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1): 255–263
INVITED REVIEW
To cite this article: Eikelboom JW, Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost 2007;
5 (Suppl. 1): 255–63.
events in high-risk ACS patients, with an acceptable increase in follow-up of about 10 days) significantly reduced the risk of
bleeding [23–26]. The combination of anticoagulant and death by 6% (95% CI, 0% to 10%; 2P = 0.03), representing
antiplatelet therapy is more effective than monotherapy for five fewer deaths per 1000 (absolute event rates, 8.6% vs. 9.1%;
the initial and long-term management of ACS and for the long- NNT = 200) [28]. Reinfarction was reduced by 10% (95% CI,
term management of patients with mechanical heart valves. 0% to 20%; 2P = 0.04), representing three fewer reinfarctions
However, the efficacy and safety of the combination of per 1000 (3.0% vs. 3.3%; NNT = 333). Major bleeds were
anticoagulant and antiplatelet therapy has not been adequately increased by about 50% (2P < 0.0001), representing an excess
compared with anticoagulant therapy (at the same intensity) of three major bleeds per 1000 [1.0% vs. 0.7%, number needed
alone for the long-term treatment of ACS, stroke or PAD. to harm (NNH) = 333] [28].
Many older patients with cardiovascular disease have separate
indications for anticoagulant treatment (e.g. AF) and for LMWH plus aspirin vs. aspirin The best evidence for the
combined antiplatelet treatment (e.g. postcoronary stent) but efficacy of adding LMWH to aspirin in NSTACS comes from
the efficacy and safety of anticoagulant and dual antiplatelet the FRISC-I study [29], which compared 6 days of treatment
therapy have not been evaluated in randomized trials. with the LMWH, dalteparin, given in a dose of 120 IU twice
This paper reviews the evidence for the effectiveness and daily by subcutaneous (s.c.) injection, with placebo in 1506
safety of combining anticoagulant and antiplatelet drugs to aspirin-treated patients. Dalteparin significantly reduced the
prevent and treat thrombosis. To provide the most valid and risk of death or MI at about 1 week (1.8% vs. 4.8%; OR, 0.37;
reliable comparisons we limit the analysis to the results of 95% CI, 0.20 to 0.68; NNT = 33), with a small non-significant
randomized controlled trials (RCTs) or meta-analyses of excess of major bleeding (0.8% vs. 0.5%; OR, 1.53; 95% CI,
RCTs. 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
Clinical settings in which there is evidence that the
adjusted dose of 3436 to 6871 IU twice daily, with placebo, in
combination of anticoagulant and antiplatelet therapy
15 570 aspirin-treated patients with STEMI. Fibrinolytic
is more effective than antiplatelet therapy alone
therapy with streptokinase or urokinase was given in three-
Numerous RCTs have evaluated the effectiveness and safety of quarters of patients and clopidogrel or ticlopidine were given in
the combination of anticoagulant and antiplatelet therapy one-half of patients. At 1 week, the addition of reviparin to
compared with antiplatelet therapy alone for the initial and antiplatelet treatment reduced death by 11% (8.0% vs. 8.9%;
long-term management of patients with ACS. Most of the OR, 0.89; 95% CI, 0.80 to 0.99; NNT = 111) and reduced MI
studies were conducted prior to the routine use of combined by about one-quarter (1.6% vs. 2.1%; OR, 0.75; 95% CI, 0.60
antiplatelet therapy with aspirin and clopidogrel and their to 0.95; NNT = 200), at the cost of a more than twofold
results therefore may not be generalizable to current clinical increase in major bleeding (0.9% vs. 0.4%; OR, 2.49; 95% CI,
practise. 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].
