were similar among older women, younger women and men.

The experience in the SPORTIF trials demonstrates that similar rates of major bleeding can be expected in older women, younger women and men when the INR is maintained within the therapeutic range of 2.0–3.0, emphasizing that gender should not be a factor in withholding antithrombotic therapy from patients with AF. In a subsequent analysis, liver disease, concomitant aspirin use and age over 75 years (rather than gender) were associated with an increased risk of bleeding [16].

Outcomes in population-based studies

There is conflicting evidence regarding the use of anticoagulant therapy in women with AF compared with men. The ATRIA study investigators found a 1.7% higher annual rate of thromboembolism among women with AF who were not treated with warfarin compared with men [1]. Furthermore, warfarin appeared to be slightly more effective in preventing thromboembolism in women than men, with a similar risk of major bleeding. This is in accordance with the results of the SPAF-I study, which found a higher risk of thromboembolism among women who were not receiving anticoagulation [10]. In the EuroHeart Survey of Atrial Fibrillation, which included 2249 women with AF of various etiologies (valvular and nonvalvular), there was no difference in anticoagulant prescription rates among men and women [17]. This may reflect the large proportion of women who had AF related to valvular heart disease, for whom anticoagulation is more consistently recommended. Again, women with AF faced a higher rate of stroke than their male counterparts; prior stroke or transient ischemic attack was the only risk factor more strongly associated with future stroke than gender. Although major bleeding was also more frequent among women, gender was not a significant independent predictor of hemorrhagic complications after multivariate analysis. In the SPORTIF trials, discontinuation of warfarin therapy raised the risk of thromboembolism more among women than men, emphasizing the particular importance of sustaining anticoagulation in women (regardless of their age) [14].

In the community-based ATRIA cohort, 28% of whom were aged over 80 years, followed for a median of 2.4 years, the annual rate of major hemorrhage was similar to that reported in clinical trials of anticoagulation for AF [18]. The annual bleeding rate was relatively low, and similar in patients taking warfarin (1.11%/year) or not (1.04%/year), but increased with age. There was a dramatic increase in the rate of intracranial hemorrhage among patients aged over 80 years on or off warfarin. There was also an increased risk of hemorrhage during the first month of anticoagulation with warfarin. Despite these concerns, the authors concluded that warfarin can be prescribed with reasonable safety even for patients of advanced age.

A prospective community cohort study by Hylek et al. of patients aged over 65 years starting anticoagulation therapy found that during the first 90 days of warfarin therapy, those aged over 80 years and with an INR of more than 4.0 were associated with increased risk of hemorrhage [19]. Although the proportion of women with AF increases with increasing age, female gender was not an independent risk factor for hemorrhage. The higher overall rate of major hemorrhage in this cohort compared with previous randomized trial populations may be explained by the inclusion of only patients starting anticoagulation therapy, the advanced age of the cohort (mean: 77 years) and the high frequency of concomitant antiplatelet therapy (40%).

Models to accurately predict an individual's risk of bleeding have been more difficult to develop. Older bleeding-risk prediction schemes included female gender [20], but this variable was the weakest component of the score. Among Medicare beneficiaries prescribed warfarin, the hemorrhages scoring system was the most accurate at predicting bleeding risk compared with older classification systems. This scheme, which was developed specifically to predict bleeding risk in elderly patients with AF, did not include female gender as a risk factor for bleeding [21].

Maintaining therapeutic anticoagulation intensity is critical to minimizing bleeding. A study of elderly patients starting warfarin therapy demonstrated the utility of interventions to reduce the risk of major bleeding [22]. Patient education and self-monitoring of prothrombin time doubled the time that the INR was maintained within the therapeutic range and reduced the incidence of major bleeding by more than half in individuals at a mean age of 75 years, yielding results comparable with those in clinical trials. An interim analysis of a randomized trial found that patients who self-managed anticoagulation maintained a therapeutic INR more consistently than those undergoing conventional anticoagulation management [23]. Despite this success in maintaining therapeutic anticoagulation intensity, the number of thromboembolic events, major bleeding events and deaths was similar in both groups. One reason that improvement in rates of thromboembolism and bleeding in the self-management group may not have been realized may be that those in the conventional management group maintained therapeutic INR nearly 60% of the time, significantly more often than in most community-based anticoagulation cohorts.

In clinical practice, the hemorrhagic risk of anticoagulation must be minimized to realize its full benefit. An analysis of patients receiving aspirin concomitant with anticoagulation in the SPORTIF III and V trials found no advantage to the combination over warfarin alone for prevention of myocardial infarction, stroke or systemic embolism, but concomitant use of aspirin was not randomized and may have been selectively recommended for patients at higher intrinsic risk [24,25]. The rate of major bleeding was 1.6%/year higher with combination therapy than when warfarin was employed as the sole antithrombotic agent [24]. Educating patients regarding the potential risk of combining warfarin with aspirin and other drugs known to increase bleeding risk appears central to safe anticoagulation.

