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Combined antiplatelet and anticoagulant

therapy: clinical benefits and risks.
ARTICLE in JOURNAL OF THROMBOSIS AND HAEMOSTASIS AUGUST 2007
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Journal of Thrombosis and Haemostasis, 5 (Suppl. 1): 255263

INVITED REVIEW

Combined antiplatelet and anticoagulant therapy: clinical

benefits and risks
J . W . E I K E L B O O M * and J . H I R S H
*Thrombosis Service, Hamilton General Hospital; and Henderson Research Centre, Hamilton Health Sciences Corporation and McMaster
University, Hamilton, Ontario, Canada

To cite this article: Eikelboom JW, Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost 2007;
5 (Suppl. 1): 25563.

Summary. The combination of anticoagulant and antiplatelet

therapy is more eective than antiplatelet therapy alone for the
initial and long-term management of acute coronary syndromes
but increases the risk of bleeding. Antiplatelet therapy is often
combined with oral anticoagulants in patients with an indication for warfarin therapy (e.g. atrial brillation) who also have
an indication for antiplatelet therapy (e.g. coronary artery
disease) but the appropriateness of such an approach is
unresolved. Anticoagulation appears to be as eective as
antiplatelet therapy for long-term management of acute
coronary syndrome and stroke, and possibly peripheral artery
disease, but causes more bleeding. Therefore, in such patients
who develop atrial brillation, switching from antiplatelet
therapy to anticoagulants might be all that is required. The
combination of anticoagulant and antiplatelet therapy has only
been proven to provide additional benet over anticoagulants
alone in patients with prosthetic heart valves. The combination
of aspirin and clopidogrel is not as eective as oral anticoagulants in patients with atrial brillation, whereas the combination of aspirin and clopidogrel is more eective than oral
anticoagulants in patients with coronary stents. Whether the
benets of triple therapy outweigh the risks in patients with
atrial brillation and coronary stents requires evaluation in
randomized trials.
Introduction
Antithrombotic drugs are widely used to prevent and treat
thrombosis in the venous and arterial circulations, including the
heart. Antiplatelet drugs are effective for the initial management
of acute coronary syndrome (ACS) [13] and for the long-term
management of coronary, cerebral and peripheral artery disease
(PAD) [1,35]. Antiplatelet drugs are also effective for the
Correspondence: John W Eikelboom, Thrombosis Service, Hamilton
General Hospital, 237 Barton Street East, Hamilton, Ontario, L8 L
2X2, Canada.
Tel.: 905 527 4322 extension 44478; fax.: 905 521 1551;
e-mail: eikelbj@mcmaster.ca
Received 2 February 2007, accepted 28 February 2007
 2007 International Society on Thrombosis and Haemostasis

prevention of thromboembolism in atrial brillation (AF) [6,7],

and for the prevention of venous thromboembolism (VTE) [8,9],
but are less effective than anticoagulants for these indications
[7,9,10]. Parenteral anticoagulants are effective for the initial
management of acute coronary syndrome (ACS) [2] and for the
initial management of suspected ischemic stroke [11], but the
benets in patients with stroke are negated by an increase in
bleeding. Both parenteral and oral anticoagulants are effective
for treatment of VTE [12]. Oral anticoagulants appear to be as
effective as antiplatelet therapy for long-term management of
ACS [9,13] and stroke [14,15] but cause more bleeding than
antiplatelet drugs and are less convenient to use.
In theory, improvements in antithrombotic therapy might be
achieved by developing new improved drugs, by optimizing
dosage regimens of existing or new drugs, by using combinations of antiplatelet drugs that target different platelet receptors, or by combining anticoagulants with antiplatelet drugs.
Another promising approach is to tailor the pharmacokinetic
properties of a drug to specic clinical situations. For example,
in the immediate management of ACS, a reversible short acting
antithrombotic drug is advantageous because it can be stopped
to reduce the risk of bleeding if emergency coronary bypass
surgery is required or can be continued if percutaneous
coronary intervention (PCI) is indicated. In contrast, longer
acting orally administered drugs that can be used once daily or
even less frequently are advantageous for long-term therapy.
Modest improvements in the effectiveness of some new
antithrombotic drugs over existing drugs have been observed
[1620]. Unlike existing antithrombotic drugs, the dosaging
regimens of most new drugs have been optimized in phase II
studies, thereby allowing them to be used in doses tailored to
the clinical situation of interest. For example, on the basis of
phase II dose-ranging studies, a low dose of fondaparinux was
selected for comparison with high (standard) dose unfractionated heparin (UFH) or low-molecular-weight heparin
(LMWH) in phase III studies in patients with ACS. Importantly, this less intense fondaparinux regimen was associated
with both a reduction in bleeding and a reduction in mortality
compared with standard dose UFH and LMWH [21,22].
The combination of aspirin and clopidogrel is more effective
than aspirin alone for the prevention of recurrent thrombotic

