Embed Size (px)
Citation preview
REVIEW ARTICLE
Gender Differences in Cardiovascular Therapy: Focuson Antithrombotic Therapy and Percutaneous CoronaryIntervention
Juan Luis Gutierrez-Chico • Julinda Mehilli
Published online: 24 October 2013
� Springer International Publishing Switzerland 2013
Abstract The epidemiology of coronary artery disease
(CAD) differs between women and men: female cardiac
patients are older and have poorer risk profiles than their
male counterparts. This results in a preferential exclusion
of women from participation in clinical trials, reducing
their power to detect differences in performance of car-
diovascular therapies in women. In general, all the anti-
platelet and anticoagulant medications used in cardiac
patients are equally effective in men and women, although
women tend to experience a higher relative benefit due to
their poorer risk profile. In particular, women with CAD
benefit the most from interventional treatment combined
with modern antithrombotic drugs. No gender-related dif-
ferences in the reduction of thromboembolic risk with more
potent antithrombotic drugs have been reported. On the
other hand, a clear trend to a higher incidence of bleeding
complications has been consistently reported in women,
which might be related to a more frequent over-dosage of
antithrombotic treatment in women than in men. Women
are therefore one of the subgroups that might benefit the
most from careful dose adjustment of available anti-
thrombotic drugs. However, the development of a gender-
based dosage guideline remains an unmet need in
cardiology.
1 Introduction
In the 1990s, evidence-based medicine confronted a wor-
risome pitfall: women were under-represented in most
clinical trials performed hitherto, particularly in those
regarding cardiovascular and antithrombotic therapies [1–
3] Therefore, the conclusions derived from these studies
were difficult to extrapolate to female patients. In 1993, the
National Institutes of Health (NIH) Revitalization Act
established guidelines to reinforce the existing policies for
inclusion of women and minorities in clinical research. As
a consequence, women are no longer under-represented in
federally funded phase III trials (in fact, more women than
men have been recently enrolled, because of large single-
sex studies [4, 5]), but they are still a minority in industry-
sponsored trials [3]. Thus, the majority of randomized
controlled trials are underpowered to detect true differ-
ences in the performance of tested drugs for women.
In a critical appraisal of 2 decades of gender-specific
analysis in evidence-based medicine, the conclusion is that
we have failed to discover consistent differences between
male and female patients regarding the efficacy of most
cardiovascular therapies, while there is consistent evidence
of increased bleeding risk in women compared with men.
In this review, we focus particularly on antithrombotic
therapy and percutaneous coronary revascularization, since
these are the cardiovascular topics in which more abundant
gender-specific evidence has been generated hitherto.
2 Biology of Gender Differences in Coronary Heart
Disease
The prevalence of ischemic cardiomyopathy is higher in
men than in women until the age of 39 years (14.2 vs.
J. L. Gutierrez-Chico � J. Mehilli (&)
Munich University Clinic, Cardiology Department,
Ludwig-Maximilian University, Marchioninistraße 15,
81377 Munich, DE, Germany
e-mail: [email protected]
Drugs (2013) 73:1921–1933
DOI 10.1007/s40265-013-0135-y
9.7 %, respectively), whereas an almost equal prevalence is
observed in the age range 40–59 years (39.3 and 37.2 %)
and in the range 60–79 years (72.6 and 71.9 %) [6]. On the
other hand, after 80 years, the prevalence of coronary heart
disease (CHD) is higher in women than in men [6].
A different pattern is observed regarding the incidence
of stroke, which is higher before the age of 75 years in
women than in men [6]. These epidemiological differences
highlight variations in underlying physiologies between
genders, which affect the clinical expression of CHD.
It is extensively believed that women and men have
different propensities to thrombosis. Regarding platelet
function, a myriad of studies have delivered inconsistent
findings about gender differences: whereas some studies
have reported similar platelet adhesion and aggregation
between male and female mouse littermates [7], other
studies have reported more platelet aggregation after
stimuli in female mice [8]. Some human studies have
reported higher adenosine diphosphate (ADP)-induced
platelet reactivity in women, while plenty have highlighted
gender-related differences in platelet counts, surface
expression of receptors, or functional reactivity [9, 10].
An interesting hypothesis, compatible with these
apparently discordant data, proposes that the differences in
platelet reactivity might be explained by sex hormones.
A putative protective role of estrogens has been pos-
tulated based on the observation that the risk for cardio-
vascular events in female subjects increases rapidly after
menopause and in case of premature cessation of ovarian
function [11, 12]. Estradiol stimulates the production of
prostacyclin, thus inhibiting platelet aggregation [13]. At
physiologic concentrations, estrogens also increase the
synthesis and release of nitric oxide from vascular endo-
thelium, resulting in potent antiplatelet effects [14, 15].
On the other hand, testosterone augments the synthesis of
and responsiveness to thromboxane A2 (TXA2), resulting
in a net prothrombotic effect [16]. These data suggest that
platelet agreeability might be lower in premenopausal
women than in men of similar age. However, a flaw in this
hormonal hypothesis is that postmenopausal hormone
replacement therapy exerts a harmful rather than a cardio-
protective effect on CHD [4, 17]. Furthermore, testoster-
one levels may be decreased in men with CHD, which
suggests limited relevance of a potential pro-thrombotic
effect.
Sex hormones also influence several components of the
coagulation and fibrinolysis systems. Estrogens decrease
the levels of fibrinogen, antithrombin-III, protein S, and
plasminogen activator inhibitor (PAI)-1 [18], while tes-
tosterone increases the levels of coagulation factor VII,
a2-antiplasmin, and plasminogen [19]. However no dif-
ference in haemostasis between women and men has been
ever proved in vivo, with the only exception being a
slightly prolonged bleeding time in women [20]. Therefore,
it is likely that the reported observations do not seem to
translate into functional differences affecting coagulation
or fibrinolysis.
Inter-gender dissimilarities in the physiology of hae-
mostasis still attract considerable attention. First, because
major bleeding is associated with a five-fold increased risk
of death at 30 days, and a 1.5-fold increased risk between
30 days and 6 months, in patients with acute coronary
syndrome (ACS) [21, 22] and second, because, despite
receiving the same peri- and post-interventional anti-
thrombotic treatment, women bleed more frequently than
men [23, 24].
In addition, pharmacokinetic considerations might
explain a higher propensity to bleed among women, par-
ticularly after administration of drugs with renal clearance.
Women have, on average, a higher proportion of fat and a
lower proportion of muscle in their body weight than men
[25], therefore, for the same renal function, women tend to
present lower serum creatinine levels than men for an
equivalent glomerular filtration rate [26, 27]. Many anti-
thrombotic treatments require adjustment of the dose by
weight and by renal function. If the dose is adjusted in base
to the serum creatinine levels, then women are at higher
risk of over-dosage [27].
3 Gender-Related Differences in Efficacy–Safety
Profile of Antithrombotic Therapy
Antithrombotic therapy is one of the fields in which gen-
der-specific research has tried to generate more evidence.
We briefly summarize the current status of evidence.
3.1 Antiplatelet Therapy
3.1.1 Aspirin
The mechanism of action of acetylsalicylic acid (ASA;
aspirin) relies on a selective and irreversible inhibition of
cyclooxygenase (COX)-1 by acetylation, thus blocking the
synthesis of TXA2 in platelets, resulting in a potent anti-
aggregator effect [28]. The inhibition of COX-1 direct
pathways is similar between both genders, but indirect
pathways for TXA2 synthesis, such as those stimulated by
collagen, ADP and epinephrine, are less inhibited in female
subjects [29]. This results in higher platelet reactivity
ex vivo in ASA-treated women than in men [30, 31].
Consistent with these findings is an in vivo observation that
women have shown higher concentrations of 11-dehydro-
thromboxane B2, a marker of ASA resistance and therefore
of platelet reactivity, than men in both the HOPE (Heart
Outcomes Prevention Evaluation) and the CHARISMA
1922 J. L. Gutierrez-Chico, J. Mehilli
(Clopidogrel for High Atherothrombotic Risk and Ischemic
Stabilization, Management, and Avoidance) trials [32, 33].
Nonetheless, whether these differences are relevant from
a clinical point of view is not so clear. A meta-analysis of
six randomized trials enrolling a total of 95,456 patients
(51,342 women) demonstrated that primary prevention
with aspirin therapy was associated with a significant
reduction in the risk of cardiovascular events, indepen-
dently from gender. ASA was associated with statistically
significant 12 and 14 % reductions in the odds of cardio-
vascular events in women and men, respectively. However,
the specific type of benefit varied among gender and was
primarily driven by a reduction of myocardial infarction in
men (odds ratio [OR] 0.68, 95 % CI 0.54–0.86; p = 0.001)
but of ischemic stroke in women (OR 0.76, 95 % CI
0.63–0.93; p \ 0.001). Importantly, the risk of bleeding
was equivalent in both genders [34]. However, a more
refined analysis demonstrated that gender does not signif-
icantly affect the proportional reduction in cardiovascular
events for primary prevention and that ASA is also equally
effective as secondary prevention in both genders [35].
