REVIEW
European Heart Journal (2017) 38, 165–171
doi:10.1093/eurheartj/ehv758
Clinical update
A review of sex-specific benefits and risks
of antithrombotic therapy in acute coronary
syndrome
William T. Wang 1, Stefan K. James 2, and Tracy Y. Wang 1*
1
Duke Clinical Research Institute, Duke University Medical Center, Duke Box 3850, 2400 Pratt Street, Durham, NC 27705, USA; and 2Uppsala Clinical Research Center,
Uppsala University, Uppsala, Sweden
Received 27 August 2015; revised 10 December 2015; accepted 27 December 2015; online publish-ahead-of-print 2 February 2016
Over the past decade, more men than women have shown improved outcomes from antithrombotic therapies after acute coronary syndrome
(ACS), which raises the question of whether there are sex-specific differences in treatment patterns and response to therapy. Differences in
presenting clinical characteristics, pathophysiologic profile, and disparities in treatment may contribute to this outcomes discrepancy. Analyses
of large trials and registry data suggest that male and female ACS patients experience similar benefits from antithrombotic therapy without
significant difference in treatment utilization rates, yet women are consistently at higher risk of bleeding than men. Bleeding may result in
antithrombotic treatment disruption, which increases the risk of long-term thrombotic events. Additionally, female ACS patients are more
likely to receive suboptimal medication dosing and have lower rates of long-term medication adherence. These differences have significant clinical implications for women, indicating the need for strategies that will optimize initial treatment and long-term management attuned to these
recognized sex-specific gaps.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Acute coronary syndrome † Antithrombotic therapy † Sex-specific differences
Introduction
According to the World Health Organization, cardiovascular disease (CVD) remains the global leading cause of death1 and is projected to cause .23.6 million deaths by the year 2030.2 While
the overall rate of coronary artery disease (CAD)-related mortality
is higher for men than for women, this difference has diminished
over the last decade, as men have demonstrated a decrease in
CAD-related mortality, while simultaneously, women have experienced a disproportionate increase in CAD-related mortality.3,4
The reasons for this observed sex-based disparity in mortality
among patients presenting with acute coronary syndrome (ACS) remain poorly understood, raising the question of whether there may
be sex-specific differences in baseline cardiovascular characteristics,
treatment patterns, or response to treatment that contribute to this
phenomenon.
Antithrombotic therapy is a major treatment modality for the
management of ACS and encompasses antiplatelet agents (aspirin,
P2Y12 receptor antagonists, and glycoprotein IIb/IIIa inhibitors)
and anticoagulants (indirect/direct thrombin inhibitors and factor
Xa inhibitors). In this article, we provide an overview of current
data examining sex differences in the use of, and outcomes related
to, antithrombotic therapy in the treatment of patients with ACS.
We are hopeful that a better understanding of the basis for sexrelated differences in post-ACS outcomes potentially leads to
more evidence-based therapeutic approaches for female and male
patients presenting with ACS.
Comparison of baseline
characteristics between female
and male acute coronary
syndrome patients
One possibility to account for the sex-specific differences in outcome from antithrombotic therapies post-myocardial infarction
(MI) is that pre-existing physiological differences between men
* Corresponding author. Tel: +1 919 668 8907, Fax: +1 919 668 7057, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
166
and women influence response to antithrombotic therapy. In fact,
several previous studies have demonstrated variations in clinical,
biological, and quality-of-life characteristics between female and
male patients presenting with ACS. To begin with, there are sex differences in the timing of initial ischaemic presentation. For instance,
data from the Can Rapid Risk Stratification of Unstable Angina
Patients Suppress Adverse Outcomes with Early Implementation
of the American College of Cardiology/American Heart Association
Guidelines (CRUSADE) registry showed that women typically
present with ACS 10 years later than men.5,6 Moreover, data
from both CRUSADE and the more contemporary registry Acute
Coronary Treatment and Intervention Outcomes Network
Registryw-Get With The GuidelinesTM (ACTION Registry-GWTG)
showed that, on average, women tend to experience a longer time
from symptom onset to medical evaluation compared with that in
men.6 One Dutch study observed that the time from the patient’s
call for help to physician consultation was 10 min longer in women
than in men suspected of ACS.7 Similarly, a Korean study of 6636
ACS patients observed that the average time lapse from symptom
onset to hospital arrival was 8 h for men and 11 h for women
(P , 0.001).8
By the time of ACS presentation, women tend to be older, more