256 J. W. Eikelboom & J. Hirsh

events in high-risk ACS patients, with an acceptable increase in

bleeding [2326]. The combination of anticoagulant and
antiplatelet therapy is more effective than monotherapy for
the initial and long-term management of ACS and for the longterm management of patients with mechanical heart valves.
However, the efcacy and safety of the combination of
anticoagulant and antiplatelet therapy has not been adequately
compared with anticoagulant therapy (at the same intensity)
alone for the long-term treatment of ACS, stroke or PAD.
Many older patients with cardiovascular disease have separate
indications for anticoagulant treatment (e.g. AF) and for
combined antiplatelet treatment (e.g. postcoronary stent) but
the efcacy and safety of anticoagulant and dual antiplatelet
therapy have not been evaluated in randomized trials.
This paper reviews the evidence for the effectiveness and
safety of combining anticoagulant and antiplatelet drugs to
prevent and treat thrombosis. To provide the most valid and
reliable comparisons we limit the analysis to the results of
randomized controlled trials (RCTs) or meta-analyses of
RCTs.
Clinical settings in which there is evidence that the
combination of anticoagulant and antiplatelet therapy
is more effective than antiplatelet therapy alone
Numerous RCTs have evaluated the effectiveness and safety of
the combination of anticoagulant and antiplatelet therapy
compared with antiplatelet therapy alone for the initial and
long-term management of patients with ACS. Most of the
studies were conducted prior to the routine use of combined
antiplatelet therapy with aspirin and clopidogrel and their
results therefore may not be generalizable to current clinical
practise.
Initial management of ACS

UFH plus aspirin vs. aspirin In patients with non-STelevation acute coronary syndrome (NSTACS), a metaanalysis of six small randomized controlled trials (RCTs)
involving 1353 patients treated with intravenous (i.v.) UFH
plus aspirin or placebo/no UFH plus aspirin for up to 7 days
demonstrated a one-third risk reduction in the composite
outcome, death or myocardial infarction (MI), at the end of
treatment [7.9% vs. 10.4%; odds ratio (OR), 0.67; 95%
condence interval (CI), 0.450.99; number needed to treat
(NNT) = 40], with a non-signicant increase in major
bleeding (1.4% vs. 0.5%; OR, 1.88; 95% CI, 0.60-5.88) [17].
In patients with ST elevation myocardial infarction (STEMI),
a meta-analysis of four small RCT trials involving 1231 patients
treated brinolytic therapy and receiving either i.v. UFH plus
aspirin or placebo/no UFH plus aspirin for up to 5 days did not
demonstrate a difference in death, MI or major bleeding [27].
However, another meta-analysis of all trials of short-term UFH
(subcutaneous or i.v.) in more than 60 000 patients with STEMI
who were routinely treated with aspirin and brinolysis revealed
that short-term UFH compared with placebo/no UFH (average