Combined, these results seem to suggest that the gender
differences reported for ASA in the primary prevention of
cardiovascular events might instead be due to individual
differences in the absolute risk for each cardiovascular
event contemplated.
3.1.2 P2Y12 Receptor Inhibitors
3.1.2.1 Clopidogrel The mechanism of action of thie-
nopyridines consists of an irreversible inhibition of the
ADP P2Y12 receptor in the platelet, thereby blocking a key
signalling pathway for platelet activation. The plasmatic
levels of the active metabolite of clopidogrel do not differ
between men and women [36]. However, some studies
describe gender-related differences in the clopidogrel-
induced inhibition of platelet aggregation [37].
The CURE (Clopidogrel in Unstable Angina to Prevent
Recurrent Ischemic Events) trial compared the addition of
clopidogrel to ASA versus ASA alone in patients with non-
ST elevation myocardial infarction (NSTEMI). Women
presented a smaller absolute (1.2 vs. 2.8 %) and relative
(12 % vs. 25 %) risk reduction in the composite endpoint
of cardiovascular death, non-fatal MI, or stroke compared
with men at 1-year follow-up [38]. Similar findings were
observed in the subgroup of patients undergoing percuta-
neous intervention (PCI) [39]. Different results were
reported from the CREDO (Clopidogrel for the Reduction
of Events During Observation) trial, in which effects of a
clopidogrel loading dose, together with the addition of
clopidogrel to ASA vs. ASA alone for 1 year in patients
undergoing elective PCI, were investigated. The risk
reduction in the composite of death, myocardial infarction,
and stroke was greater in women than in men (32 % vs.
25 %) at 1-year follow-up [40].
Other clinical trials, as well as a recent meta-analysis,
have found no differences between genders regarding the
efficacy of clopidogrel [41–43].
3.1.2.2 Prasugrel Prasugrel is a third-generation oral
thienopyridine that, due to a more favourable metabolic
conversion, produces higher concentrations of its active
metabolite and therefore more potent platelet P2Y12
inhibitory effects than clopidogrel. In the TRITON-TIMI-
38 (Trial to assess improvement in therapeutic outcomes by
optimizing platelet inhibition with prasugrel–Thrombolysis
In Myocardial Infarction 38) trial, prasugrel was associated
with a significant 19 % reduction in ischemic events
compared with clopidogrel in patients with ACS under-
going PCI. The net clinical benefit (composite of death
from any cause, myocardial infarction, stroke, and TIMI
major bleedings) was also in favor of prasugrel in the
overall population, despite an increased risk of bleeding
compared with clopidogrel. There were no significant
interactions between treatment and gender, despite higher
absolute (2.4 % vs. 1.6 %) and relative (21 % vs. 12 %)
reduction of the primary ischemic endpoint with prasugrel
in men than in women [44].
3.1.2.3 Ticagrelor Ticagrelor, a cyclo-pentyl-triazolo-
pyrimidine, reversibly inhibits the P2Y12 receptor on plate-
lets. The PLATO (Platelet Inhibition and Patient Outcomes)
trial compared ticagrelor versus clopidogrel in ACS patients,
irrespective of their revascularisation status. Ticagrelor
demonstrated a 16 % reduction in the composite ischemic
endpoint, with no significant differences in overall bleeding,
but with higher rates of TIMI major bleeding not related to
coronary-artery bypass grafting, including more cases of fatal
intracranial bleeding. No differences between genders were
observed for any of these endpoints [45].
3.1.3 Intravenous Glycoprotein IIb–IIIa Inhibitors
Different molecules block the final common pathway
leading to platelet aggregation by inhibiting the binding of
fibrinogen to the glycoprotein (GP) IIb/IIIa receptor on the
surface of activated platelets. The inhibition can be irre-
versible (abciximab) or reversible (tirofiban or eptifibatide).
No differences between genders have been observed for
any GP IIb/IIIa receptor inhibitor (GPI) in vitro [46, 47].
Consistent with this, a pooled analysis of randomized trials
about PCI with adjunctive use of abciximab, demonstrated
no gender difference in terms of major adverse outcomes
out to 1 year of follow-up, although women had higher
rates of major and minor bleeding [48]. Similar observa-
tions have been reported for reversible GPI, such as in the
Gender Differences in Cardiovascular Therapy 1923
ESPRIT (Enhanced suppression of the platelet GPI recep-
tor with Integrilin therapy) trial, involving eptifibatide [49],
or in meta-analysis in which no gender differences were
demonstrated after adjustment for differences in risk profile
[50]. One important lesson learned from the GPI trials is
that women have higher rates of major bleeding, irre-
spective of whether or not they receive treatment with GPI
[27]. Alexander and colleagues tried to elucidate the rea-
sons underlying this observation, and they found that
women had a higher prevalence of impaired renal function
(creatinine clearance\50 ml/min) than men, although their
serum creatinine levels were lower. As a consequence,
women are more prone to overdose with GPI or heparin
than are men [27]. This important potential confounder
might partially explain some inter-gender differences in
efficacy and toxicity of some drugs, particularly if they
have total or partial renal clearance. This mechanism has
not been sufficiently taken into account in many studies on
this topic hitherto.
When GPIs are given after pre-treatment with high-dose
clopidogrel or prasugrel, the bleeding risk increases sub-
stantially [23, 51]. In the ISAR-REACT 2 (Intracoronary
Stenting and Antithrombotic Regimen – Rapid Early
Action for Coronary Treatment) trial, we compared the
efficacy of abciximab versus placebo in patients undergo-
ing PCI after pre-treatment with 600 mg clopidogrel [52].
The results showed similar efficacy of abciximab in women
as in men, although the incidence of major bleeding was
significantly higher in women [23]. Whether this can be
explained by poorer baseline risk profile, higher risk of
overdose, or a true biological independent propensity in
women, remains open to discussion.
A summary of the published evidence about gender-
related efficacy and safety of antiplatelet therapy is shown
in Table 1.
3.2 Anticoagulants
3.2.1 Indirect Thrombin Inhibitors
Unfractioned heparin (UFH) and low-molecular-weight
heparin (LMWH) bind to antithrombin-III and enhance
inactivation of factor Xa and thrombin. LMWHs have a
higher anti-factor Xa:IIa ratio and more prolonged duration
of the anti-factor Xa activity, so they have the advantage of
a more predictable dose-response and do not usually
require laboratory monitoring. LMWHs also show a kinetic
advantage over UFHs, as they inhibit the early steps of the
coagulation cascade and thrombin generation [53].
In addition to body weight, age, smoking history, and
diabetes mellitus, gender is considered one of the factors
that affect the response to UFH. In particular, women are
more likely to achieve higher activated partial
thromboplastin time (aPTT) after UFH administration [53,
54]. Additionally, the risk of heparin-associated thrombo-
cytopenia is increased by a factor of 5 in female patients
[55].
The evidence regarding LMWH is substantially more
conflicting and confusing. A post hoc analysis of the TIMI-
11A trial, a multicenter dose-ranging trial to evaluate
safety of enoxaparin in patients with ACS, showed that the
pharmacokinetic and pharmacodynamic profiles after en-
oxaparin administration were consistent between genders
[56, 57]. Nonetheless, the only placebo-controlled trial of
LMWH use reporting data stratified by gender was the
FRISC (Fragmin and Fast Revascularization during In-
Stability in Coronary artery disease) trial, comparing dal-
teparin versus placebo in patients with ACS. The results
suggested that women were more sensitive than men to
dalteparin: they presented larger absolute (4.5 vs. 2.2 %)
and relative reductions (13.1 vs. 28.9 %) in the composite
of death and myocardial infarction, along with a higher
incidence of minor bleeding than men, even after adjust-
ment for eventual confounders [58, 59]. Additional data
from meta-analysis have proven the superiority of LMWH
versus UFH for the reduction of major adverse cardiovas-
cular events in patients with ACS in a vast array of sub-
groups. Surprisingly, although the reduction in the triple
endpoint (death, myocardial infarction, recurrent angina)
was significant in both genders, the reduction in the com-
posite of death or myocardial infarction was significant in
women but not in men [60]. Interestingly, other clinical
trials have failed to reproduce the superiority of LMWH
over UFH, or to find any difference in efficacy or in tox-
icity between genders [61]. Finally, the ExTRACT-TIMI
25 (Enoxaparin and Thrombolysis Reperfusion for Acute
Myocardial Infarction Treatment-Thrombolysis in Myo-
cardial Infarction 25) trial compared enoxaparin versus
UFH as adjunctive antithrombin therapy in STEMI patients
undergoing fibrinolysis[62]. Women experienced a greater
absolute reduction in the composite of death, myocardial
infarction, and major bleeding than did men (2.6 vs. 1.6 %)
when treated with enoxaparin, but the relative risk reduc-
tion was comparable (16 vs. 19 %), which suggests that the
differences in absolute risk reduction are likely due to
differences in the baseline risk profile [63].