Initial management of ACS
Fondaparinux plus aspirin vs. aspirin The OASIS-6
UFH plus aspirin vs. aspirin In patients with non-ST- study randomized 12 092 aspirin-treated patients with STEMI
elevation acute coronary syndrome (NSTACS), a meta- to receive up to 8 days of treatment with s.c. fondaparinux
analysis of six small randomized controlled trials (RCTs) 2.5 mg once daily or standard care with either placebo among
involving 1353 patients treated with intravenous (i.v.) UFH patients in whom UFH was felt not to be indicated (stratum 1)
plus aspirin or placebo/no UFH plus aspirin for up to 7 days or with intravenous UFH for 48 h among patients in whom
demonstrated a one-third risk reduction in the composite anticoagulation was felt to be indicated (stratum 2) [22]. The
outcome, death or myocardial infarction (MI), at the end of results in stratum 1 demonstrated that adding fondaparinux to
treatment [7.9% vs. 10.4%; odds ratio (OR), 0.67; 95% aspirin reduced the risk of death or MI at 9 days by about one-
confidence interval (CI), 0.45–0.99; number needed to treat quarter (8.5% vs. 11.1%; relative risk (RR), 0.76; 95% CI,
(NNT) = 40], with a non-significant increase in major 0.64–0.89; NNT = 38) with a non-significant reduction in
bleeding (1.4% vs. 0.5%; OR, 1.88; 95% CI, 0.60-5.88) [17]. major bleeding (1.8% vs. 2.1%; RR, 0.83; 95% CI, 0.84 to
In patients with ST elevation myocardial infarction (STEMI), 1.06). A consistent benefit of fondaparinux was seen in the 16%
a meta-analysis of four small RCT trials involving 1231 patients of patients who were treated with clopidogrel or ticlopidine as
treated fibrinolytic therapy and receiving either i.v. UFH plus well as aspirin [22], suggesting an incremental benefit of
aspirin or placebo/no UFH plus aspirin for up to 5 days did not anticoagulants when added to ÔdualÕ antiplatelet therapy.
demonstrate a difference in death, MI or major bleeding [27].
However, another meta-analysis of all trials of short-term UFH Summary of combination of anticoagulant and antiplatelet
(subcutaneous or i.v.) in more than 60 000 patients with STEMI therapy for the initial management of ACS There is a
who were routinely treated with aspirin and fibrinolysis revealed consistent body of data from randomized trials involving more
that short-term UFH compared with placebo/no UFH (average than 90 000 patients with ACS that adding UFH, LMWH or
fondaparinux to aspirin is more effective than aspirin alone for LMWH plus aspirin vs. aspirin The efficacy and safety
preventing recurrent ischemic events or death during the first of extended-duration treatment (for up to 3 months) with
week. Subgroup data suggest that the benefits of anticoagulant LMWH in aspirin-treated patients with NSTACS has been
therapy are also evident when LMWH or fondaparinux is evaluated in five large randomized studies involving a
added to the combination of aspirin and clopidogrel. In trials in combined total of 12 099 patients [17]. Pooled data from all
which UFH or LMWH were added to aspirin, a reduction in the trials indicate that the addition of LMWH to aspirin
ischemic events or death was achieved at the cost of an increase compared with aspirin alone did not reduce myocardial
in bleeding. When fondaparinux was added to aspirin with or infarction or death but increased major bleeding (2.2% vs.
without clopidogrel, a reduction in ischemic events or death 0.9%; OR, 2.26; 95% CI, 1.63 to 3.14; NNH = 77) [17]. In
was achieved without an increase in bleeding. The absence of four of the five trials the dose of LMWH was reduced after the
an increase in bleeding when fondaparinux was added to first week of treatment and it remains to be demonstrated
antiplatelet therapy is unexplained. whether higher dose of LMWH continued long term may of
benefit.
Long-term management of ACS
Summary of combined anticoagulant and antiplatelet
Warfarin plus aspirin vs. aspirin At least 14 randomized therapy vs. antiplatelet therapy alone for long-term
trials have examined the efficacy and safety of adding warfarin management of ACS Adding an anticoagulant, either
to aspirin in patients with NSTACS or STEMI [31]. The warfarin or ximelagatran, to aspirin reduces recurrent ischemic
intensity of the International Normalized Ratio (INR) was not but does not reduce death and increases major bleeding. The
uniform among all of the studies. Most trials enrolled patients increase in bleeding appears to be outweighed by the reduction
within 1 week of the acute event but some trials enrolled patients in recurrent MI but the potential for an increase in intracranial
up to 8 weeks after the acute event. Patients were followed for up bleeding with the combination of warfarin and aspirin is
to 5 years. Pooled data from all the trials indicated no benefit of concerning. A benefit of continuing LMWH beyond the first
adding warfarin to aspirin, but the results were statistically week in aspirin-treated patients with NSTACS has not been
heterogeneous and the lack of effect of adding warfarin to demonstrated but it is not clear whether the optimal dose of
aspirin appeared to be related to the use of low intensity warfarin LMWH was evaluated.