follow-up of about 10 days) signicantly reduced the risk of

death by 6% (95% CI, 0% to 10%; 2P = 0.03), representing
ve fewer deaths per 1000 (absolute event rates, 8.6% vs. 9.1%;
NNT = 200) [28]. Reinfarction was reduced by 10% (95% CI,
0% to 20%; 2P = 0.04), representing three fewer reinfarctions
per 1000 (3.0% vs. 3.3%; NNT = 333). Major bleeds were
increased by about 50% (2P < 0.0001), representing an excess
of three major bleeds per 1000 [1.0% vs. 0.7%, number needed
to harm (NNH) = 333] [28].
LMWH plus aspirin vs. aspirin The best evidence for the
efcacy of adding LMWH to aspirin in NSTACS comes from
the FRISC-I study [29], which compared 6 days of treatment
with the LMWH, dalteparin, given in a dose of 120 IU twice
daily by subcutaneous (s.c.) injection, with placebo in 1506
aspirin-treated patients. Dalteparin signicantly reduced the
risk of death or MI at about 1 week (1.8% vs. 4.8%; OR, 0.37;
95% CI, 0.20 to 0.68; NNT = 33), with a small non-signicant
excess of major bleeding (0.8% vs. 0.5%; OR, 1.53; 95% CI,
0.44 to 5.30) [29].
The CREATE trial [30] compared 7 days of treatment with
the LMWH, reviparin, given by s.c. injection in a weight
adjusted dose of 3436 to 6871 IU twice daily, with placebo, in
15 570 aspirin-treated patients with STEMI. Fibrinolytic
therapy with streptokinase or urokinase was given in threequarters of patients and clopidogrel or ticlopidine were given in
one-half of patients. At 1 week, the addition of reviparin to
antiplatelet treatment reduced death by 11% (8.0% vs. 8.9%;
OR, 0.89; 95% CI, 0.80 to 0.99; NNT = 111) and reduced MI
by about one-quarter (1.6% vs. 2.1%; OR, 0.75; 95% CI, 0.60
to 0.95; NNT = 200), at the cost of a more than twofold
increase in major bleeding (0.9% vs. 0.4%; OR, 2.49; 95% CI,
1.61 to 3.87; NNH = 200) and intracranial bleeding (0.3% vs.
0.1%; OR, 2.20; 95% CI, 1.04 to 4.65; NNH = 500) [30].
Fondaparinux plus aspirin vs. aspirin The OASIS-6
study randomized 12 092 aspirin-treated patients with STEMI
to receive up to 8 days of treatment with s.c. fondaparinux
2.5 mg once daily or standard care with either placebo among
patients in whom UFH was felt not to be indicated (stratum 1)
or with intravenous UFH for 48 h among patients in whom
anticoagulation was felt to be indicated (stratum 2) [22]. The
results in stratum 1 demonstrated that adding fondaparinux to
aspirin reduced the risk of death or MI at 9 days by about onequarter (8.5% vs. 11.1%; relative risk (RR), 0.76; 95% CI,
0.640.89; NNT = 38) with a non-signicant reduction in
major bleeding (1.8% vs. 2.1%; RR, 0.83; 95% CI, 0.84 to
1.06). A consistent benet of fondaparinux was seen in the 16%
of patients who were treated with clopidogrel or ticlopidine as
well as aspirin [22], suggesting an incremental benet of
anticoagulants when added to dual antiplatelet therapy.
Summary of combination of anticoagulant and antiplatelet
therapy for the initial management of ACS There is a
consistent body of data from randomized trials involving more
than 90 000 patients with ACS that adding UFH, LMWH or
 2007 International Society on Thrombosis and Haemostasis

Combined antiplatelet and anticoagulant therapy 257

fondaparinux to aspirin is more effective than aspirin alone for

preventing recurrent ischemic events or death during the rst
week. Subgroup data suggest that the benets of anticoagulant
therapy are also evident when LMWH or fondaparinux is
added to the combination of aspirin and clopidogrel. In trials in
which UFH or LMWH were added to aspirin, a reduction in
ischemic events or death was achieved at the cost of an increase
in bleeding. When fondaparinux was added to aspirin with or
without clopidogrel, a reduction in ischemic events or death
was achieved without an increase in bleeding. The absence of
an increase in bleeding when fondaparinux was added to
antiplatelet therapy is unexplained.
Long-term management of ACS