likely to have comorbidities such as diabetes and hypertension, and
are generally at higher risk of adverse outcomes including thrombotic and bleeding events than men.5 In fact, in a US-based study of
patients with acute MI treated with percutaneous coronary intervention (PCI), female patients were more likely to present with
prior stroke, heart failure, peripheral arterial disease, and worse
renal function than men.9 When examining mortality after ACS,
the Swedish Web-system for Enhancement and Development of
Evidence-based Care in Heart Disease Evaluated According to
Recommended Therapies registry showed that women had a higher
risk than men in terms of in-hospital mortality even after adjustment
for baseline characteristic differences,10 as well as a higher risk of
developing in-hospital complications such as cardiogenic shock,
heart failure, bleeding, and vascular complications;11 these risks persisted despite women being less likely than men to have high-risk
angiographic features or high-grade stenosis among those evaluated
with coronary angiography.12
These differences in age, timing of symptom onset, and preexisting comorbidities at the time of ACS occurrence may point
to underlying sex-specific biological variations affecting thrombosis
risk.13 Several studies have hypothesized that a pleiotropic hormonal effect, in combination with platelet hyperactivity, can induce
metabolic and vascular changes that lead to faster atherosclerotic
progression in post-menopausal women than in men.14 The delayed
onset and more rapid progression of atherosclerosis in postmenopausal women may in part be explained by the loss of the
endothelial protective effect of oestrogen after menopause, resulting in endothelial dysfunction that speeds atherosclerotic progression. Consistent with this hypothesis, Becker et al. showed that
compared with men, women had consistently more reactive platelets in response to aspirin therapy in both whole blood and
platelet-rich plasma.15 Yet whether these differences in platelet
reactivity are clinically significant remain unclear, since a separate
study showed no sex differences in several composite endpoints
(including all-cause death, occurrence of ischaemic symptoms
W.T. Wang et al.
with elevated cardiac biomarkers, and number of definite stent
thrombosis events and ischaemic stroke events) even though
women had a higher baseline platelet count and exhibited a higher
magnitude of platelet reactivity on aspirin and clopidogrel.16
Moreover, key demographic and psychosocial characteristics also
differ between male and female ACS patients. On the basis of the
Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute
Coronary Syndrome study,9 which examined ST-segment elevation
MI (STEMI) and non-STEMI (NSTEMI) patients treated with PCI,
women were more often of non-white race, unmarried, or
unemployed than their male counterparts. In terms of functional
characteristics, women scored lower on all EuroQoL-5 Dimension
domains (mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression) and were more likely to report symptoms of
depression and lower quality-of-life scores than men.17
Men and women show similar
efficacy from antithrombotic
therapies
Despite the differences in pre-existing biological characteristics between men and women presenting with ACS, it is unknown whether
these variances translate into differences in antithrombotic therapy
efficacy. Recent studies appear to show largely equivalent efficacy of
antithrombotic treatment for ACS between men and women.
In a meta-analysis of five major antiplatelet therapy trials, it was
found that clopidogrel significantly reduced the risk of MI, but also
increased bleeding risk (regardless of patient sex) when compared
with placebo. Notably, there were no significant sex differences in
cardiovascular mortality with the use of clopidogrel.18 The Platelet
Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor significantly reduced mortality rates compared with clopidogrel
in ACS patients, but in pre-specified subgroup analyses, found no
significant sex differences in the absolute and relative reductions
of adverse cardiovascular events with ticagrelor compared with clopidogrel at 1 year (interaction P-value 0.78) and all-cause death
(interaction P-value 0.49).19,20 With prasugrel, the mortality risk
for women with confirmed epicardial CAD was at least as high as
that for men following unstable angina, STEMI, or NSTEMI. The Trial
to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 was the only study that showed prasugrel to
have greater absolute (2.4 vs. 1.6%) and relative (21 vs. 12%) reductions in major adverse cardiovascular events in men than women
when compared with clopidogrel.21 Additionally, a German study
compared the clinical outcome of women and men presenting
with STEMI undergoing primary PCI with concomitant use of glycoprotein IIb/IIIa inhibitors and found that female sex did not emerge
as an independent predictor of major adverse cardiovascular
events.22 When considered together, these studies indicate
that sex is not a major differentiator of antiplatelet efficacy in the
management of ACS.
