Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Dual antiplatelet therapy in the drug-eluting stent era
Lars Wallentin*
Clinical Research Centre, Uppsala, Sweden
* Corresponding author. Tel: +46 18 506638. E-mail address: lars.wallentin{at}ucr.uu.se
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Abstract
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Data continue to accumulate showing that implantation of coronary
stents, particularly drug-eluting stents (DES), is associated
with persistent, long-term risk of thrombotic events. Dual antiplatelet
therapy with aspirin and clopidogrel has reduced the risk of
early and late thrombosis. However, early risk persists due
to implantation, stent-related factors, and suboptimal response
to clopidogrel, whereas late risk persists due not only to these
factors, but to the limited duration of dual antiplatelet therapy
as well. Third-generation oral P2Y
12 antagonists that exhibit
faster onset of action and greater and more consistent inhibition
of platelet aggregation than clopidogrel include the new thienopyridine
prasugrel and the reversible P2Y
12 inhibitor AZD6140. Prospective,
randomized, long-term trials are warranted to investigate the
benefits and risks of more effective P2Y
12 antagonists as part
of dual antiplatelet therapy after both bare-metal stent and
DES implantation.
Key Words: AZD6140 • Clopidogrel • Drug-eluting stent • PCI • P2Y12 antagonists
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Introduction
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The use of coronary bare-metal stents (BMS) as an adjunct to
plain balloon angioplasty substantially reduces the risks of
total occlusion and restenosis after percutaneous coronary intervention
(PCI). The introduction of drug-eluting stents (DES) in 2003
resulted in a further reduction in risk of restenosis and frequency
of target vessel revascularization. However, PCI with stenting
is associated with platelet activation and risk of thrombosis.
An elevated risk of thrombosis is present both shortly after
PCI and during the period when stent struts are exposed to the
circulation, prior to re-endothelialization. With use of BMS,
re-endothelialization occurs at
1 month after stent implantation.
Re-endothelialization, however, contributes to in-stent restenosis.
The drugs in DES—e.g. sirolimus and paclitaxel—reduce
the risk of restenosis by inhibiting proliferation of endothelial
cells; this inhibition of normal healing is associated with
vessel-wall remodelling and sustained exposure of stent struts
to the bloodstream for months or years after implantation. The
use of dual antiplatelet therapy of aspirin, which inhibits
thromboxane production, and a thienopyridine (e.g. clopidogrel),
which inhibits platelet P2Y
12 receptors, results in markedly
reduced risk of thrombotic events associated with stenting.
However, there is still need for further improvement in antiplatelet
therapy in this setting. Stent implantation is associated with
persistent long-term risk of thrombosis, with the late risk
being greater with DES than with BMS. Accordingly, there may
be a need for more prolonged dual antiplatelet therapy than
is currently available, particularly with use of DES. Poor response
to clopidogrel contributes to both early and late stent thrombosis,
and there is thus a need for more effective P2Y
12 inhibition
as part of dual antiplatelet therapy.
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Stenting and risk of thrombosis
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As noted, risk of thrombosis with stenting has been markedly
reduced by dual antiplatelet therapy with aspirin and thienopyridines
when compared with therapy using aspirin or anticoagulants without
thienopyridines.
1 For example, data on 6186 patients receiving
BMS from the Harvard Clinical Research Institute Stent-Database
show that risk of thrombosis was markedly reduced by treatment
with the thienopyridine ticlopidine compared with no ticlopidine
both during the first several days following PCI and over the
course of a month of follow-up. The CREDO trial of 2116 patients
with planned PCI demonstrated the clinical benefit of aspirin
plus clopidogrel treatment for 1 year following PCI compared
with PCI alone: the risk of the composite end point of death,
myocardial infarction (MI), or stroke was reduced by 27% in
patients receiving a clopidogrel 300 mg loading dose followed
by 75 mg/day for 1 year compared with those pretreated with
placebo and receiving clopidogrel 75 mg/day maintenance immediately
following PCI through Day 28 (
Figure 1).
2
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Figure 1 Occurrence of composite end point of death/MI/stroke in patients with planned PCI receiving clopidogrel vs. placebo in the CREDO trial. The clopidogrel group received a 300 mg clopidogrel loading dose followed by 75 mg/day. The placebo group received clopidogrel 75 mg/day after PCI through Day 28. All patients received aspirin and other standard therapies. RRR, relative risk reduction. Reproduced with permission from Steinhubl et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288:2411–2420.2
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No stenting trial has directly examined the use of dual antiplatelet
therapy for >1 year. Some indication of a potential benefit
of longer-term antiplatelet therapy comes from the CHARISMA
trial in a broad population of patients at elevated risk for
atherothrombotic events.