Warfarin plus aspirin vs. aspirin At least 14 randomized

trials have examined the efcacy and safety of adding warfarin
to aspirin in patients with NSTACS or STEMI [31]. The
intensity of the International Normalized Ratio (INR) was not
uniform among all of the studies. Most trials enrolled patients
within 1 week of the acute event but some trials enrolled patients
up to 8 weeks after the acute event. Patients were followed for up
to 5 years. Pooled data from all the trials indicated no benet of
adding warfarin to aspirin, but the results were statistically
heterogeneous and the lack of effect of adding warfarin to
aspirin appeared to be related to the use of low intensity warfarin
[31]. Thus, in the 10 trials (n = 12 488) that either titrated
warfarin to an INR of 2.0 to 3.0 or achieved a mean INR of
between 2.0 and 3.0, the addition of warfarin to aspirin reduced
the risk of death, MI or thromboembolic stroke by about onequarter (9.4% vs. 12.4%; OR, 0.73; 95% CI, 0.63 to 0.84;
NNT = 33) [31]. The benets of adding warfarin to aspirin
were achieved at a cost of an increase in major bleeding (2.6% vs.
1.1%; OR, 2.32; 95% CI, 1.62 to 3.29; NNH = 67) and a nonsignicant increase in intracranial bleeding (2.6% vs. 0.5%; OR,
3.02; 95% CI, 0.61 to 15.02), with no difference in deaths [31]. An
independently conducted meta-analysis of the same 10 studies
yielded similar results and demonstrated a consistent benet of
adding warfarin to aspirin in NSTACS and STEMI trials [32].
Ximelagatran plus aspirin vs. aspirin Ximelagatran is
the rst orally active DTI and has been extensively evaluated as
a replacement for warfarin for the prevention and treatment of
arterial and venous thrombosis [33].
The ESTEEM trial randomized 1883 patients within 14 days
of ST-elevation or non-ST-elevation MI to receive oral
ximelagatran at a dose of 24 mg, 36 mg, 48 mg or 60 mg
twice daily, or placebo, respectively for 6 months [34]. All
patients were treated with aspirin. The addition of ximelagatran to aspirin compared with aspirin alone reduced the risk of
death, MI or severe recurrent ischemia by about one-quarter
(16.3% vs. 12.7%; hazard ratio (HR), 0.76; 95% CI, 0.590.98;
NNT = 28), with a non-signicant increase in major bleeding
(1.8% vs. 0.9%; HR, 1.97; 95% CI, 0.804.84). Ximelagatran
was subsequently withdrawn, primarily because of concerns
about liver toxicity.
 2007 International Society on Thrombosis and Haemostasis

LMWH plus aspirin vs. aspirin The efcacy and safety

of extended-duration treatment (for up to 3 months) with
LMWH in aspirin-treated patients with NSTACS has been
evaluated in ve large randomized studies involving a
combined total of 12 099 patients [17]. Pooled data from all
the trials indicate that the addition of LMWH to aspirin
compared with aspirin alone did not reduce myocardial
infarction or death but increased major bleeding (2.2% vs.
0.9%; OR, 2.26; 95% CI, 1.63 to 3.14; NNH = 77) [17]. In
four of the ve trials the dose of LMWH was reduced after the
rst week of treatment and it remains to be demonstrated
whether higher dose of LMWH continued long term may of
benet.
Summary of combined anticoagulant and antiplatelet
therapy vs. antiplatelet therapy alone for long-term
management of ACS
Adding an anticoagulant, either
warfarin or ximelagatran, to aspirin reduces recurrent ischemic
but does not reduce death and increases major bleeding. The
increase in bleeding appears to be outweighed by the reduction
in recurrent MI but the potential for an increase in intracranial
bleeding with the combination of warfarin and aspirin is
concerning. A benet of continuing LMWH beyond the rst
week in aspirin-treated patients with NSTACS has not been
demonstrated but it is not clear whether the optimal dose of
LMWH was evaluated.
Since the completion of RCTs evaluating the efcacy and
safety of adding warfarin or LMWH to aspirin in patients
with ACS, the combination of aspirin and clopidogrel
compared with aspirin alone has been shown to reduce the
risk of recurrent ischemic events in large RCTs and has
been widely adopted as the standard of care [2,3,3538].
Indirect comparisons suggest that the magnitude of benet
of adding clopidogrel to aspirin [23,24] is not as great as the
magnitude of the benet of adding warfarin to aspirin [31],
but the increase in bleeding with adding warfarin to aspirin
is probably greater than the increase in bleeding with adding
clopidogrel to aspirin. Only a direct randomized comparison
between warfarin and clopidogrel in aspirin-treated
patients will establish which of these treatment strategies is
superior.
Clinical settings in which there is evidence that the
combination of anticoagulant and antiplatelet therapy is
more effective than anticoagulant therapy alone
The only evidence from randomized trials that adding
antiplatelet therapy to anticoagulant therapy is more effective
than anticoagulant therapy alone comes from trials in patients
with mechanical heart valves [39].
Mechanical heart valves