With regard to anticoagulant therapy, the use of fondaparinux
was studied in the Fifth and Sixth Organization to Assess Strategies
in Acute Ischemic Syndromes trials, and there were no sex
Sex-specific benefits and risks
differences in clinical outcomes found between fondaparinux and
unfractionated heparin.23 For bivalirudin, the Acute Catheterization
and Urgent Intervention Triage Strategy (ACUITY) trial demonstrated that women with NSTEMI undergoing PCI had similar
30-day composite ischaemic complications compared with men,
despite the fact that female enrolees in the trial were older and
had more comorbidities.24 Furthermore, no significant sex interaction was observed when comparing bivalirudin vs. heparin therapy
and glycoprotein IIb/IIIa among STEMI patients in the Harmonizing
Outcomes with Revascularization and Stents in Acute Myocardial
Infarction study. 25 In summary, there has been no evidence to
date of sex differences in anticoagulant therapy effectiveness.
Women are consistently at higher
risk of bleeding than men
Nevertheless, female sex has consistently been associated with increased risk-adjusted bleeding among ACS patients26,27 (Figures 1
and 2). Notably, in the CRUSADE bleeding score,27 female sex is
one of eight significant and independent predictors of in-hospital
major bleeding. This bleeding risk includes both nuisance bleeding
(e.g. Bleeding Academic Research Consortium Type 1) and bleeding
of worse severity.9 A CRUSADE registry analysis showed higher
rates of in-hospital major bleeding in women than in men; this
includes those treated with glycoprotein IIb/IIIa inhibitors (15.7 vs.
7.3%, P , 0.001), as well as those not treated (8.5 vs. 5.4%, P ,
0.0001).26 Similarly, a recent Italian study observed that women
with ACS undergoing coronary angiography and PCI experience a
significantly higher incidence of in-hospital bleeding than their
167
male counterparts.29 Studies have also observed sex-based differences in the locations most prone to bleeding after catheterization.
In women, the majority of bleeding observed after PCI was related
to the vascular access site, whereas complications in men were
largely related to gastrointestinal bleeding.35 Local anatomical differences may contribute to a greater risk of access site bleeding among
women undergoing invasive coronary procedures; consistent with
this, a German study showed that women had a two-fold increase
in access site bleeding compared with men, but no significant
difference was observed for non-access site bleeding.34 Data from
a British study further supported these observations, revealing
that the use of transradial access for PCI, compared with transfemoral access, resulted in a decrease in the rate of bleeding events
in men and women, but particularly among women.36
While women have a higher observed risk of bleeding compared
with men, the interaction of gender with the effect of antithrombotic therapy on bleeding remains less clear. In reviewing data from
randomized controlled trials and registries over the past 15 years,
there appears to be a discrepancy in findings of sex-based differences in bleeding risk conferred by antithrombotic therapies. While
large registry studies such as CRUSADE showed that women were
more likely than men to experience bleeding complications from antithrombotic therapy,26 the authors of the ACUITY trial observed
no significant interaction between sex and the effects of antithrombotic therapy with respect to bleeding risk at 1 year.37 Similarly, data
from TRITON-TIMI 38,21 PLATO,19,20 and A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who
Require Percutaneous Coronary Intervention (CHAMPION
PHOENIX)18 showed no significant interactions between sex
and antithrombotic therapy with regard to bleeding risk. This
Figure 1 Sex-based differences in major adverse cardiovascular events*. This figure displays the sex-based differences in major adverse
cardiovascular events. *This figure contains references.5,9,10,28 – 33
168
Figure 2 Sex-based differences in bleeding*. This figure displays
the sex-based differences in bleeding, with female sex being
consistently associated with increased risk-adjusted bleeding
among acute coronary syndrome patients. *This figure contains
references.9,26,28,29,34 – 36
discrepancy between clinical trial subgroup analysis and observational registry analysis results may partially be due to an underrepresentation of women in clinical trials.38 Another explanation
may be the proclivity towards excess dosing among female patients
when treated with antithrombotic therapy in routine practice,
which is attributed to inaccuracies in either weight-based or renal
function-based dosing.
Sex-based differences in acute
coronary syndrome management
and outcomes
What may account for the higher bleeding risk in women compared
with men despite equivalent efficacy and response to antithrombotic therapy? One reason for the higher bleeding risk among women
may be that women have an increased propensity to be given higher
antithrombotic doses than men. For instance, several studies
showed that during the course of ACS care, women are not only
more likely to receive excess dosing of any antithrombotic agent,
but are more likely to receive excess dosing of multiple antithrombotic agents.26,39 The observation that women were more likely
than men to receive different medications and dosing suggests
that perceived differences in antithrombotic response may contribute to observed sex disparities in ACS management. For example,
female ACS patients are more likely than males to be treated with
conservative, non-invasive management.22 Even among STEMI patients, women were less likely than men to receive reperfusion.28
These disparities have not diminished with time. In a study of four
registries spanning a decade, women with ACS were consistently
less likely than men to be treated with coronary angiography inhospital and had higher in-hospital mortality.40 In the CRUSADE
registry, women were not only less likely than men to receive coronary artery bypass grafting or PCI,41 but were less likely to receive
antithrombotic therapy despite having higher risk profiles.5
W.T. Wang et al.