3.2.2 Direct Thrombin Inhibitors
Whilst heparins inhibit thrombin mainly through an indi-
rect mechanism, enhancing the action of antithrombin-III,
other drugs bind directly to the thrombin molecule to
inhibit the coagulation cascade. Direct thrombin inhibitors
can be classified into two main groups: (i) poly-peptide
direct inhibitors are derivatives from hirudin, a natural
substance produced in the parapharyngeal glands of
1924 J. L. Gutierrez-Chico, J. Mehilli
Ta
ble
1G
end
er-r
elat
edef
fica
cyan
dsa
fety
of
anti
pla
tele
td
rug
s
Ref
eren
ceD
rug
No
.o
f
ind
ivid
ual
s
Fo
llo
w-u
pT
arg
etp
op
ula
tio
nE
ffica
cyen
dp
oin
tR
elat
ive
risk
(95
%C
I)
Saf
ety
end
po
int
Rel
ativ
eri
sk
(95
%C
I)
Ber
ger
etal
.
[34
]
Asp
irin
aW
=5
1,3
42
M=
44
,11
4
3.6
–1
0y
ears
Ap
par
entl
yh
ealt
hy
ind
ivid
ual
s(B
1ri
sk
fact
or
for
CV
D)
CV
dea
th,
no
nfa
tal
MI,
or
no
nfa
tal
stro
ke
W:
0.8
8
(0.7
9–
0.9
9)
M:
0.8
6
(0.7
8–
0.9
4)
Maj
or
ble
edin
gW
:1
.68
(1.1
3–
2.5
2)
M:
1.7
2
(1.3
5–
2.2
)
AT
T
Co
llab
ora
tors
[35]
W=
2,9
08
M=
14
,09
2
NA
Ind
ivid
ual
sw
ith
pre
vio
us
MI,
stro
ke
or
TIA
CV
dea
th,
no
nfa
tal
MI,
or
no
nfa
tal
stro
ke
W:
0.8
1
(0.7
2–
0.9
2)
M:
0.7
3
(0.5
1–
1.0
3)
Maj
or
ble
edin
gb
2.6
9
(1.2
4–
5.7
6)
No
gen
der
-
rela
ted
anal
ysi
s
P2
Y12
rece
pto
rin
hib
ito
rs
CU
RE
Inv
esti
gat
ors
[38]
Clo
pid
og
relc
W=
4,8
36
M=
7,7
26
12
mo
nth
sP
atie
nts
pre
sen
tin
gw
ith
AC
S
CV
dea
th,
no
nfa
tal
MI,
or
no
nfa
tal
stro
ke
W:
0.8
9
(0.7
5–
1.0
6)
M:
0.7
6
(0.6
7–
0.8
7)
Ble
edin
gn
eces
sita
tin
g
tran
sfu
sio
n[
2b
loo
du
nit
so
r
life
-th
reat
enin
g
1.3
8
(1.2
4–
5.7
6)
No
gen
der
-
rela
ted
anal
ysi
s
Ste
inh
ub
l
etal
.[4
0]
Clo
pid
og
relc
W=
60
6
M=
1,5
10
12
mo
nth
sP
atie
nts
refe
rred
for
a
pla
nn
edP
CI
Dea
th,
MI,
or
stro
ke
W:
32
.1
(58
.9to
-1
2.1
)
M:
24
.5
(45
.5to
-4
.6)
TIM
Im
ajo
rb
leed
ing
1.3
2
(0.9
7–
1.8
0)
No
gen
der
-
rela
ted
anal
ysi
s
Wiv
iott
etal
.
[44]
Pra
sug
reld
W=
3,5
23
M=
10
,08
5
15
mo
nth
sA
CS
pat
ien
tsw
ith
sch
edu
led
PC
I
CV
dea
th,
no
nfa
tal
MI,
or
no
nfa
tal
stro
ke
W:
0.8
8
(0.7
2–
1.0
5)
M:
0.7
9
(0.7
1–
0.9
0)
No
n-C
AB
G-r
elat
edT
IMI
maj
or
ble
edin
g
1.3
2
(1.0
3–
1.6
8)
No
gen
der
-
rela
ted
anal
ysi
s
Wal
len
tin
etal
.[4
5]
Tic
agre
lord
W=
5,2
88
M=
13
,33
6
15
mo
nth
sP
atie
nts
pre
sen
tin
gw
ith
AC
S
CV
dea
th,
no
nfa
tal
MI,
or
no
nfa
tal
stro
ke
W:
0.8
3
(0.7
1–
0.9
7)
M:
0.8
5
(0.7
6–
0.9
5)
PL
AT
Om
ajo
rb
leed
ing
W:
1.0
1
(0.8
5–
1.2
1)
M:
1.0
5
(0.9
4–
1.1
6)
Gly
cop
rote
inII
b/I
IIa
rece
pto
rin
hib
ito
rs
Ch
oet
al.
[48]
Ab
cix
imab
aW
=1
,77
1
M=
4,8
24
6m
on
ths
Pat
ien
tsu
nd
erg
oin
gP
CI
Dea
th,M
I,o
ru
rgen
t
rev
ascu
lari
zati
on
W:
0.6
2
(0.4
4–
0.8
6)
M:
0.5
9
(0.4
8–
0.7
3)
TIM
Im
ajo
rb
leed
ing
W:
1.0
2
(0.5
0–
2.1
6)
M:
0.4
8
(0.2
8–
0.8
4)
Meh
illi
etal
.
[23]
Ab
cix
imab
aW
=4
98
M=
1,5
24
30
day
sA
CS
pat
ien
tsu
nd
erg
oin
g
PC
I
Dea
th,M
I,o
ru
rgen
t
rev
ascu
lari
zati
on
W:
0.9
8
(0.5
5–
1.7
4)
M:
0.6
9
(0.5
0–
0.9
3)
TIM
Im
ajo
rb
leed
ing
W:
0.8
9
(0.3
1–
2.4
6)
M:
1.4
4
(0.3
4–
6.9
4)
Gender Differences in Cardiovascular Therapy 1925
medicinal leeches (hirudin, lepirudin, desirudin, bivaliru-
din); (ii) non-peptide, direct inhibitors (argatroban, ximel-
agatran, dabigatran).
One potential advantage of these drugs is their ability to
also inhibit the thrombin-mediated activation of platelets,
which gives them mixed anticoagulant and antiplatelet
properties.
Bivalirudin is the molecule in this group that has gained
the largest acceptance and that has generated the most solid
evidence about its efficacy and safety for interventional
indications to date. It is currently recommended as class I,
level of evidence B, for primary PCI in patients with
STEMI, regardless of previous treatment with UFH and for
NSTEMI patients managed with an invasive strategy [64,
65]. It is also preferred in cases of heparin-induced
thrombocytopenia or in those at high risk of bleeding [64,
65]. The use of bivalirudin seems to provide similar ben-
efits in both genders, but women seem to be at higher risk
of bleeding. This is a consistent finding through several
studies, although it might be partially due to worse baseline
co-morbidities or to overdose. Studies showing a higher
incidence of bleeding in women include the REPLACE-2
(Randomized Evaluation in PCI Linking Angiomax to
Reduced Clinical Events-2) trial (including patients
scheduled for elective PCI [66–68]), the ACUITY (Acute
Catheterization and Urgent Intervention Triage strategY)
and the ISAR-REACT 4 trials, both including patients with
ACS [24, 52, 69, 70], and a European registry comprising
patients with varied indications [71]. However, no differ-
ences in efficacy or major bleeding were found between
men and women with STEMI undergoing PCI within the
setting of HORIZONS-AMI (Harmonizing Outcomes with
Revascularization and Stents in Acute Myocardial Infarc-
tion) trial [72, 73]. On the other hand, a gender-specific
analysis of the ISAR-REACT 4 trial showed that women
tended to have more bleeding complications than men,
irrespective of the anti-thrombotic regime they underwent,
but the advantage of bivalirudin in reducing bleeding
complications with respect to the combination of
UFH plus abciximab was similar in both genders [74].