Aspirin plus warfarin vs. warfarin Four RCTs

involving a combined total of 869 patients have examined
the efcacy and safety of adding antiplatelet therapy to oral

258 J. W. Eikelboom & J. Hirsh

anticoagulation for the long-term management of mechanical

heart valves [40]. Two trials were conducted in the 1970s, one
was conducted in the early 1990s, and one in the late 1990s.
The largest study, by Turpie and colleagues, was published in
1993 and involved 370 patients with a mechanical aortic or
mitral valve or multiple mechanical valves who were
randomized to receive aspirin 100 mg once daily or placebo
in addition to warfarin (target INR 3.0 to 4.5) for a mean of
2.5 years. In the other studies, the dose of warfarin was
titrated to an INR of 2.5 to 3.5 or the thrombotest or
prothrombin time ratio was used to monitor anticoagulation.
Pooled data from the four studies indicate that adding
aspirin to warfarin compared with warfarin alone was
associated with a 67% reduction in thromboembolic
events (3.5% vs. 11.3%; RR, 0.33; 95% CI, 0.19 to 0.58;
NNT = 13) and a 58% increase in bleeding (13.1% vs.
8.1%; RR, 1.58; 95% CI, 1.02 to 2.44; NNH = 20). The
addition of aspirin to warfarin was also associated with a
reduction in all cause mortality (5.4% vs. 7.9%; RR0, 43;
95% CI, 0.23 to 1.83) [40].
In the study by Meschengieser and colleagues [41], 503
patients with a mechanical aortic or mitral valve replacement
or both were randomized to receive aspirin 100 mg once daily
plus warfarin (target INR 2.5 to 3.5) or warfarin alone (target
INR 3.5 to 4.5) for a median of 2 years in an open-label study.
The combination of aspirin and warfarin did not signicantly
reduce thromboembolic events or bleeding but reduced all
cause mortality by about one-half (3.5% vs. 8.6%; RR, 0.41;
95% CI, 0.23 to 0.81; NNT = 19).
Risk of intracranial bleeding

A pooled estimate restricted to trials in which aspirin was

compared with no aspirin in patients treated with the same
intensity of oral anticoagulation revealed a twofold excess of
intracranial bleeding with aspirin (RR, 2.6; 95% CI, 1.3 to 5.4)
[42]. An excess of bleeding when aspirin is added to oral
anticoagulants has also been reported in an observational study
[43]. Intracranial bleeding has been reported in as many as
1.5% of patients per year who are treated with the combination
of aspirin and warfarin [42]. The risk of intracranial bleeding is
increased with increasing age, increasing intensity of warfarin
treatment, poorly controlled blood pressure, and a prior
history of cerebrovascular disease [42].
Summary of combined anticoagulant and antiplatelet
therapy vs. anticoagulant therapy alone Adding aspirin to
oral anticoagulants reduces thromboembolic events in patients
with mechanical heart valves but increases the risk of bleeding.
For all other indications tested, there is no evidence that adding
aspirin to oral anticoagulants provides additional benet
(discussed further below). The decision to add aspirin to
warfarin in patients who have a clear indication for warfarin
treatment should thus be individualized by taking into account
the potential benets and risks, including the risk for
intracranial bleeding.