Significant sex differences in long-term adherence to evidencebased medication have also been observed, which may further contribute to disparities in bleeding risk from antithrombotic therapy. In
a study of consecutive MI patients in the Duke Databank for Cardiovascular Disease, female sex was associated with lower long-term
medication adherence to aspirin, angiotensin-converting enzyme inhibitors, and lipid-lowering therapies.42 Similarly, the Patterns of
Nonadherence to Antiplatelet Regimens in Stented Patients registry
reported that in patients undergoing PCI and discharged on antiplatelet agents, higher rates of nonadherence were observed in women
compared with men. At 1-year post-discharge, more women than
men ceased antiplatelet therapy due to physician-recommended
discontinuation (11.2 vs. 9.5%, P ¼ 0.09), disruption [due to noncompliance or bleeding (10.7 vs. 7.8%, P ¼ 0.001)], and interruption
[for surgery (5.5 vs. 4.3%)].43 Among patients who develop bleeding, antiplatelet therapy was more often temporarily discontinued
in men than in women,44 even for minor bleeds.45 Importantly,
43% of post-discharge bleeding events were never brought to clinical attention and 28% of changes to antiplatelet therapy in response
to bleeding were made without a cardiologist’s involvement.44
These findings underscore the importance of close clinical monitoring to permit early recognition of bleeding complications to avoid
premature antithrombotic discontinuation.
The significantly higher bleeding rates in female ACS patients may
underscore the recommendation for use of bleeding risk prediction
tools to guide treatment strategies, particularly for the consideration of bleeding avoidance strategies, such as radial artery access
or arterial closure devices. Additionally, since many of the antithrombotic therapies have similar effectiveness for men and women,
estimated bleeding risks can help drive the selection of antithrombotic treatment options for women. In terms of treatment, a greater
awareness of sex-based differences can guide intensity of monitoring by healthcare providers. Although women are managed with the
same pharmacological therapy as men, closer attention should be
paid to avoid excess dosing by measuring actual body weights and
calculating weight-adjusted creatinine clearance among female
patients.
Future directions
To date, the pathophysiologic reasons for the observed bleeding
disparities between men and women remain unclear. In order to
better understand sex differences in antithrombotic therapy use
and associated outcomes, more women need to be represented
in major clinical trials (Table 1). On average, among 801 198
patients enrolled in 156 cardiovascular trials, only 30.6% were women and only one-third of the trials reported sex-specific results.38
One possible explanation for this disparity is that within the age
range most likely to be included in clinical studies, there is a substantially higher prevalence of symptomatic CAD in men than women. Nevertheless, female sex is significantly associated with
non-participation in clinical trials among screened and eligible
patients.49 The under-representation of women in clinical trials
warrants further attention, both to ascertain causes of lower
female study enrolment and to target actions that effectively
improve female representation in clinical trials contributing to
treatment recommendations.
169
Sex-specific benefits and risks
Table 1
Comparison of men’s and women’s major adverse cardiovascular event and bleeding outcomes
Author
Year of
study
Female (%)
Endpoint (MACE/bleeding)
Comparison [women vs.
men (%), P-value]
Yu et al.28
2015
23.4
In-hospital MACE
30-day MACE
3-year MACE
In-hospital major bleeding
30-day major bleeding
3-year major bleeding
Solinas et al.29
2015
30.3
In-hospital bleeding
8.6 vs. 5.8, P ¼ 0.004
Kwok et al.46
2015
25.9
In-hospital MACE
In-hospital bleeding
30-day mortality
2.0 vs. 1.5, P , 0.001
0.6 vs. 0.3, P , 0.001
2.1 vs. 1.4, P , 0.001
Vogel et al.30
2015
42.1
In-hospital all-cause mortality
7-year all-cause mortality
8.2 vs. 7.2, P ¼ 0.549
54.8 vs. 39.3, P , 0.001
De Carlo et al.47
2015
47.0
27.6 vs. 38.7, P , 0.001
Hess et al.9
2014
27.5
1-year composite (death, non-fatal MI, stroke,
cardiac rehospitalization, severe bleeding;
NSTEMI patients ≥75 years)
Unadjusted 1-year MACE
Post-PCI GUSTO bleeding
Post-discharge BARC bleeding
Lawesson et al.10
2013
35.0
In-hospital mortality
1-year mortality
Long-term mortality
Long-term re-infarction
13.1 vs. 7.1, P , 0.001
22.6 vs. 14.0, P , 0.001
45.5 vs. 32.3, P , 0.001
18.0 vs. 17.3, P ¼ 0.07
Ndrepepa et al.34
2013
50.0
Poon et al.40
2012
34.3
Bleeding 30 days post-PCI
BARC bleeding ≥2
Access site bleeds
In-hospital mortality
In-hospital death or myocardial re-infarction
In-hospital stroke
In-hospital bleeding events
15.5 vs. 10.6, P , 0.001
9.4 vs. 6.5, P , 0.001
10.1 vs. 5.4, P , 0.001
2.7 vs. 1.6, P , 0.001
6.8 vs. 5.6, P ¼ 0.06
0.8 vs. 0.3, P ¼ 0.001
2.0 vs. 1.5, P ¼ 0.014
Akhter et al.12
2009
34.1
...............................................................................................................................................................................