[31]. Thus, in the 10 trials (n = 12 488) that either titrated Since the completion of RCTs evaluating the efficacy and
warfarin to an INR of 2.0 to 3.0 or achieved a mean INR of safety of adding warfarin or LMWH to aspirin in patients
between 2.0 and 3.0, the addition of warfarin to aspirin reduced with ACS, the combination of aspirin and clopidogrel
the risk of death, MI or thromboembolic stroke by about one- compared with aspirin alone has been shown to reduce the
quarter (9.4% vs. 12.4%; OR, 0.73; 95% CI, 0.63 to 0.84; risk of recurrent ischemic events in large RCTs and has
NNT = 33) [31]. The benefits of adding warfarin to aspirin been widely adopted as the standard of care [2,3,35–38].
were achieved at a cost of an increase in major bleeding (2.6% vs. Indirect comparisons suggest that the magnitude of benefit
1.1%; OR, 2.32; 95% CI, 1.62 to 3.29; NNH = 67) and a non- of adding clopidogrel to aspirin [23,24] is not as great as the
significant increase in intracranial bleeding (2.6% vs. 0.5%; OR, magnitude of the benefit of adding warfarin to aspirin [31],
3.02; 95% CI, 0.61 to 15.02), with no difference in deaths [31]. An but the increase in bleeding with adding warfarin to aspirin
independently conducted meta-analysis of the same 10 studies is probably greater than the increase in bleeding with adding
yielded similar results and demonstrated a consistent benefit of clopidogrel to aspirin. Only a direct randomized comparison
adding warfarin to aspirin in NSTACS and STEMI trials [32]. between warfarin and clopidogrel in aspirin-treated
patients will establish which of these treatment strategies is
Ximelagatran plus aspirin vs. aspirin Ximelagatran is superior.
the first orally active DTI and has been extensively evaluated as
a replacement for warfarin for the prevention and treatment of
Clinical settings in which there is evidence that the
arterial and venous thrombosis [33].
combination of anticoagulant and antiplatelet therapy is
The ESTEEM trial randomized 1883 patients within 14 days
more effective than anticoagulant therapy alone
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 The only evidence from randomized trials that adding
twice daily, or placebo, respectively for 6 months [34]. All antiplatelet therapy to anticoagulant therapy is more effective
patients were treated with aspirin. The addition of ximelaga- than anticoagulant therapy alone comes from trials in patients
tran to aspirin compared with aspirin alone reduced the risk of with mechanical heart valves [39].
death, MI or severe recurrent ischemia by about one-quarter
(16.3% vs. 12.7%; hazard ratio (HR), 0.76; 95% CI, 0.59–0.98;
Mechanical heart valves
NNT = 28), with a non-significant increase in major bleeding
(1.8% vs. 0.9%; HR, 1.97; 95% CI, 0.80–4.84). Ximelagatran Aspirin plus warfarin vs. warfarin Four RCTs
was subsequently withdrawn, primarily because of concerns involving a combined total of 869 patients have examined
about liver toxicity. the efficacy and safety of adding antiplatelet therapy to oral
titrated to an INR of 2.0 to 3.0, with oral anticoagulants alone cause mortality (OR, 1.57; 95% CI, 1.16–2.12) and bleeding
titrated to the same INR intensity [47]. The trial was stopped (OR, 2.13; 95% CI, 1.27–3.57) [52]. The third trial,
early after only 157 patients had been recruited because of an the Warfarin and Vascular Evaluation (WAVE) Study,
increase in bleeding among patients treated with the combina- randomized 2161 patients with PAD to receive warfarin
tion of aspirin and oral anticoagulants compared with oral titrated to an INR of 2.0 to 3.0 plus antiplatelet therapy
anticoagulants alone. (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 significantly different
Non-cardioembolic stroke
in the two groups (12.2% vs. 13.3%; RR, 0.91; 95% CI, 0.73–
Antiplatelet therapy is effective for preventing recurrent 1.16) but life-threatening bleeding was significantly increased
ischemic events and death during the initial phase and the among patients treated with the combination of warfarin and
long term in patients with acute non-cardioembolic ischemic antiplatelet therapy (4.0% vs. 1.2%; RR, 3.41; 95% CI, 1.84 to
stroke [1,48,49]. UFH, LMWH and heparinoids have not been 6.35) (presented at the European Society of Cardiology meeting
shown to be beneficial for the initial management of acute 2006).