3 Although clopidogrel plus aspirin
did not significantly reduce risk for the composite end point
of cardiovascular death/MI/stroke compared with placebo plus
aspirin over a median of 28 months in the entire patient population,
there was a marginally significant 12% reduction in risk with
clopidogrel in the 12 153 patients who entered the trial on
the basis of documented cardiovascular disease [6.9 vs. 7.9%;
relative risk (RR), 0.88; 95% confidence interval (CI), 0.77–0.998;
P = 0.046]. Risk was numerically increased (6.6 vs. 5.5%,
P = 0.20) with clopidogrel among the 3284 patients entering the
trial on the basis of multiple atherothrombotic risk factors
without documented cardiovascular disease. Risk of severe bleeding
was numerically greater (1.7 vs. 1.3%,
P = 0.09) and risk of
moderate bleeding significantly greater (2.1 vs. 1.3%,
P <
0.001) for clopidogrel vs. placebo.
Numerous data from patient registries and cohort studies document an increased risk of thrombosis or thrombotic events with inadequate duration of antiplatelet therapy in patients receiving stents. For example, data from the PREMIER registry showed that among 500 MI patients receiving DES and discharged on thienopyridine therapy, mortality at 12 months was 7.5% among the 68 who discontinued therapy within 30 days of discharge vs. 0.7% among those who continued thienopyridine treatment [adjusted hazard ratio (HR), 9.0; 95% CI, 1.3–60.6; P < 0.0001].4 Patients discontinuing thienopyridine treatment also had a numerically greater risk of cardiac re-hospitalization (23 vs. 14%; adjusted HR, 1.5; 95% CI, 0.78–3.0; P = 0.08). In a prospective observational cohort study in 2229 consecutive patients receiving DES, patients were to have continued aspirin indefinitely together with ticlopidine or clopidogrel for at least 3 months after sirolimus-eluting stent implantation and 6 months after paclitaxel-eluting stent implantation.5 Among the 29 patients (1.3%) with stent thrombosis at 9 months, premature antiplatelet therapy discontinuation was associated with the greatest HRs for thrombosis among categorical variables on univariate analysis (HR, 152; 95% CI 52–442; P < 0.001) and among independent predictors of stent thrombosis (HR, 89.78; 95% CI, 29.9–269.6; P < 0.001); other independent predictors of thrombosis were renal failure (HR, 6.49; P < 0.001), bifurcation lesion (HR, 6.42; P < 0.001), diabetes (HR, 3.71; P = 0.001), and a 10% decrease in left ventricular ejection fraction (HR, 1.09; P < 0.001).
Data from a large two-institution (Bern, Rotterdam) cohort study including 8146 patients receiving DES showed that angiography-documented late stent thrombosis (>30 days after PCI) occurred at a constant rate of 0.6% per year for up to 3 years after implantation (Figure 2).6 Depending on the institution, patients were to have received clopidogrel for at least 3 or 6 months (Rotterdam, depending on type of DES) or for at least 12 months irrespective of DES type (Bern) in addition to aspirin. Although absence of clopidogrel was not a significant predictor of overall or late stent thrombosis in the Rotterdam cohort (not examined in the Bern cohort), it was noted that among patients with late stent thrombosis, 31 (51%) received only one antiplatelet drug and 16 (26%) were not on antiplatelet therapy; of 31 patients with late thrombosis who were receiving only aspirin, 30 experienced thrombosis after the prescription for clopidogrel had expired.
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Figure 2 Cumulative incidence of DES thrombosis among 8146 patients in the Bern/Rotterdam cohorts study. ST, stent thrombosis. Reprinted from The Lancet, 369, Daemen J, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study, 667–678, 2007, with permission from Elsevier.6
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A more specific analysis of the impact of the presence or absence
of clopidogrel on atherothrombotic risk is provided by an observational
study at the Duke Heart Center involving 4666 consecutive patients
receiving BMS (
n = 3165) or DES (
n = 1501).
7 Patients were followed
up at 6, 12, and 24 months for death, non-fatal MI, or the composite
of death/MI. Among patients with DES who were event-free at
6 months, clopidogrel use vs. non-use was significantly associated
with reduced rates of death (2.0 vs. 5.3%,
P = 0.03) and death/MI
(3.1 vs. 7.2%,
P = 0.02) at 24 months (
Figure 3). Similarly,
among patients with DES who were event-free at 12 months, clopidogrel
use was associated with reduced rates of death (0 vs. 3.5%,
P = 0.004) and death/MI (0 vs. 4.5%,
P < 0.001) at 24 months.
Among patients with BMS who were event-free at 6 months, use
of clopidogrel was not associated with significantly reduced
rates of death (3.7 vs. 4.5%) or death/MI (5.5 vs. 6.0%) at
24 months; similarly, among those event-free at 12 months, clopidogrel
use was not associated with significantly reduced rates of death
(3.3 vs. 2.7%) or death/MI (4.7 vs. 3.6%) at 24 months. These
findings strongly suggest that prolonged antiplatelet therapy
may be beneficial with DES.