Dabigatran is an oral direct competitive thrombin
inhibitor that is administered twice a day and does not
require monitoring. In the RE-LY (Randomized Evaluation
of Long-Term Anticoagulation Therapy) trial, dabigatran
met the non-inferiority criteria versus warfarin for the
prevention of thromboembolic complications in patients
with atrial fibrillation. No significant differences between
genders were observed [75]. Argatroban is an intravenous
direct thrombin inhibitor approved for patients with hepa-
rin-induced thrombocytopenia. Argatroban clearance has
been reported to be greater in women than in men [92], but
these pharmacokinetic differences do not seem to translate
into differences in the anticoagulant response [76, 77].Ta
ble
1co
nti
nu
ed
Ref
eren
ceD
rug
No
.o
f
ind
ivid
ual
s
Fo
llo
w-u
pT
arg
etp
op
ula
tio
nE
ffica
cyen
dp
oin
tR
elat
ive
risk
(95
%C
I)
Saf
ety
end
po
int
Rel
ativ
eri
sk
(95
%C
I)
Fer
nan
des
etal
.[4
9]
Ep
tifi
bat
idea
W=
56
2
M=
1,5
02
12
mo
nth
sP
atie
nts
un
der
go
ing
PC
ID
eath
,M
I,o
rT
VR
W:
30
%
RR
R
M:
15
%
RR
R
TIM
Im
ajo
rb
leed
ing
W:
3.0
7
(0.5
6–
30
.9)
M:
3.3
0
(0.6
3–
32
.7)
Bo
ersm
aet
al.
[50]
Ab
cix
imab
,
epti
fib
atid
e,
lam
ifib
an,
tiro
fib
ana
W=
10
,99
1
M=
20
,41
1
30
day
sP
atie
nts
pre
sen
tin
gw
ith
AC
S
Dea
tho
rM
IW
:1
.15
(1.0
1–
1.3
0)
M:
0.8
1
(0.7
5–
0.8
9)
Maj
or
ble
edin
gW
:2
.20
(1.6
0–
2.9
0)
M:
1.6
0
(1.3
0–
2.0
0)
AC
Sac
ute
coro
nar
ysy
nd
rom
e,C
AB
Gco
ron
ary
arte
ryb
yp
ass
gra
ft,
CV
card
iov
ascu
lar,
CV
Dca
rdio
vas
cula
rd
isea
se,
Mm
en,
MI
my
oca
rdia
lin
farc
tio
n,
NA
no
tav
aila
ble
,P
CI
per
cuta
neo
us
coro
nar
yin
terv
enti
on
,P
LA
TO
pla
tele
tin
hib
itio
nan
dp
atie
nt
ou
tco
mes
,R
RR
rela
tiv
eri
skre
du
ctio
n,T
IAtr
ansi
ent
isch
emic
atta
ck,T
IMI
thro
mb
oly
sis
inm
yo
card
ial
infa
rcti
on
,T
VR
targ
etv
esse
l
rev
ascu
lari
zati
on
,W
wo
men
aT
est
dru
g(a
spir
in,
abci
xim
ab,
epti
fib
atid
e)v
s.co
ntr
ol/
pla
ceb
ob
No
tav
aila
ble
inal
lin
div
idu
als
and
no
gen
der
-rel
ated
anal
ysi
sin
the
pap
erc
Clo
pid
og
rel
vs.
asp
irin
alo
ne
dT
est
dru
g(p
rasu
gre
l,ti
cag
relo
r)v
s.cl
op
ido
gre
l
1926 J. L. Gutierrez-Chico, J. Mehilli
Ta
ble
2G
end
er-r
elat
edef
fica
cyan
dsa
fety
of
anti
coag
ula
nt
dru
gs
Ref
eren
ces
Dru
gN
o.
of
ind
ivid
ual
sM
ean
foll
ow
-up
Tar
get
po
pu
lati
on
Effi
cacy
end
poin
tR
elat
ive
risk
(95
%C
I)S
afet
yen
dp
oin
tR
elat
ive
risk
(95
%C
I)
Ind
irec
tth
rom
bin
inh
ibit
ors
Meg
aet
al.
[63
]E
no
xap
arin
aW
=4
,783
M=
15
,69
6
30
day
sS
TE
MI
pat
ien
tsu
nd
ergo
ing
thro
mbo
lysi
sD
eath
or
no
nfa
tal
MI
W:
0.8
4(0
.74
–0
.95)
M:
0.8
2(0
.74
–0
.90)
TIM
Im
ajo
rb
leed
ing
W:
1.6
4(1
.07
–2
.51)
M:
NA
To
sset
al.
[59]
Dal
tepar
inb
W=
27
0
M=
46
7
50
day
sP
atie
nts
pre
senti
ng
wit
hu
nst
able
ang
ina
pec
tori
sN
AN
AM
ajor
ble
edin
gW
:0
.73
(0.4
5–
1.1
7)
M:
0.8
8(0
.49
–1
.57)
Dir
ect
thro
mbin
inh
ibit
ors
Chac
ko
etal
.[6
6]
Biv
alir
ud
inc
W=
1,5
37
M=
4,4
65
12
mon
ths
Pat
ien
tsu
nd
ergo
ing
PC
IA
ll-c
ause
dea
thW
:0
.72
(0.4
0–1
.30)
M:
0.8
2(0
.53
–1
.26)
Maj
or
ble
edin
gin
-hosp
ital
W:
0.6
1(0
.38
–0
.99)
M:
0.5
4(0
.37
–0
.79)
Lan
sky
etal
.[2
4]
W=
4,1
57
M=
9,6
62
30
day
sP
atie
nts
pre
senti
ng
wit
hN
ST
EM
IA
ll-c
ause
dea
th,
recu
rren
tM
I,o
ru
rgen
tre
vas
cula
riza
tio
nW
:1
.23
(0.9
2–1
.65)
M:
NA
No
n-C
AB
GT
IMI
maj
or
ble
edin
gW
:0
.31
(0.1
4–
0.6
5)
M:
NA
Meh
illi
etal
.[7
4]
W=
39
9
M=
1,3
22
12
mon
ths
NS
TE
MI
pat
ien
tsu
nd
ergo
ing
PC
ID
eath
,re
curr
ent
MI,
or
TV
RW
:0
.80
(0.5
5–1
.17)
M:
1.1
0(0
.86
–1
.40)
No
n-C
AB
GT
IMI
maj
or
ble
edin
gW
:1
.00
(0.3
1–
3.3
0)
M:
0.7
5(0
.28
–1
.93)
Dau
gh
erty
etal
.[1
03]
W=
18
5,5
02
M=
38
5,2
75
In-h
osp
ital
Pat
ien
tsu
nd
ergo
ing
PC
IN
AN
AP
eri-
pro
ced
ura
lb
leed
ing
W:
0.7
1(0
.67
–0
.74)
M:
0.7
4(0
.70
–0
.78)
Con
no
lly
etal
.[7
5]
Dab
igat
ran
dW
=6
,598
M=
11
,51
4
2y
ears
Pat
ien
tsw
ith
no
n-v
alv
ula
rA
FS
tro
ke
or
syst
emic
embo
lism
W:
1.1
4v
s.2
.03
%p
ery
ear
M:
1.1
0v
s.1
.49
%p
ery
ear
Maj
or
ble
edin
g1
.16
(1.0
0–
1.3
4)
No
gen
der
-re
late
dan
aly
sis
Fac
tor
Xa
inhib
ito
rs
OA
SIS
-5In
ves
tig
ato
rs[7
8]
Fo
nd
apar
inu
xe
W=
7,6
99
M=
12
,37
9
9d
ays
Pat
ien
tsp
rese
nti
ng
wit
hA
CS
Dea
th,
MI,
or
refr
acto
ryis
chem
iaW
:1
.08
(0.8
9–1
.30)
M:
0.9
7(0
.83
–1
.12)
Maj
or
ble
edin
gW
:0
.46
(0.3
4–
0.5
8)
M:
0.6
1(0
.49
–0
.76)
OA
SIS
-6In
ves
tig
ato
rs[7
9]
W=
3,3
45
M=
8,7
46
30
day
sP
atie
nts
pre
senti
ng
wit
hS
TE
MI
Dea
tho
rre
curr
ent
MI
W:
0.8
7(0
.74
–1
.04)
M:
0.8
6(0
.74
–1
.00)
Mo
difi
edT
IMI
maj
or
ble
edin
g0
.77
(0.5
5–
1.0
8)
No
gen
der
-re
late
dan
aly
sis
Gender Differences in Cardiovascular Therapy 1927
Ta
ble
2co
nti
nu
ed
Ref
eren
ces
Dru
gN
o.
of
ind
ivid
ual
sM
ean
foll
ow
-up
Tar
get
po
pu
lati
on
Effi
cacy
end
poin
tR
elat
ive
risk
(95
%C
I)S
afet
yen
dp
oin
tR
elat
ive
risk
(95
%C
I)
EIN
ST
EIN
Inv
esti
gat
ors
[80]
Riv
aro
xab
anf
W=
1,4
89
M=
1,9
60
Inte
nded
3-,
6-
and
12
mon
ths
Pat
ien
tsw
ith
acute
DV
TS
ym
pto
mat
icre
curr
ent
VT
W:
0.7
2(0
.40
–1
.29)
M:
0.6
9(0
.37
–1
.28)
Maj
or
and
clin
ical
lyre
lev
ant
no
n-m
ajo
rb
leed
ing
W:
1.0
2(0
.72
–1
.45)
M:
0.9
9(0
.72
–1
.36)
EIN
ST
EIN
-PE
Inv
esti
gat
ors
[81]
W=
2,5
50
M=
2,2
82
Inte
nded
3-,
6-
and
12
mo
nth
sP
atie
nts
wit
hac
ute
PE
Sy
mpto
mat
icre
curr
ent
VT
W:
1.1
4(0
.65
–2
.01)
M:
1.1
3(0
.63
–2
.03)
Maj
or
and
no
n-m
ajo
rcl
inic
ally
rele
van
tb
leed
ing
W:
0.9
6(0
.76
–1
.21)
M:
0.8
6(0
.67
–1
.11)
Pat
elet
al.