ischemic stroke [48,49] and oral anticoagulants are no more
effective than aspirin but cause more bleeding [4,14,15]. Data
Other indications
on the effectiveness and safety of the combination of antico-
agulants and antiplatelet therapy are very limited in patients The combination of antiplatelet therapy and oral anticoagu-
with non-cardioembolic ischemic stroke. lants was not shown to produce an incremental benefit over
oral anticoagulants alone or aspirin alone for primary preven-
UFH plus aspirin vs. aspirin The only large RCT that tion of atherothrombosis in high-risk men (oral anticoagulants
has evaluated the combination of anticoagulant and in this study were titrated to a target INR < 1.5) [53], or for
antiplatelet therapy in ischemic stroke was the International the prevention of recurrent ischemic events or death after MI
Stroke Trial (IST) [50]. The IST randomized 19,435 patients [54,55]. In the latter studies, oral anticoagulants were titrated to
with acute ischemic stroke to receive aspirin 300 mg or no an INR of 2.0 to 2.5 in the oral anticoagulants plus antiplatelet
aspirin, and to receive s.c. UFH 12 500 IU twice daily, s.c. group and were titrated to an INR of 2.8 to 4.2 [54] or 3.0 to 4.0
UFH 5000 IU twice daily, or no heparin, using an open-label [55] in the oral anticoagulants alone group.
3 · 2 factorial design. UFH was associated with a modest
benefit, which was counterbalanced by an excess of
Clinical settings in which the combination of
hemorrhagic stroke. Data were not reported separately for
anticoagulants and antiplatelet therapy is commonly
the combined UFH and aspirin group but there was no
used despite the lack of evidence (no definitive trials
evidence of an interaction between UFH and aspirin,
performed)
suggesting no incremental benefit of adding UFH to
aspirin. Similar results were reported in the subgroup of
Patients with separate indications for anticoagulant and
patients with AF and presumed cardioembolic stroke [51].
antiplatelet therapy
Thus, the IST does not provide any evidence to support the
use of UFH for the initial management of acute ischemic Despite lack of evidence of effectiveness and safety from RCTs,
stroke in patients with or without AF who are treated with the combination of anticoagulant and antiplatelet therapy is
aspirin. 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
Peripheral arterial disease
disease) [43,56,57]. The practise is based on the assumption that
Antiplatelet therapy is effective for the prevention of ischemic net benefit of combined treatment outweighs the increase in
events and death in patients with PAD [1,5]. The efficacy of risk of bleeding.
oral anticoagulants appears to be similar to the efficacy of
antiplatelet therapy but oral anticoagulants cause more bleed-
Percutaneous coronary intervention
ing [5,52].
There is a substantial body of evidence from RCTs that
Warfarin plus antiplatelet therapy vs. antiplatelet antiplatelet therapy with aspirin, clopidogrel and a glycopro-
therapy The combination of oral anticoagulants and tein IIb/IIIa inhibitor (the latter in selected high-risk patients),
antiplatelet therapy has been compared with antiplatelet is effective in patients undergoing PCI with stent insertion
therapy alone in three trials of patients with PAD [52]. [37,38]. The use of UFH or a suitable alternative (e.g.
Pooled data from the first two trials involving 887 patients bivalirudin) during PCI is based on the belief that anticoagu-
suggested that the combination of warfarin and aspirin did not lant therapy is necessary during the procedure, but has never
significantly reduce graft failure compared with aspirin alone been tested in RCTs. UFH is recommended during PCI by
(OR, 0.84; 95% CI, 0.62–1.12) but significantly increased all treatment guidelines [37,38].
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