Clinical settings in which there is no convincing evidence

that anticoagulant plus antiplatelet therapy is more
effective than either antiplatelet therapy alone or
anticoagulant therapy alone
The combination of anticoagulant and antiplatelet therapy
compared with anticoagulant therapy alone has not been
adequately evaluated in patients with AF, and has not been
shown to be superior to antiplatelet therapy alone during the
acute phase of stroke or in patients with PAD.
Atrial fibrillation

The rationale for evaluating the combination of antiplatelet

therapy and oral anticoagulants in patients with AF has been
two-fold: to reduce the risk of bleeding in the elderly AF
population by using a lower intensity of warfarin in those who
are also treated with aspirin; and to enhance the efcacy of
antithrombotic therapy in AF patients considered to be at very
high risk of thrombotic complications or in AF patients with
concomitant coronary artery disease, PAD or diabetes.
Warfarin is substantially more effective than aspirin for
preventing stroke or systemic embolism in patients with AF
[10]. Consequently, trials evaluating the efcacy and safety of
the combination of antiplatelet plus anticoagulant therapy
have used warfarin rather than aspirin as the comparator.
Warfarin plus aspirin vs. warfarin Low-dose oral
anticoagulants plus aspirin has been compared with oral
anticoagulants alone in the setting of AF in three RCTs [7]. The
Stroke Prevention in Atrial Fibrillation (SPAF) III trial
compared adjusted-dose low-intensity warfarin, INR 1.2 to
1.5, plus aspirin 325 mg once-daily with warfarin, INR 2.0 to
3.0 [44], while the Copenhagen Atrial Fibrillation, Aspirin and
Anticoagulation (AFASAK) II study compared xed-dose
warfarin, 1.25 mg daily, plus aspirin 300 mg once daily, with
warfarin, INR 2.0 to 3.0 [45]. Neither of these studies
demonstrated a benet of anticoagulant plus antiplatelet
therapy.
The Spanish National Study for Primary Prevention of
Embolism in Nonrheumatic Atrial Fibrillation (NASPEAF)
trial compared the antiplatelet drug, triusal, 600 mg once
daily, plus oral anticoagulants titrated to an INR of 1.4 to 2.4
(high-risk patients) or titrated to an INR of 1.25 to 2.0 (low-risk
patients) vs. oral anticoagulants titrated to an INR of 2.0 to 3.0
in 1209 patients with non-valvular AF [46]. After a median
follow-up of 2.8 years, the combination of triusal and oral
anticoagulants compared with oral anticoagulants alone signicantly reduced the risk of thromboembolism or cardiovascular death in both high-risk patients (2.4% vs. 4.8%; HR, 0.51;
95% CI, 0.27 to 0.96) and low-risk patients (0.9% vs. 2.7%;
HR, 0.33; 95% CI, 0.12 to 0.91) with no difference in bleeding
[46].
Only one trial, the French Fluindione-Aspirin Combination
in High Risk patients with AF (FFAACS) study, has
compared the combination of aspirin and oral anticoagulants,
 2007 International Society on Thrombosis and Haemostasis

Combined antiplatelet and anticoagulant therapy 259

titrated to an INR of 2.0 to 3.0, with oral anticoagulants alone

titrated to the same INR intensity [47]. The trial was stopped
early after only 157 patients had been recruited because of an
increase in bleeding among patients treated with the combination of aspirin and oral anticoagulants compared with oral
anticoagulants alone.
Non-cardioembolic stroke