[82
]W
=5
,663
M=
8,6
01
20
mon
ths
Pat
ien
tsw
ith
no
n-v
alv
ula
rA
Fan
dC
HA
DS
2sc
ore
C2
Str
ok
ean
dsy
stem
icem
bo
lism
W:
0.8
9(0
.70
–1
.12)
M:
0.8
7(0
.70
–1
.09)
Maj
or
and
no
n-m
ajo
rcl
inic
ally
rele
van
tb
leed
ing
W:
0.8
9(0
.79
–1
.01)
M:
1.1
2(1
.02
–1
.22)
Gra
ng
eret
al.
[83]
Ap
ixab
ang
W=
6,4
16
M=
11
,78
5
1.8
yea
rsP
atie
nts
wit
hat
rial
flu
tter
or
AF
Isch
emic
or
hae
mo
rrh
agic
stro
ke
and
syst
emic
embo
lism
W:
0.7
5(0
.56
–1
.00)
M:
0.8
3(0
.66
–1
.04)
Maj
or
ble
edin
gac
cord
ing
toIS
TH
crit
eria
W:
0.6
0(0
.47
–0
.76)
M:
0.7
7(0
.64
–0
.91)
Ho
ku
sai-
VT
EIn
ves
tig
ato
rs[8
4]
Ed
oxab
ang
W=
3,5
24
M=
4,7
13
12
mon
ths
Pat
ien
tsw
ith
acute
VT
Sy
mpto
mat
icre
curr
ent
VT
W:
0.8
7(0
.56
–1
.20)
M:
0.9
4(0
.70
–1
.27)
Maj
or
and
no
n-m
ajo
rcl
inic
ally
rele
van
tb
leed
ing
W0
.99
(0.8
2–
1.2
0)
M:
0.6
7(0
.54
–0
.83)
AC
Sac
ute
coro
nar
ysy
nd
rom
e,A
Fat
rial
fib
rill
atio
n,
CA
BG
coro
nar
yar
tery
by
pas
sg
raft
,C
HA
DS
2co
nges
tive
hea
rtfa
ilure
,hyper
tensi
on,
age
C7
5y
ears
,d
iabet
esm
elli
tus,
pri
or
stro
ke
or
TIA
or
thro
mbo
emb
oli
sm,
DV
Tdee
pvei
nth
rom
bosi
s,G
PI
gly
copro
tein
IIb/I
IIa
rece
pto
rin
hib
itor,
IST
HIn
tern
atio
nal
So
ciet
yo
nT
hro
mb
osi
san
dH
aem
ost
asis
,M
men
,M
Im
yo
card
ial
infa
rcti
on
,N
Anot
avai
lable
,N
ST
EM
Inon
ST
-seg
men
tel
evat
ion
myoca
rdia
lin
farc
tion,
OA
SIS
Org
aniz
atio
nto
asse
ssst
rate
gie
sin
acute
isch
emic
syndro
mes
,P
Ep
ulm
on
ary
embo
lism
,P
CI
per
cuta
neo
us
coro
nar
yin
terv
enti
on
,S
TE
MI
ST
-seg
men
tel
evat
ion
myoca
rdia
lin
farc
tion,
TIA
tran
sien
tis
chem
icat
tack
,T
IMI
thro
mboly
sis
inm
yoca
rdia
lin
farc
tion,
TV
Rta
rget
ves
sel
revas
cula
riza
tion,
VT
ven
ous
thro
mbo
emb
oli
sm,
Ww
om
en,
aE
no
xap
arin
vs.
un
frac
tio
nat
edh
epar
inb
Hig
hd
ose
vs.
ho
me
trea
tmen
td
ose
cB
ival
iru
din
vs.
hep
arin
san
dG
PI
dD
abig
atra
n1
50
mg
vs.
vit
amin
Kan
tag
on
ists
,ef
fica
cyd
ata
are
sho
wn
asra
tes
per
yea
re
Fo
nd
apar
inu
xv
s.u
nfr
acti
on
ated
hep
arin
fR
ivar
ox
aban
vs.
eno
xap
arin
plu
sv
itam
inK
anta
go
nis
tsg
Ap
ixab
ano
red
ox
aban
vs.
vit
amin
Kan
tago
nis
ts
1928 J. L. Gutierrez-Chico, J. Mehilli
3.2.3 Factor Xa Inhibitors
Fondaparinux is a selective inhibitor of the coagulation
factor Xa. It binds to antithrombin-III, leading to confor-
mational changes that result in increased affinity for factor
Xa. Fondaparinux has long half-life and a predictable
sustained anti-coagulant effect, which enables once-daily
subcutaneous administration. The results for fondaparinux
regarding inter-gender differences parallel those of biva-
lirudin: similar clinical benefit, although women tend to
bleed more when the indication was ACS, with no clear
difference when the indication was STEMI.
The OASIS-5 (Organization to Assess Strategies in
Acute Ischemic Syndromes) trial compared fondaparinux
versus enoxaparin for the management of patients with
ACS. Fondaparinux was non-inferior to enoxaparin for the
prevention of ischemic events, but it also significantly
reduced the incidence of major bleeding and mortality rates
up to 6 months [78]. In the subgroup analysis, major
bleeding was more frequent in women than in men in the
enoxaparin arm, but not in the fondaparinux arm. As a
consequence, fondaparinux resulted in a greater reduction
of the risk of bleeding in women, compared with men,
close to statistical significance [78].
The OASIS-6 (Sixth Organization to Assess Strategies in
Acute Ischemic Syndromes) trial compared fondaparinux
versus UFH or placebo (as indicated) in STEMI patients.
Fondaparinux reduced the composite of death and myocardial
re-infarction at 30 days, mainly due to the superior effect on
those patients undergoing fibrinolysis or no reperfusion
strategy. This effect was similar in women and men [79].
Rivaroxaban, apixaban, and edoxaban are also selective
factor Xa inhibitors, which are administered orally in once-
daily doses (rivaroxaban and edoxaban) or twice daily
(apixaban). Rivaroxaban has proven non-inferiority versus
enoxaparin followed by vitamin K antagonists for treat-
ment of deep venous thrombosis [80] and pulmonary
embolism [81]. It has also demonstrated to be non-inferior
to chronic treatment with vitamin K antagonists for
embolism prevention in patients with non-valvular atrial
fibrillation, with no significant differences in major
bleeding, but with a reduction of intracranial and fatal
bleeding in the rivaroxaban group [82]. In all these trials,
the pre-specified subgroup analysis did not show any dif-
ference in efficacy or safety between men and women [80–
82]. Apixaban significantly reduced the rates of stroke or
systemic embolism (hazard ratio [HR] 0.79; 95 %
CI 0.66–0.95), overall mortality (HR 0.89; 95 % CI
0.80–0.99), and major bleeding (HR 0.69; 95 % CI
0.80–0.90) compared with vitamin-K antagonists for
thromboembolic prevention in patients with non-valvular
atrial fibrillation in the ARISTOTLE (Apixaban for
Reduction In Stroke and Other Thromboembolic Events in
Atrial Fibrillation) trial; apixaban showed comparable
efficacy in both genders, but women tended to benefit from
a greater reduction in major bleeding complications than
men when treated with apixaban [83]. Interestingly, this
has not been observed with edoxaban: akin other oral
selective factor inhibitors, it has proved non-inferiority to
vitamin K antagonists for the treatment of patients with
deep venous thrombosis or pulmonary embolism. The
significant reduction in the incidence of major or clinically
relevant bleeding observed with edoxaban was significant
among men but not among women [84].
3.2.4 Vitamin K Antagonists
The so-called ‘vitamin K antagonists’ or coumadins (war-
farin, acenocoumarol) remain the most widely used anti-
coagulant therapy for chronic indications in cardiology.
Their mechanism of action consists of inhibiting the vita-
min K epoxide-reductase, thus blocking the recycling of
vitamin K epoxide into the active form of vitamin K and
vitamin K hydroquinone, required for the c-carboxylation
of the coagulation factors II, VII, IX, and X in the liver.
The main pharmacokinetic advantage of this group of
medications is the possibility of oral administration, which
is the historical reason they gained such a large acceptance.