The mechanism underlying differences between males and females in AF-related thromboembolism risk has not yet been elucidated. It has been speculated that prothrombotic factors, diastolic dysfunction or endothelial dysfunction may contribute to the observed difference. Multiple hemostatic factors, including fibrinogen, von Willebrand factor antigen, tissue plasminogen activator antigen and plasminogen activator inhibitor-1 antigen have been studied as potential contributors to increased thromboembolic risk. An analysis from the Framingham Heart Study demonstrated that patients with AF had higher tissue plasminogen activator antigen levels than those without AF; however, after stratification according to cardiovascular disease status, this difference was no longer observed [26]. Although estrogen-replacement therapy has been linked to an increased risk of ischemic stroke in the general population, hormone supplementation was not a significant risk factor in the ATRIA study.

Conclusion

Women with nonvalvular AF, particularly those aged over 75 years, are at high risk of stroke and systemic embolism. With close attention to maintaining anticoagulation in the therapeutic range of INR 2.0–3.0, more women with AF could be safely anticoagulated with warfarin, significantly reducing AF-related stroke morbidity and mortality. Direct thrombin inhibitors and factor Xa inhibitors are under development as alternatives to vitamin K antagonist anticoagulants and, if proven safe and effective, could expand the number of individuals who can safely benefit from anticoagulation.

Future perspective

Although warfarin is effective for thromboembolism prevention in patients with AF, limitations to its use include the need for monitoring and frequent dose adjustments, a narrow therapeutic window, and bleeding complications. For these reasons, other antithrombotic agents, including platelet inhibitors, factor Xa inhibitors and direct thrombin inhibitors, are under investigation as alternatives to warfarin for anticoagulation in patients with AF and other thromboembolic disorders. In the ACTIVE-W trial, the combination of aspirin (75–81 mg daily) plus clopidogrel (75 mg daily) was inferior to dose-adjusted vitamin K antagonist therapy in preventing strokes in patients with AF, and rates of major bleeding were no lower with the platelet inhibitor regimen [27]. The ACTIVE-A trial is comparing the efficacy and safety of adding clopidogrel to aspirin therapy in patients with AF who are not candidates for oral anticoagulation.

Although the first oral direct thrombin inhibitor, ximelagatran, was withdrawn from development because of potential hepatotoxicity, it proved noninferior to warfarin in preventing thromboembolism in patients with AF in the SPORTIF trials, paving the way for investigation of other direct thrombin inhibitors in this indication. In BISTRO-II, a double-blind study of patients undergoing major orthopedic surgery, the oral direct thrombin inhibitor dabigatran etexilate compared favorably with warfarin in preventing thromboembolism [28]. In the open-label PETRO-Ex study, dabigatran in a dose of 150 mg twice-daily showed acceptable safety and efficacy for prevention of stroke in patients with AF, and the Phase III RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy with Dabigatran Etexilate) trial is comparing two doses of dabigatran with warfarin for stroke prevention in AF, with completion expected in late 2009.

The factor Xa inhibitor idraparinux (administered once-weekly by subcutaneous injection) is compared against dose-adjusted vitamin K antagonist therapy in patients with AF in the AMADEUS trial [29]. The main theoretical concern is related to the long duration of the anticoagulant effect of idraparinux and the risk of bleeding; thus, the BOEALIS-AF trial is evaluating a reversible, biotinylated form of the anticoagulant. The oral factor Xa inhibitor rivaroxaban showed efficacy and safety comparable with enoxaparin in preventing venous thromboembolism after major orthopedic surgery [30]. A large Phase III noninferiority trial (ROCKET-AF) is underway, comparing rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with AR Another orally administered inhibitor of factor Xa, apixaban, is also under investigation in a large-scale, Phase III trial involving patients with AF [31].

Conflicts of interest

DAR: none; JLH: consulting fees from the following companies that are engaged in the development of new anticoagulants, none of which are presently approved for clinical use in any indication: AstraZeneca, Astellas Pharma, Bayer Health Care, Boehringer Ingelheim, Daiichi Sanyo Pharma, GlaxoSmithKline, Johnson & Johnson, Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Female gender is an emerging risk factor for stroke & systemic embolism related to atrial fibrillation

The SPAF trials were the first to demonstrate an increased risk of stroke among women aged over 75 years with nonvalvular atrial fibrillation (AF).

Gender-based differences in rates of thromboembolism & bleeding in randomized trials

The SPORTIF trials, representing the largest female cohort studied with AF on anticoagulant therapy, demonstrate that older women are more likely than men to sustain thromboembolic events.

The SPORTIF trial demonstrated similar rates of major bleeding among men and women, although minor bleeding was more common among females.

Outcomes in population-based studies

The community-based ATRIA cohort found a higher rate of thromboembolism among women with AF compared with men, with a similar risk of major bleeding.

The EuroHeart Survey of Atrial Fibrillation found that women with AF faced a higher rate of stroke than men.

Advanced age, the initiation phase of anticoagulation therapy, concomitant antiplatelet therapy and supratheraputic international normalized ratio are more consistently correlated with bleeding than gender.

Future perspective

Platelet inhibitors, factor Xa inhibitors and direct thrombin inhibitors are under development as safer alternatives to warfarin for anticoagulation in patients with AF and other thromboembolic disorders.

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