Antiplatelet therapy is effective for preventing recurrent

ischemic events and death during the initial phase and the
long term in patients with acute non-cardioembolic ischemic
stroke [1,48,49]. UFH, LMWH and heparinoids have not been
shown to be benecial for the initial management of acute
ischemic stroke [48,49] and oral anticoagulants are no more
effective than aspirin but cause more bleeding [4,14,15]. Data
on the effectiveness and safety of the combination of anticoagulants and antiplatelet therapy are very limited in patients
with non-cardioembolic ischemic stroke.
UFH plus aspirin vs. aspirin The only large RCT that
has evaluated the combination of anticoagulant and
antiplatelet therapy in ischemic stroke was the International
Stroke Trial (IST) [50]. The IST randomized 19,435 patients
with acute ischemic stroke to receive aspirin 300 mg or no
aspirin, and to receive s.c. UFH 12 500 IU twice daily, s.c.
UFH 5000 IU twice daily, or no heparin, using an open-label
3 2 factorial design. UFH was associated with a modest
benet, which was counterbalanced by an excess of
hemorrhagic stroke. Data were not reported separately for
the combined UFH and aspirin group but there was no
evidence of an interaction between UFH and aspirin,
suggesting no incremental benet of adding UFH to
aspirin. Similar results were reported in the subgroup of
patients with AF and presumed cardioembolic stroke [51].
Thus, the IST does not provide any evidence to support the
use of UFH for the initial management of acute ischemic
stroke in patients with or without AF who are treated with
aspirin.
Peripheral arterial disease

Antiplatelet therapy is effective for the prevention of ischemic

events and death in patients with PAD [1,5]. The efcacy of
oral anticoagulants appears to be similar to the efcacy of
antiplatelet therapy but oral anticoagulants cause more bleeding [5,52].
Warfarin plus antiplatelet therapy vs. antiplatelet
therapy The combination of oral anticoagulants and
antiplatelet therapy has been compared with antiplatelet
therapy alone in three trials of patients with PAD [52].
Pooled data from the rst two trials involving 887 patients
suggested that the combination of warfarin and aspirin did not
signicantly reduce graft failure compared with aspirin alone
(OR, 0.84; 95% CI, 0.621.12) but signicantly increased all
 2007 International Society on Thrombosis and Haemostasis

cause mortality (OR, 1.57; 95% CI, 1.162.12) and bleeding

(OR, 2.13; 95% CI, 1.273.57) [52]. The third trial,
the Warfarin and Vascular Evaluation (WAVE) Study,
randomized 2161 patients with PAD to receive warfarin
titrated to an INR of 2.0 to 3.0 plus antiplatelet therapy
(aspirin or clopidogrel) or antiplatelet therapy alone, continued
for a mean of almost 3 years. The primary outcome, a
composite of MI, stroke or death was not signicantly different
in the two groups (12.2% vs. 13.3%; RR, 0.91; 95% CI, 0.73
1.16) but life-threatening bleeding was signicantly increased
among patients treated with the combination of warfarin and
antiplatelet therapy (4.0% vs. 1.2%; RR, 3.41; 95% CI, 1.84 to
6.35) (presented at the European Society of Cardiology meeting
2006).
Other indications

The combination of antiplatelet therapy and oral anticoagulants was not shown to produce an incremental benet over
oral anticoagulants alone or aspirin alone for primary prevention of atherothrombosis in high-risk men (oral anticoagulants
in this study were titrated to a target INR < 1.5) [53], or for
the prevention of recurrent ischemic events or death after MI
[54,55]. In the latter studies, oral anticoagulants were titrated to
an INR of 2.0 to 2.5 in the oral anticoagulants plus antiplatelet
group and were titrated to an INR of 2.8 to 4.2 [54] or 3.0 to 4.0
[55] in the oral anticoagulants alone group.
Clinical settings in which the combination of
anticoagulants and antiplatelet therapy is commonly
used despite the lack of evidence (no definitive trials
performed)
Patients with separate indications for anticoagulant and
antiplatelet therapy

Despite lack of evidence of effectiveness and safety from RCTs,

the combination of anticoagulant and antiplatelet therapy is
commonly used in patients who have an indication for
anticoagulant therapy (e.g. AF) as well as an indication for
antiplatelet therapy (e.g. cerebrovascular or peripheral arterial
disease) [43,56,57]. The practise is based on the assumption that
net benet of combined treatment outweighs the increase in
risk of bleeding.
Percutaneous coronary intervention

There is a substantial body of evidence from RCTs that

antiplatelet therapy with aspirin, clopidogrel and a glycoprotein IIb/IIIa inhibitor (the latter in selected high-risk patients),
is effective in patients undergoing PCI with stent insertion
[37,38]. The use of UFH or a suitable alternative (e.g.
bivalirudin) during PCI is based on the belief that anticoagulant therapy is necessary during the procedure, but has never
been tested in RCTs. UFH is recommended during PCI by
treatment guidelines [37,38].