Otherwise, they have a very labile pharmacokinetic and
pharmacodynamic profile, and are very sensitive to small
oscillations and interactions, which results in a somewhat
unpredictable therapeutic effect. Periodic control of the
anticoagulation status through the international normalized
ratio (INR) is compulsory for patients receiving vitamin K
antagonists. The most common indications for chronic
anticoagulation in cardiology are atrial fibrillation, pros-
thetic valves, and pulmonary embolism.
Women with atrial fibrillation have a significantly
higher risk of stroke than men [85]. Although warfarin is at
least equally as effective in reducing the risk of thrombo-
embolism in both genders, some studies have highlighted a
potentially higher benefit in women, which might be
explained by the higher baseline risk [86, 87]. There are no
differences in the risk of major bleeding risk associated
with warfarin use between men and women [86, 87].
However, women might require lower doses to achieve and
maintain therapeutic INR levels [88]. A summary of the
published evidence about gender-related efficacy and
safety of anticoagulant therapy is shown in Table 2.
4 Gender Bias in the Use of Evidence-Based Invasive
Coronary Procedures
Although cardiovascular mortality for both genders has
continuously decreased over the last decade, more women die
Gender Differences in Cardiovascular Therapy 1929
of CHD each year than men [6]. In particular, younger women
with coronary artery disease have a greater mortality risk than
younger men [89]. However, gender-related risk difference
attenuates and even reverses at later ages of CHD presentation
[89–91]. Large population-based studies have shown differ-
ences in the temporal pattern of mortality between women
and men. The reported in-hospital and 30-day unadjusted
mortality in women—particularly in those presenting with
ACS—is up to twofold higher than in men, whilst, during the
course of the first year, this early excess risk gradually
attenuates [1, 92–94]. The early hazard in women might be
partially attributed to the older age and more adverse risk
profile than male patients, so the reported differences disap-
pear after an adjusted multivariate analysis [95].
In addition, large registry studies, such as the CRU-
SADE (Can Rapid Risk Stratification of Unstable Angina
Patients Suppress Adverse Outcomes with Early Imple-
mentation of the ACC/AHA Guidelines) national quality
improvement initiative, have unveiled reasons that go
beyond female physiology: despite their higher risk profile
compared with men, women with ACS receive guideline-
recommended antithrombotic therapies less often [1].
Likewise, women are less likely than men to be referred for
cardiac testing and catheterization when they experience an
ACS [2, 15, 27, 96]. Several factors might partially explain
this observation.
First, women have a worse baseline risk profile and
poorer general condition than men: on average, women are
6–10 years older than men at the onset of CHD and have a
higher prevalence of diabetes, renal insufficiency, cere-
brovascular disease, or congestive heart failure than men
[1, 4, 91–93, 97].
Second, women more frequently have atypical symp-
toms of CHD and, in the case of typical clinical presen-
tation of ACS, they are more likely to have normal or
non-obstructive atherosclerosis of epicardial coronary
arteries (20 %) than are men (10 %) [89, 91, 92, 98].
Impaired endothelial function of both epicardial and
intramyocardial coronary arteries and differences in vas-
cular structure might explain the presence of myocardial
ischemia despite coronary angiography appearing normal
in women [96].
Third, women demand medical attention an average of
1.5–2 h later than men [90, 91, 99], which might affect their
likelihood to receive active reperfusion treatment when they
experience a STEMI. Meanwhile, there is a large body of
evidence showing that increasing the access to evidence-
based care is associated with reduced mortality for both
women and men with ACS, with women deriving the
greatest benefit at long term [91, 97, 100]. Moreover, some
studies suggest that, in women who undergo a proper
reperfusion strategy, accompanied by the right adjuvant
antithrombotic therapy, the amount of jeopardized
myocardium salvage is larger than in men [90]. We could
speculate about many different mechanisms to explain this
intriguing finding. Regardless, it seems to be in line with the
observed 35 % reduction of age-adjusted mortality in
women as compared with men 1 year after primary PCI [91].
Fourth, even after adjustment for body mass index,
women have smaller coronary arteries than men. However,
despite this and the more frequent presence of diabetes in
women, the risk of restenosis after implantation of bare
metal stents is 20 % lower than in men [101]. Furthermore,
the benefit derived from newer drug-eluting stent plat-
forms, such as everolimus-eluting stents, might be more
pronounced in women than in men [102].
Finally, as we have extensively explained in the previ-
ous sections, women seem to be more sensitive to bleeding
complications under different antithrombotic regimes, and
are also more often prone to peri-PCI peripheral vascular
complications. In this regard, an adequate dose adjustment
or the use of modern and more specific agents might be
particularly beneficial for women. From an interventional
perspective, experience is wider and evidence more solid
with bivalirudin as adjuvant therapy during PCI for the
treatment of women with ACS of any kind [24, 74]. In this
regard, the radial approach, although substantially more
challenging in women than in men, results in similar
clinical outcomes and similar incidences of major bleeding
in both gender groups, although women tend to present a
higher incidence of minor local hematomas [103].
5 Conclusion
In summary, it is undeniable that women with CHD are a
high-risk subset of patients. However, this is not a reason to
search for newer female-specific therapies and treatment
strategies, but to increase access for women to evidence-
based medicine that is already available. Furthermore,
although there is increasing awareness about gender-rela-
ted differences, particularly in the safety profile of anti-
thrombotic drugs, gender-based protocols for their
adequate use remain an unmet need in cardiology.
Funding Supported by the DZHK (German Centre for Cardio-
vascular Research) and by the BMBF (German Ministry of Education
and Research).
References
1. Blomkalns AL, et al. Gender disparities in the diagnosis and
treatment of non-ST-segment elevation acute coronary syn-
dromes: large-scale observations from the CRUSADE (Can
Rapid Risk Stratification of Unstable Angina Patients Suppress
Adverse Outcomes With Early Implementation of the American
College of Cardiology/American Heart Association Guidelines)
1930 J. L. Gutierrez-Chico, J. Mehilli
National Quality Improvement Initiative. J Am Coll Cardiol.
2005;45(6):832–7.
2. Kim ES, Menon V. Status of women in cardiovascular clinical
trials. Arterioscler Thromb Vasc Biol. 2009;29(3):279–83.
3. Capodanno D, Angiolillo DJ. Impact of race and gender on
antithrombotic therapy. Thromb Haemost. 2010;104(3):471–84.
4. Rossouw JE, et al. Risks and benefits of estrogen plus progestin
in healthy postmenopausal women: principal results From the
Women’s Health Initiative randomized controlled trial. JAMA.
2002;288(3):321–33.
5. Ridker PM, et al. A randomized trial of low-dose aspirin in the
primary prevention of cardiovascular disease in women. N Engl
J Med. 2005;352(13):1293–304.
6. Roger VL, et al. Heart disease and stroke statistics–2012 update:
a report from the American Heart Association. Circulation.
2012;125(1):e2–220.
7. Eshel-Green T, et al. Effect of sex difference on platelet adhe-
sion, spreading and aggregate formation under flow. Thromb
Haemost. 2009;102(5):958–65.
8. Leng XH, et al. Platelets of female mice are intrinsically more
sensitive to agonists than are platelets of males. Arterioscler
Thromb Vasc Biol. 2004;24(2):376–81.
9. Haque SF, et al. Sex difference in platelet aggregation detected
by new aggregometry using light scattering. Endocr J. 2001;48
(1):33–41.
10. Stevens RF, Alexander MK. A sex difference in the platelet
count. Br J Haematol. 1977;37(2):295–300.
11. Gordon T, et al. Menopause and coronary heart disease. The
Framingham Study. Ann Intern Med. 1978;89(2):157–61.
12. Rosenberg L, et al. Early menopause and the risk of myocardial
infarction. Am J Obstet Gynecol. 1981;139(1):47–51.
13. Mikkola T, et al. 17 beta-estradiol stimulates prostacyclin, but
not endothelin-1, production in human vascular endothelial
cells. J Clin Endocrinol Metab. 1995;80(6):1832–6.
14. Caulin-Glaser T, et al. 17 beta-estradiol regulation of human
endothelial cell basal nitric oxide release, independent of cyto-
solic Ca2? mobilization. Circ Res. 1997;81(5):885–92.
15. Arora S, et al. Estrogen improves endothelial function. J Vasc
Surg. 1998;27(6):1141–6 (discussion 1147).
16. Ajayi AA, Mathur R, Halushka PV. Testosterone increases
human platelet thromboxane A2 receptor density and aggrega-
tion responses. Circulation. 1995;91(11):2742–7.
17. Grady D, et al. Postmenopausal hormone therapy increases risk
for venous thromboembolic disease. The Heart and Estrogen/
progestin Replacement Study. Ann Intern Med. 2000;132(9):
689–96.
18. Mendelsohn ME, Karas RH. The protective effects of estrogen on
the cardiovascular system. N Engl J Med. 1999;340(23):1801–11.
19. Bonithon-Kopp C, et al. Relationship between sex hormones and
haemostatic factors in healthy middle-aged men. Atherosclero-
sis. 1988;71(1):71–6.