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Figure 3 Cumulative rates of composite death/MI among 3165 patients with DES and 1501 with BMS in the Duke Heart Center observational study according to whether patients were (+C) or were not (–C) receiving clopidogrel at 6, 12, and 24 months. Inset shows difference between groups in adjusted cumulative rates. Reproduced with permission from Eisenstein EL, et al. Clopidogrel use and long-term clinical outcome after durg-eluting stent implanatation. JAMA 2007;297:159–168.7
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The increased risk of late thrombosis with DES is supported
by other data. In a pooled analysis of double-blind trials,
4-year rates of stent thrombosis were numerically increased
with sirolimus-eluting stents vs. BMS (1.2 vs. 0.6%) among 1748
randomized patients and with paclitaxel-eluting stents vs. BMS
(1.3 vs. 0.9%) among 3513 randomized patients.
8 However, beyond
1 year, there were five episodes of stent thrombosis in patients
with sirolimus-eluting stents vs. none in those with BMS (0.6
vs. 0%,
P = 0.025) and nine episodes in patients with paclitaxel-eluting
stents vs. two in patients with BMS (0.7 vs. 0.2%,
P = 0.028).
Both DES stent types significantly reduced target vessel revascularization
compared with BMS. There were no differences between DES and
BMS with regard to death or MI. Analysis of outcomes among 6033
patients receiving DES and 13 738 receiving BMS in the Swedish
Coronary Angiography and Angioplasty Registry showed no difference
between groups with regard to the composite of death/MI over
3 years of follow-up.
9 However, at 6 months, there was a trend
towards a reduced adjusted event rate (reduction of 13.4 events/1000
patients) in patients with DES, whereas after 6 months the rate
in patients with DES was significantly higher, showing an increase
of 12.7 events/1000 patients per year (adjusted RR, 1.20; 95%
CI, 1.05–1.37) (
Figure 4). Furthermore, at 3 years, patients
with DES had a significantly greater risk for mortality (adjusted
RR, 1.18; 95% CI, 1.04–1.35), and a greater risk of mortality
between 6 months and 3 years (adjusted RR, 1.32; 95% CI, 1.11–1.57).
No data on long-term use of clopidogrel was available in the
analysis, but it was known that most patients were prescribed
dual antiplatelet treatment for 6 months after DES and 1–3
months after BMS implantation. The authors conjectured that
the early reduction in events in the DES group may have been
related to improved clopidogrel coverage during the first 6
months compared with the BMS group, whereas the late increase
in risk with DES may have indicated a prolonged need for dual
therapy beyond 6 months.
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Figure 4 Adjusted cumulative event rates for composite of death/MI (A), death (B), and MI (C) among 6033 patients receiving DES and 13 738 receiving BMS in the Swedish Coronary Angiography and Angioplasty Registry during first 6 months after implantation and from 6 months through 3 years. Risk ratios (RR) (with 95% CI) are for DES vs. MS. Reproduced with permission from Lagerqvist B, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009–1019. Copyright © 2007 Massachusetts Medical Society. All rights reserved.9
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Clopidogrel and new P2Y12 antagonists
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Clopidogrel clearly has been a valuable antithrombotic drug.
Dual therapy with aspirin and clopidogrel has reduced cardiovascular
events in patients in the settings of PCI, acute coronary syndromes
(ACS), peripheral arterial disease, cerebrovascular disease,
and coronary artery disease. However, clopidogrel has a number
of recognized limitations. It is a prodrug requiring metabolic
activation, has a slow onset of effect, and has a slow offset
of effect due to its irreversible binding to the P2Y
12 receptor.
Clopidogrel has also been associated with a wide variability
in inhibition of platelet aggregation (IPA) response.