260 J. W. Eikelboom & J. Hirsh

Recurrent venous thromboembolism despite adequate
anticoagulant therapy

warfarin in patients with coronary stents [68,69]. Whether the

benets of triple therapy outweigh the risks in patients with AF
and coronary stents requires evaluation in randomized trials.

Patients who experience recurrent VTE during warfarin

treatment are sometimes treated by adding aspirin or another
antiplatelet drug to oral anticoagulant therapy [58]. There are
no data from RCTs to support this practise.

New antithrombotic drugs

Areas requiring further research

Many questions remain about the effectiveness and safety of
combining anticoagulants with single or dual antiplatelet
therapy in different clinical settings.
Antiplatelet therapy plus anticoagulation vs. anticoagulation
alone

Antiplatelet therapy is often combined with oral anticoagulants

in patients with an indication for warfarin therapy (e.g. AF) as
well as an indication for antiplatelet therapy (e.g. CAD). The
appropriateness of such an approach is unresolved. Anticoagulation appears to be as effective as antiplatelet therapy for
long-term management of ACS and stroke, and possibly PAD,
but increases the risk of bleeding. Therefore, in such patients
who develop AF, switching from antiplatelet therapy to
anticoagulants might be all that is required. Combining
anticoagulant and antiplatelet therapy further increases bleeding risk, but has only been proven to provide additional benet
over anticoagulants alone in patients with prosthetic heart
valves.
In two recent randomized anticoagulant trials, about onequarter of patients with AF were also treated with aspirin [39],
often for unproven indications. Reducing the risk of bleeding
by discontinuing unnecessary or unproven antiplatelet therapy
may also reduce the risk of thrombotic outcomes because
bleeding appears to be an independent predictor of ischemic
events and death [59,60].
Anticoagulants plus dual antiplatelet therapy

Clopidogrel is being used in combination with aspirin increasingly across the spectrum of patients with arterial thrombosis.
Clopidogrel is associated with a similar risk of bleeding as
aspirin [16] but the combination of clopidogrel and aspirin
causes more bleeding than monotherapy with either drug [61].
It seems reasonable to assume that the bleeding risk associated
with combining anticoagulants with clopidogrel will be similar
to the bleeding risk associated with combining anticoagulants
with aspirin, and that the risk of bleeding would be increased
by adding anticoagulants to the combination of clopidogrel
and aspirin [6266]. There is a reasonable rationale to use
triple antithrombotic therapy with oral anticoagulant, clopidogrel and aspirin in patients with AF who have a coronary
stent. The combination of aspirin and clopidogrel is not as
effective as warfarin in patients with AF [67], whereas the
combination of aspirin and clopidogrel is more effective than

A large number of new oral direct thrombin inhibitors and oral

factor Xa inhibitors are being directly compared with existing
anticoagulants in RCTs for the prevention and treatment of
arterial and venous thrombosis. Future studies will need to
evaluate whether the new anticoagulants can replace the
combination of anticoagulants and antiplatelet drugs, or
whether adding an antiplatelet drug to a new anticoagulant
will be more effective than the new anticoagulant alone.
Implications for clinical practise
The combination of anticoagulant and antiplatelet therapy is
more effective than antiplatelet therapy alone for the acute and
long-term management of ACS, and is more effective than
anticoagulant therapy alone in patients with mechanical heart
valves. Bleeding is increased (compared with monotherapy)
when anticoagulants are combined with antiplatelet therapy
and there is no evidence that the combination is more effective
than either treatment alone in other clinical settings. Any
decision to use the combination of antiplatelet therapy and
anticoagulants in these other clinical settings should be
individualized and should take into account the potential risks
as well as potential benets.
Disclosure of conflict of interests
The authors state that they have no conict of interests.
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