20. Bain B, Forster T. A sex difference in the bleeding time.
Thromb Haemost. 1980;43(2):131–2.
21. Ndrepepa G, et al. Periprocedural bleeding and 1-year outcome
after percutaneous coronary interventions: appropriateness of
including bleeding as a component of a quadruple end point.
J Am Coll Cardiol. 2008;51(7):690–7.
22. Rao SV, et al. Bleeding and blood transfusion issues in patients
with non-ST-segment elevation acute coronary syndromes. Eur
Heart J. 2007;28(10):1193–204.
23. Mehilli J, et al. Sex and effect of abciximab in patients with
acute coronary syndromes treated with percutaneous coronary
interventions: results from Intracoronary Stenting and Anti-
thrombotic Regimen: Rapid Early Action for Coronary Treat-
ment 2 trial. Am Heart J. 2007;154(1):158 e1–7.
24. Lansky AJ, et al. Impact of gender and antithrombin strategy on
early and late clinical outcomes in patients with non-ST-eleva-
tion acute coronary syndromes (from the ACUITY trial). Am J
Cardiol. 2009;103(9):1196–203.
25. Durnin JV, Womersley J. Body fat assessed from total body
density and its estimation from skinfold thickness: measure-
ments on 481 men and women aged from 16 to 72 years. Br J
Nutr. 1974;32(1):77–97.
26. Levey AS, et al. A more accurate method to estimate glomerular
filtration rate from serum creatinine: a new prediction equation.
Modification of Diet in Renal Disease Study Group. Ann Intern
Med. 1999;130(6):461–70.
27. Alexander KP, et al. Sex differences in major bleeding with
glycoprotein IIb/IIIa inhibitors: results from the CRUSADE
(Can Rapid risk stratification of Unstable angina patients Sup-
press ADverse outcomes with Early implementation of the
ACC/AHA guidelines) initiative. Circulation. 2006;114(13):
1380–7.
28. Patrono C, et al. Low-dose aspirin for the prevention of ather-
othrombosis. N Engl J Med. 2005;353(22):2373–83.
29. Becker DM, et al. Sex differences in platelet reactivity and
response to low-dose aspirin therapy. JAMA. 2006;295(12):
1420–7.
30. Gum PA, et al. A prospective, blinded determination of the
natural history of aspirin resistance among stable patients with
cardiovascular disease. J Am Coll Cardiol. 2003;41(6):961–5.
31. Qayyum R, et al. Platelet inhibition by aspirin 81 and
325 mg/day in men versus women without clinically apparent
cardiovascular disease. Am J Cardiol. 2008;101(9):1359–63.
32. Eikelboom JW, et al. Incomplete inhibition of thromboxane
biosynthesis by acetylsalicylic acid: determinants and effect on
cardiovascular risk. Circulation. 2008;118(17):1705–12.
33. Eikelboom JW, et al. Aspirin-resistant thromboxane biosynthe-
sis and the risk of myocardial infarction, stroke, or cardiovas-
cular death in patients at high risk for cardiovascular events.
Circulation. 2002;105(14):1650–5.
34. Berger JS, et al. Aspirin for the primary prevention of cardio-
vascular events in women and men: a sex-specific meta-analysis
of randomized controlled trials. JAMA. 2006;295(3):306–13.
35. Antithrombotic Trialists’ (ATT) Collaboration, et al. Aspirin in
the primary and secondary prevention of vascular disease: col-
laborative meta-analysis of individual participant data from
randomised trials. Lancet. 2009;373(9678):1849–60.
36. Jochmann N, et al. Female-specific aspects in the pharmaco-
therapy of chronic cardiovascular diseases. Eur Heart J.
2005;26(16):1585–95.
37. Ferreiro JL, Angiolillo DJ. Clopidogrel response variability:
current status and future directions. Thromb Haemost. 2009;102
(1):7–14.
38. Yusuf S, et al. Effects of clopidogrel in addition to aspirin in
patients with acute coronary syndromes without ST-segment
elevation. N Engl J Med. 2001;345(7):494–502.
39. Mehta SR, et al. Effects of pretreatment with clopidogrel and
aspirin followed by long-term therapy in patients undergoing
percutaneous coronary intervention: the PCI-CURE study.
Lancet. 2001;358(9281):527–33.
40. Steinhubl SR, et al. Early and sustained dual oral antiplatelet
therapy following percutaneous coronary intervention: a ran-
domized controlled trial. JAMA. 2002;288(19):2411–20.
41. Sabatine MS, et al. Addition of clopidogrel to aspirin and
fibrinolytic therapy for myocardial infarction with ST-segment
elevation. N Engl J Med. 2005;352(12):1179–89.
42. Bhatt DL, et al. Clopidogrel and aspirin versus aspirin alone for
the prevention of atherothrombotic events. N Engl J Med. 2006;
354(16):1706–17.
Gender Differences in Cardiovascular Therapy 1931
43. Berger JS, et al. The relative efficacy and safety of clopidogrel
in women and men a sex-specific collaborative meta-analysis.
J Am Coll Cardiol. 2009;54(21):1935–45.
44. Wiviott SD, et al. Prasugrel versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.
45. Wallentin L, et al. Ticagrelor versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.
46. Coller BS, et al. A murine monoclonal antibody that completely
blocks the binding of fibrinogen to platelets produces a
thrombasthenic-like state in normal platelets and binds to gly-
coproteins IIb and/or IIIa. J Clin Invest. 1983;72(1):325–38.
47. Tardiff BE, et al. Pharmacodynamics and pharmacokinetics of
eptifibatide in patients with acute coronary syndromes: prospec-
tive analysis from PURSUIT. Circulation. 2001;104(4):399–405.
48. Cho L, et al. Clinical benefit of glycoprotein IIb/IIIa blockade
with Abciximab is independent of gender: pooled analysis
from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3
for the Prevention of Ischemic Complications. Evaluation in
Percutaneous Transluminal Coronary Angioplasty to Improve
Long-Term Outcome with Abciximab GP IIb/IIIa blockade.
Evaluation of Platelet IIb/IIIa Inhibitor for Stent. J Am Coll
Cardiol. 2000;36(2):381–6.
49. Fernandes LS, et al. Is glycoprotein IIb/IIIa antagonism as
effective in women as in men following percutaneous coronary
intervention? Lessons from the ESPRIT study. J Am Coll Car-
diol. 2002;40(6):1085–91.
50. Boersma E, et al. Platelet glycoprotein IIb/IIIa inhibitors in
acute coronary syndromes: a meta-analysis of all major ran-
domised clinical trials. Lancet. 2002;359(9302):189–98.
51. Hochholzer W, et al. Predictors of bleeding and time depen-
dence of association of bleeding with mortality: insights from
the Trial to Assess Improvement in Therapeutic Outcomes by
Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in
Myocardial Infarction 38 (TRITON-TIMI 38). Circulation.
2011;123(23):2681–9.
52. Kastrati A, et al. Abciximab and heparin versus bivalirudin for
non-ST-elevation myocardial infarction. N Engl J Med.
2011;365(21):1980–9.
53. Hirsh J, et al. Heparin and low-molecular-weight heparin:
mechanisms of action, pharmacokinetics, dosing considerations,
monitoring, efficacy, and safety. Chest. 1998;114(5 Suppl):
489S–510S.
54. Granger CB, et al. Activated partial thromboplastin time and
outcome after thrombolytic therapy for acute myocardial
infarction: results from the GUSTO-I trial. Circulation. 1996;93
(5):870–8.
55. Falvo N, et al. Heparin-associated thrombocytopenia in 24,401
patients with venous thromboembolism: findings from the RI-
ETE Registry. J Thromb Haemost. 2011;9(9):1761–8.
56. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial
Investigators. Dose-ranging trial of enoxaparin for unstable
angina results of TIMI 11A. J Am Coll Cardiol. 1997;29(7):
1474–82.
57. Becker RC, et al. Influence of patient characteristics and renal
function on factor Xa inhibition pharmacokinetics and phar-
macodynamics after enoxaparin administration in non-ST-seg-
ment elevation acute coronary syndromes. Am Heart J.
2002;143(5):753–9.
58. Fragmin during Instability in Coronary Artery Disease (FRISC)
study group. Low-molecular-weight heparin during instability in
coronary artery disease. Lancet. 1996;347(9001):561–8.
59. Toss H, Wallentin L, Siegbahn A. Influences of sex and smoking
habits on anticoagulant activity in low-molecular-weight hepa-
rin treatment of unstable coronary artery disease. Am Heart J.
1999;137(1):72–8.
60. Cohen M, et al. Enoxaparin in unstable angina/non-ST-segment
elevation myocardial infarction: treatment benefits in prespeci-
fied subgroups. J Thromb Thrombolysis. 2001;12(3):199–206.