Procedural outcomes post-PCI:
Cardiogenic shock
Congestive heart failure
Any bleeding event
5.9 vs. 3.9, P ¼ 0.01
7.4 vs. 4.9, P ¼ 0.01
24.0 vs. 21.2, P ¼ 0.046
10.5 vs. 5.6, P , 0.0001
11.3 vs. 6.0, P , 0.0001
13.8 vs. 7.2, P , 0.0001
15.7 vs. 13.6, P ¼ 0.02
9.1 vs. 5.7, P , 0.001
39.6 vs. 27.9, P , 0.0001
1.6 vs. 1.2, P , 0.01
1.8 vs. 1.3, P ¼ 0.002
4.4 vs. 2.1, P , 0.01
Berger et al.18
2009
28.0
30-day mortality (all ACS)
Mega et al.31
2007
23.0
Unadjusted 30-day death or non-fatal
recurrent MI
Major bleeding with enoxaparin
13.2 vs. 5.4, P , 0.001
Aguado-Romeo et al.32
2007
35.6
In-hospital mortality
11.8 vs. 8.3, P , 0.0001
Alexander et al.26
Bounhoure et al.48
2006
2004
37.3
21.8
Major bleeding with GP IIb/IIIa inhibitors
In-hospital MACE (high-risk ACS patients)
15.8 vs. 7.3, P , 0.0001
4.0 vs. 3.8, P ¼ 0.56
Peterson et al.33
2001
33.0
In-hospital mortality
Post-PCI stroke
Post-PCI Q-wave MI
Post-PCI vascular complication
9.6 vs. 5.3, P , 0.001
2.3 vs. 2.0, P ¼ 0.39
1.8 vs. 1.0, P ¼ 0.001
0.4 vs. 0.2, P ¼ 0.001
1.5 vs. 1.2, P ¼ 0.001
5.4 vs. 2.7, P ¼ 0.001
ACS, acute coronary syndrome; BARC, Bleeding Academic Research Consortium; GP IIb/IIIa, glycoprotein IIb/IIIa inhibitor; GUSTO, Global Use of Strategies to Open Occluded
Arteries; MACE, major adverse cardiac event; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary
intervention.
Conclusions
personalized approaches to antithrombotic therapy selection that
optimize the balance between treatment benefit and risk.
Data from studies presented in this article suggest that sex-based
differences exist in the pathophysiology and clinical presentation
of MI. Recommended antithrombotic therapies for acute MI are
similar in efficacy for males and females, but females are consistently
at higher risk of bleeding complications. The evident sex disparities
in the management and outcomes of ACS patients warrant novel
Authors’ contributions
W.T.W., S.K.J., and T.Y.W. performed statistical analysis, acquired
the data, conceived and designed the research, drafted the
170
W.T. Wang et al.
manuscript, and made critical revision of the manuscript for key
intellectual content. T.Y.W. handled funding and supervision.
Acknowledgements
We thank Erin Hanley, MS for her editorial contributions to this article. Ms. Hanley did not receive compensation for her assistance,
apart from her employment at the institution where this study
was conducted.
Conflict of interest: T.Y.W. reports consultancy for Astra
Zeneca; grants from Lilly USA, Daiichi Sankyo, Gilead Science,
GlaxoSmithKline, American College of Cardiology, American Society of Nuclear Cardiology; payment for lectures/speakers bureaus
for the American College of Cardiology Foundation; and payment
for development of educational presentations from the American
College of Cardiology Foundation.
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