In an initial study of the consequences of poor response to clopidogrel,10 60 consecutive patients undergoing stenting for ST-segment elevation MI received clopidogrel 300 mg followed by 75 mg/day for 3 months and were stratified by quartile according to reduction in respective baseline platelet aggregation at 5 µM ADP at Day 6. The first quartile (Q1) exhibited clopidogrel resistance, with aggregation of 103% of baseline values, whereas aggregation was 69, 58, and 32% of baseline values in Q2, Q3, and Q4, respectively (Figure 5). During a 6-month follow up, recurrent cardiovascular events (consisting of recurrent ST-segment elevation MI, recurrent ACS, acute peripheral arterial occlusion requiring urgent surgery, and ischaemic stroke) occurred in six (40%) of 15 patients in Q1, compared with one (7%) in Q2, and none in Q3 or Q4 (P = 0.007). In a recently reported prospective observational cohort study,11 804 patients with successful DES implantation received aspirin and a clopidogrel 600 mg loading dose followed by 75 mg/day for 6 months; patients were assessed for platelet aggregation at 10 µM ADP after the loading dose, with 105 (13%) being categorized as non-responders based on aggregation 
70% OBS. In figure 6 there is an unfotunate mistake as the correct patient numbers should show Responders (n=699) and Nonresponders (n=105). Please correct. At 6 months, the incidence of stent thrombosis was 8.6% in non-responders vs. 2.3% in responders (P < 0.001) (Figure 6). On multivariate analysis, non-response was an independent predictor of stent thrombosis, with a HR of 3.08 (P = 0.009). Other studies identifying clinical consequences of non-response to clopidogrel in terms of stent thrombosis and ischaemic events are summarized in Table 1.10–22
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Figure 5 Platelet aggregation (Plt Agg) at 5 µM after 300 mg clopidogrel (CLOP) loading dose followed by 75 mg/day among 60 patients with ST-segment elevation MI (STEMI) undergoing PCI; patients were stratified by quartile (Q, n = 15 each) according to percent of baseline aggregation observed at Day 6. As shown at right, risk of recurrent events at 6 months (m) was greater in patients in the quartile (Q1) in which clopidogrel had least effect. Matetzky S, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–3175. Reproduced with permission from Lippincott, Williams and Wilkins.10
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Figure 6 Percentage of responders and non-responders to clopidogrel remaining free of DES thrombosis over 6 months in a single-institution cohort study. Table shows predictors of thrombosis on univariate and multivariate analyses. Asterisk indicates variables with a P-value < 0.10 that were entered in the multivariate model. LVEF, left ventricular ejection fraction. Reprinted from J Am Coll Cardiol, 49, Buonamici J, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis, 2312–2317, 2007, with permission from Elsevier.11
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P2Y
12 antagonists with a more rapid onset of action and greater
and more consistent IPA may provide better protection against
both early and late stent thrombosis than clopidogrel. Two new
oral P2Y
12 antagonists with these characteristics currently
are being evaluated in Phase 3 clinical trials in the settings
of ACS and PCI—the irreversible thienopyridine antagonist
prasugrel
23 and the reversible direct antagonist AZD6140.
24 Prasugrel is a third-generation thienopyridine that is more
efficiently metabolized to its active form than clopidogrel.
AZD6140 does not require metabolic activation. In addition to
exhibiting improved IPA, the agent provides more rapid offset
of effect compared with irreversible antagonists. As shown in
Figure 7, only small proportions of patients exhibit IPA <25%
at
Ctrough, using AZD6140 maintenance doses of 100 mg twice
daily or greater, or prasugrel maintenance doses of 10 mg/day
or greater, compared with patients receiving clopidogrel 75
mg/day.
25,26 In the recent large scale TRITON trial comparing
prasugrel and clopidogrel on top of aspirin in patients with
ACS accepted for PCI procedures after a coronary angiogram,
there was a 19% relative (2.2% absolute) reduction in MI. Prasugrel
treatment was associated with a halving in stent thrombosis
(52% relative and 1.3% absolute reduction). Simultaneously,
however, there was a significant further increase in bleeding
(34% relative and 1% absolute increase in major bleeding or
requirement for transfusion).
27
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Figure 7 Distribution of IPA at 20 µM ADP pre-dose on Day 28 among 200 patients with stable atherosclerotic disease receiving AZD6140 or clopidogrel and aspirin (left) and among 101 patients with stable coronary artery disease receiving prasugrel (PRAS) or clopidogrel (CLOP) and aspirin (right). Left panel is adapted with permission from Husted et al.25; right panel is adapted with permission from Jernberg et al.26
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Summary
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Dual antiplatelet therapy with aspirin and clopidogrel substantially
reduces stent thrombosis-related events. Early events are rare
but severe and occur more often when there is poor response
to clopidogrel. Late stent thrombosis occurs more frequently
with DES than BMS and when there is poor response to clopidogrel
or after cessation of clopidogrel treatment. Dual antiplatelet
therapy with aspirin and clopidogrel for >6 months may prevent
some proportion of cases of late thrombosis, but its effectiveness
would still be limited by the frequency of poor response to
clopidogrel. Prospective, randomized long-term trials of the
benefits and risks of more effective P2Y
12 antagonists as part
of dual antiplatelet therapy after BMS and DES implantation
are warranted.
Conflict of interest: Lars Wallentin has received research grants from AstraZeneca, Eli Lilly, Sanofi-Aventis, Bristol Meyers Squibb, and Boehringer-Ingelheim.
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Funding
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This symposium and proceedings were sponsored by a grant from
AstraZeneca.
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Abstract
Introduction