61. White HD, et al. Efficacy and safety of enoxaparin compared
with unfractionated heparin in high-risk patients with non-ST-
segment elevation acute coronary syndrome undergoing percu-
taneous coronary intervention in the Superior Yield of the New
Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/
IIIa Inhibitors (SYNERGY) trial. Am Heart J. 2006;152(6):
1042–50.
62. Antman EM, et al. Enoxaparin versus unfractionated heparin
with fibrinolysis for ST-elevation myocardial infarction. N Engl
J Med. 2006;354(14):1477–88.
63. Mega JL, et al. Outcomes and optimal antithrombotic therapy in
women undergoing fibrinolysis for ST-elevation myocardial
infarction. Circulation. 2007;115(22):2822–8.
64. O’Gara PT, et al. 2013 ACCF/AHA guideline for the manage-
ment of ST-elevation myocardial infarction: executive sum-
mary: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines. Circulation. 2013;127(4):529–55.
65. Anderson JL, et al. 2011 ACCF/AHA Focused Update Incor-
porated Into the ACC/AHA 2007 Guidelines for the Manage-
ment of Patients With Unstable Angina/Non-ST-Elevation
Myocardial Infarction: a report of the American College of
Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines. Circulation. 2011;123(18):e426–579.
66. Chacko M, et al. Ischemic and bleeding outcomes in women
treated with bivalirudin during percutaneous coronary inter-
vention: a subgroup analysis of the Randomized Evaluation in
PCI Linking Angiomax to Reduced Clinical Events
(REPLACE)-2 trial. Am Heart J. 2006;151(5):1032 e1–7.
67. Lincoff AM, et al. Long-term efficacy of bivalirudin and pro-
visional glycoprotein IIb/IIIa blockade vs heparin and planned
glycoprotein IIb/IIIa blockade during percutaneous coronary
revascularization: REPLACE-2 randomized trial. JAMA. 2004;
292(6):696–703.
68. Lincoff AM, et al. Bivalirudin and provisional glycoprotein IIb/
IIIa blockade compared with heparin and planned glycoprotein
IIb/IIIa blockade during percutaneous coronary intervention:
REPLACE-2 randomized trial. JAMA. 2003;289(7):853–63.
69. Stone GW, et al. Bivalirudin for patients with acute coronary
syndromes. N Engl J Med. 2006;355(21):2203–16.
70. Stone GW, et al. Bivalirudin in patients with acute coronary
syndromes undergoing percutaneous coronary intervention: a
subgroup analysis from the Acute Catheterization and Urgent
Intervention Triage strategy (ACUITY) trial. Lancet. 2007;369
(9565):907–19.
71. Madsen JK, et al. Ischaemic events and bleeding in patients
undergoing percutaneous coronary intervention with concomi-
tant bivalirudin treatment. EuroIntervention. 2008;3(5):610–6.
72. Stone GW, et al. Bivalirudin during primary PCI in acute
myocardial infarction. N Engl J Med. 2008;358(21):2218–30.
73. Mehran R, et al. Bivalirudin in patients undergoing primary
angioplasty for acute myocardial infarction (HORIZONS-AMI):
1-year results of a randomised controlled trial. Lancet.
2009;374(9696):1149–59.
74. Mehilli J, et al. Sex-related effectiveness of bivalirudin versus
abciximab and heparin in non-ST-segment elevation myocardial
infarction. Am Heart J. 2013;165(4):537–43.
75. Connolly SJ, et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.
76. Swan SK, Hursting MJ. The pharmacokinetics and pharmaco-
dynamics of argatroban: effects of age, gender, and hepatic or
renal dysfunction. Pharmacotherapy. 2000;20(3):318–29.
1932 J. L. Gutierrez-Chico, J. Mehilli
77. Jang IK, et al. Argatroban therapy in women with heparin-
induced thrombocytopenia. J Womens Health (Larchmt). 2007;
16(6):895–901.
78. Fifth Organization to Assess Strategies in Acute Ischemic
Syndromes Investigators, et al. Comparison of fondaparinux and
enoxaparin in acute coronary syndromes. N Engl J Med.
2006;354(14):1464–76.
79. Yusuf S, et al. Effects of fondaparinux on mortality and reinfarction
in patients with acute ST-segment elevation myocardial infarction:
the OASIS-6 randomized trial. JAMA. 2006;295(13):1519–30.
80. EINSTEIN Investigators, et al. Oral rivaroxaban for symptomatic
venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.
81. EINSTEIN-PE Investigators, et al. Oral rivaroxaban for the
treatment of symptomatic pulmonary embolism. N Engl J Med.
2012;366(14):1287–97.
82. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. N Engl J Med. 2011;365(10):883–91.
83. Granger CB, et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med. 2011;365(11):981–92.
84. The Hokusai-VTE Investigators. Edoxaban versus warfarin for
the treatment of symptomatic venous thromboembolism. N Engl
J Med. 2013;369(15):1406-1415.
85. Avgil Tsadok M, et al. Sex differences in stroke risk among
older patients with recently diagnosed atrial fibrillation. JAMA.
2012;307(18):1952–8.
86. Fang MC, et al. Gender differences in the risk of ischemic stroke
and peripheral embolism in atrial fibrillation: the AnTicoagu-
lation and Risk factors In Atrial fibrillation (ATRIA) study.
Circulation. 2005;112(12):1687–91.
87. Gomberg-Maitland M, et al. Anticoagulation in women with
non-valvular atrial fibrillation in the stroke prevention using an
oral thrombin inhibitor (SPORTIF) trials. Eur Heart J. 2006;27
(16):1947–53.
88. Garcia D, et al. Warfarin maintenance dosing patterns in clinical
practice: implications for safer anticoagulation in the elderly
population. Chest. 2005;127(6):2049–56.
89. Canto JG, et al. Association of age and sex with myocardial
infarction symptom presentation and in-hospital mortality.
JAMA. 2012;307(8):813–22.
90. Mehilli J, et al. Gender and myocardial salvage after reperfusion
treatment in acute myocardial infarction. J Am Coll Cardiol.
2005;45(6):828–31.
91. Mehilli J, et al. Sex-based analysis of outcome in patients with
acute myocardial infarction treated predominantly with percu-
taneous coronary intervention. JAMA. 2002;287(2):210–5.
92. Mehilli J, et al. Differences in prognostic factors and outcomes
between women and men undergoing coronary artery stenting.
JAMA. 2000;284(14):1799–805.
93. Berger JS, et al. Sex differences in mortality following acute
coronary syndromes. JAMA. 2009;302(8):874–82.
94. Daly C, et al. The impact of guideline compliant medical ther-
apy on clinical outcome in patients with stable angina: findings
from the Euro Heart Survey of stable angina. Eur Heart J.
2006;27(11):1298–304.
95. Wijnbergen I, et al. Gender differences in long-term outcome
after primary percutaneous intervention for ST-segment eleva-
tion myocardial infarction. Catheter Cardiovasc Interv.
2013;82(3):379–84.
96. Anderson RD, Pepine CJ. Gender differences in the treatment
for acute myocardial infarction: bias or biology? Circulation.
2007;115(7):823–6.
97. Alfredsson J, et al. Similar outcome with an invasive strategy in
men and women with non-ST-elevation acute coronary syn-
dromes: from the Swedish Web-System for Enhancement and
Development of Evidence-Based Care in Heart Disease Evalu-
ated According to Recommended Therapies (SWEDEHEART).
Eur Heart J. 2011;32(24):3128–36.
98. Dey S, et al. Sex-related differences in the presentation, treat-
ment and outcomes among patients with acute coronary syn-
dromes: the Global Registry of Acute Coronary Events. Heart.
2009;95(1):20–6.
99. Diercks DB, et al. Gender differences in time to presentation for
myocardial infarction before and after a national women’s car-
diovascular awareness campaign: a temporal analysis from the
Can Rapid Risk Stratification of Unstable Angina Patients
Suppress ADverse Outcomes with Early Implementation
(CRUSADE) and the National Cardiovascular Data Registry
Acute Coronary Treatment and Intervention Outcomes Net-
work-Get with the Guidelines (NCDR ACTION Registry-
GWTG). Am Heart J. 2010;160(1):80–87 e3.
100. Glaser R, et al. Benefit of an early invasive management strategy
in women with acute coronary syndromes. JAMA. 2002;288
(24):3124–9.
101. Mehilli J, et al. Gender and restenosis after coronary artery
stenting. Eur Heart J. 2003;24(16):1523–30.
102. Ng VG, et al. Three-year results of safety and efficacy of the
everolimus-eluting coronary stent in women (from the SPIRIT
III randomized clinical trial). Am J Cardiol. 2011;107(6):841–8.
103. Daugherty SL, et al. Patterns of use and comparative effec-
tiveness of bleeding avoidance strategies in men and women
following percutaneous coronary interventions: an observational
study from the National Cardiovascular Data Registry. J Am
Coll Cardiol. 2013;61(20):2070–8.
Gender Differences in Cardiovascular Therapy 1933
